Clinical trial NCT03087760
Conditions: Non-small Cell Lung Cancer
Sponsor: Abramson Cancer Center at Penn Medicine
Start date: 2017-11-29; Completion date: 2023-09-12
Enrollment: 32 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The main purpose of this study is to assess the safety, tolerability and anti-tumor activity of the experimental study drug pembrolizumab (also known as Keytruda or MK-3475) in people with non-small cell lung cancer (NSCLC) that has come back after radiation therapy.

Detailed description:

Arms: arm 1: Single Arm, Open Label
Interventions: intervention 1: Pembrolizumab
Intervention descriptions: intervention 1: Concurrent Pembrolizumab after proton reirradiation

Protocol documents:
Prot_SAP_000.pdf: 
 
CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study 
sponsor 
CLINICAL RESEARCH PROTOCOL 
 
 
 
 
 
PHASE II TRIAL OF CONSOLIDATION PEMBROLIZUMAB AFTER 
CONCURRENT CHEMOTHERAPY AND PROTON REIRRADIATION 
FOR THORACIC RECURRENCES OF  
NON-SMALL CELL LUNG CANCER  
 
Regulatory Sponsor: 
Steven Feigenberg, MD  
University of Pennsylvania 
Perelman Center for Advanced Medicine 
3400 Civic Center Blvd 
TRC 2 West 
Philadelphia, Pennsylvania 19104 
Phone: 215-615-3659 
Email: Steven.Feigenberg@pennmedicine.upenn.edu  
 
Sub-Investigators: 
 
 
 
 
 
 
 
Funding Sponsor: 
 
 
 
 
Statistician:  
Christine Ciunci, MD MSCE 
Corey Langer, MD 
Roger Cohen, MD 
Charu Aggarwal, MD 
Josh Bauml, MD 
William Levin, MD  
Manuj Agarwal, MD 
 
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
One Merck Drive 
P.O. Box 100 
Whitehouse Station, NJ 08889-0100  
 
Rosemarie Mick, MS  
Department of Biostatistics & Epidemiology 
University of Pennsylvania Perelman School of Medicine 
609 Blockley Hall, 423 Guardian Drive 
Philadelphia, PA 19104-6021 
Office: 215-898-9057 
Fax: 215-573-4865 
Email: rmick@mail.med.upenn.edu 
 
Study Product: 
Pembrolizumab (MK 3475)  
Protocol Number: 
UPCC 16516//IRB # 825877 
IND Number: 
 
IND-exempt 
 
Medical Monitor: 
Dan Vogl, MD 
 
 


Phase II Pembrolizumab Reirradiation 
 
 
 
CONFIDENTIAL 
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sponsor 
ii
Initial version: 8/31/15 
Amended: 
2/5/2019 
Amended:  
6/29/2021 
Amended:  
10/28/2021 
Amended: 
4/6/2022 
 
Table of Contents 
 
STUDY SUMMARY ...................................................................................................................................... 1 
1 
INTRODUCTION .................................................................................................................................. 2 
1.1 
BACKGROUND ................................................................................................................................ 2 
1.2 
INVESTIGATIONAL AGENT ................................................................................................................ 3 
1.3 
PRECLINICAL DATA ........................................................................................................................ 3 
1.4 
CLINICAL DATA TO DATE................................................................................................................. 4 
1.5 
DOSE RATIONALE AND RISK/BENEFITS ............................................................................................ 5 
2 
STUDY OBJECTIVES ......................................................................................................................... 5 
3 
STUDY DESIGN ................................................................................................................................... 5 
3.1 
GENERAL DESIGN .......................................................................................................................... 5 
3.2 
PRIMARY STUDY ENDPOINTS .......................................................................................................... 6 
3.3 
SECONDARY STUDY ENDPOINTS ..................................................................................................... 7 
3.4 
PRIMARY SAFETY ENDPOINTS ......................................................................................................... 7 
4 
SUBJECT SELECTION AND WITHDRAWAL .................................................................................... 7 
4.1 
INCLUSION CRITERIA ...................................................................................................................... 7 
4.2 
EXCLUSION CRITERIA ..................................................................................................................... 8 
4.3 
SUBJECT RECRUITMENT AND SCREENING ....................................................................................... 8 
4.4 
EARLY WITHDRAWAL OF SUBJECTS................................................................................................. 8 
4.4.1 
When and How to Withdraw Subjects ..................................................................................... 8 
4.4.2 
Data Collection and Follow-up for Withdrawn Subjects .......................................................... 9 
5 
STUDY DRUG ...................................................................................................................................... 9 
5.1 
DESCRIPTION ................................................................................................................................. 9 
5.2 
TREATMENT REGIMEN .................................................................................................................... 9 
5.3 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ....................................................... 12 
5.4 
PREPARATION AND ADMINISTRATION OF STUDY DRUG ................................................................... 12 
5.5 
SUBJECT COMPLIANCE MONITORING ............................................................................................. 13 
5.6 
PRIOR AND CONCOMITANT THERAPY ............................................................................................. 13 
5.6.1 
Acceptable Concomitant Medications ................................................................................... 13 
5.6.2 
Prohibited Concomitant Medications ..................................................................................... 14 
5.7 
RESCUE MEDICATIONS AND SUPPORTIVE CARE ............................................................................. 14 
5.7.1 
Supportive Care Guidelines .................................................................................................. 14 
 
5.7.1.1 Supportive Care Guidelines for Events of Clinical Interest and Immune- .....................  
             related Adverse Events (irAEs) ............................................................................................. 19 
 
5.7.1.2 Supportive Care Guidelines for Pneumonitis ............................................................ 20 
5.8 
CONTRACEPTION AND PREGNANCY ............................................................................................... 20 
5.8.1 
Contraception ........................................................................................................................ 20 
5.8.2 
Use in Pregnancy .................................................................................................................. 21 
5.8.3 
Use in Nursing Women ......................................................................................................... 21 
5.9 
SUBJECT WITHDRAWAL/DISCONTINUATION CRITERIA ..................................................................... 21 
5.10 
SUBJECT REPLACEMENT STRATEGY ............................................................................................. 22 
5.11 
CLINICAL CRITERIA FOR EARLY TRIAL TERMINATION ...................................................................... 22 
6 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES ......................... 23 


Phase II Pembrolizumab Reirradiation 
 
 
 
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iii
6.1 
LABELING .................................................................................................................................... 23 
6.2 
STORAGE AND HANDLING REQUIREMENTS .................................................................................... 23 
6.3 
RETURNS AND RECONCILIATION .................................................................................................... 23 
7 
TRIAL FLOW CHART ........................................................................................................................ 24 
7.1 
TRIAL FLOW CHART ...................................................................................................................... 24 
8 
TRIAL PROCEDURES ...................................................................................................................... 25 
8.1 
TRIAL PROCEDURES ..................................................................................................................... 25 
8.1.1 
Administrative Procedures .................................................................................................... 25 
 
8.1.1.1 Informed Consent ...................................................................................................... 25 
 
   8.1.1.1.1 General Informed Consent .................................................................................. 25 
             8.1.1.2 Inclusion/Exclusion Criteria ....................................................................................... 26 
             8.1.1.3 Medical History .......................................................................................................... 26 
 
8.1.1.4 Prior and Concomitant Medications Review ............................................................. 26 
                8.1.1.4.1 Prior Medications................................................................................................. 26 
 
   8.1.1.4.2 Concomitant Medications .................................................................................... 27 
 
8.1.1.5 Disease Details and Treatments ............................................................................... 27 
                8.1.1.5.1 Disease Details ................................................................................................... 27 
 
   8.1.1.5.2 Prior Treatment Details ....................................................................................... 27 
                8.1.1.5.3 Subsequent Anti-Cancer Therapy Status ........................................................... 27 
 
8.1.1.6 Trial Compliance (Medication/Diet/Activity/Other) .................................................... 27 
8.1.2 
Clinical Procedures/Assessments ......................................................................................... 27 
 
8.1.2.1 Adverse Event (AE) Monitoring ................................................................................. 27   
 
8.1.2.2 Full Physical Exam .................................................................................................... 27  
 
8.1.2.3 Directed Physical Exam ............................................................................................ 28  
 
8.1.2.4 Vital Signs ................................................................................................................. 28 
 
8.1.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale ........................ 28   
 
8.1.2.6 Tumor Imaging and Assessment of Disease ............................................................ 28   
8.1.3 
Laboratory Procedures/Assessments ................................................................................... 29 
 
8.1.3.1 Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) ................. 29 
 
   8.1.3.1.1 Blood Collection for Additional Correlative Samples ........................................... 30 
8.1.4 
Other Procedures .................................................................................................................. 31 
 
8.1.4.1 Withdrawal/Discontinuation ....................................................................................... 31  
 
8.1.4.2 Blinding/Unblinding ................................................................................................... 31  
8.1.5 
Visit Requirements ................................................................................................................ 31 
 
8.1.5.1 Screening .................................................................................................................. 31   
 
8.1.5.2 Proton Reirradiation +/- Chemotherapy .................................................................... 31 
 
8.1.5.3 Pre-Pembrolizumab Screening ................................................................................. 32 
 
8.1.5.4 Pembrolizumab Treatment Cycles ............................................................................ 32 
 
8.1.5.5 Post-Treatment Visits ................................................................................................ 32  
 
8.1.5.6 Safety Follow-Up Visit ............................................................................................... 32  
 
8.1.5.7 Follow-Up Visit .......................................................................................................... 32 
 
8.1.5.8 Survival Follow-Up .................................................................................................... 32 
8.2 
ASSESSING AND RECORDING ADVERSE EVENTS ............................................................................ 32 
8.2.1 
Definition of an Overdose for This Protocol and Reporting of Overdose to the       
 Sponsor ............................................................................................................................................. 35 
8.2.2 
Reporting of Pregnancy and Lactation to the Sponsor ......................................................... 36 
8.2.3 
Immediate Reporting of Adverse Events to the Sponsor ...................................................... 36 
 
8.2.3.1 Serious Adverse Events ............................................................................................ 36  
 
8.2.3.2 Events of Clincial Interest .......................................................................................... 36 
8.2.4 
Evaluating Adverse Events ................................................................................................... 38 


Phase II Pembrolizumab Reirradiation 
 
 
 
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iv 
8.2.5 
Sponsor Responsibility for Reporting Adverse Events.......................................................... 41 
9 
STATISTICAL PLAN ......................................................................................................................... 41 
9.1 
STATISTICAL ANALYSIS PLAN SUMMARY ........................................................................................ 41 
9.2 
SAMPLE SIZE DETERMINATION ...................................................................................................... 41 
9.3 
HYPOTHESIS EVALUATION ............................................................................................................ 41 
9.3.1 
Analysis Endpoints ................................................................................................................ 42 
9.3.2 
Efficacy Analysis Populations ................................................................................................ 42 
 
9.3.3 
Safety Analysis Populations .................................................................................................. 42 
9.4 
STATISTICAL METHODS ................................................................................................................ 43 
9.5 
UNBLINDING PROCEDURES ........................................................................................................... 43 
10 
ADMINISTRATIVE AND REGULATORY DETAILS ......................................................................... 43 
10.1 
CONFIDENTIALITY ......................................................................................................................... 43 
10.1.1 Confidentiality of Data ........................................................................................................... 43 
10.1.2 Confidentiality of Subject Records ........................................................................................ 44 
10.1.3 Confidentiality of Investigator Information ............................................................................. 44 
10.2 
COMPLIANCE WITH FINANCIAL DISCLOSURE REQUIREMENTS .......................................................... 44 
10.3 
COMPLIANCE WITH LAW, AUDIT AND DEBARMENT .......................................................................... 45 
10.4 
COMPLIANCE WITH TRIAL REGISTRATION AND RESULTS POSTING REQUIREMENTS .......................... 46 
10.5 
QUALITY MANAGEMENT SYSTEM ................................................................................................... 46 
10.6 
DATA MANAGEMENT ..................................................................................................................... 46 
11 
PUBLICATION PLAN ........................................................................................................................ 46 
12 
APPENDICES .................................................................................................................................... 47 
12.1 
ECOG PERFORMANCE STATUS .................................................................................................... 47 
12.2 
COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS V5.0 (CTCAE) ..................................... 47 
12.3 
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (RECIST 1.1) CRITERIA FOR EVALUATING 
RESPONSE IN SOLID TUMORS   .................................................................................................................. 48 
13 
REFERENCES ................................................................................................................................... 48 
 
 
 


Phase II Pembrolizumab Reirradiation 
 
 
 
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sponsor 
v
List of Abbreviations 
 
 
CTCAE- Common Terminology Criteria for Adverse Events 
CTEP - Cancer Therapy Evaluation Program 
CTV – clinical target volume 
ECOG - Eastern Cooperative Oncology Group  
NCI – National Cancer Institute 
NSCLC- non-small cell lung cancer 
OS- overall survival  
PD-1- programmed cell death 1 
PFS- progression-free survival 
ULN – upper limit of normal 
 
 
 
 
 
 


Phase II Pembrolizumab Reirradiation 
 
 
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Study Summary 
Title 
Phase 
II trial 
of consolidation Pembrolizumab after 
concurrent 
chemotherapy and proton reirradiation for thoracic recurrences of non-
small cell lung cancer 
Short Title 
Phase II of Pembrolizumab after chemotherapy and proton reirradiation for 
recurrent NSCLC 
Protocol Number 
UPCC 16516//IRB 825877 
Phase 
Phase II 
Methodology 
Single arm, open label 
Study Duration 
2 - 2.5 years 
Study Center(s) 
Single-center (The Hospital of the University of Pennsylvania and Penn 
Presbyterian Medical Center) 
Objectives 
The primary objective is progression-free survival. Secondary objectives 
include overall survival and toxicity determination. 
Number of Subjects 
41 
Diagnosis and Main 
Inclusion Criteria 
Patients with a histologic or cytologic diagnosis of NSCLC who have 
received previous intrathoracic radiation therapy with definitive intent and 
have a tumor recurrence in or near the prior irradiation fields, age 18 or 
older, with an ECOG performance status of 0 to 1. 
Study Product, Dose, 
Route, Regimen 
Pembrolizumab 200 mg intravenously approximately every 21 days for 17 
cycles (about 12 months). 
Duration 
of 
administration 
Pembrolizumab will be started 4 to 12 weeks after completion of proton 
reirradiation +/- concurrent chemotherapy. Pembrolizumab will be given at 
a dose of 200 mg intravenously every 21 days for 17 cycles (about 12 
months) if there is no evidence of progressive disease or intolerable side 
effects.   
Reference therapy 
The study product is being compared to historical controls 
Statistical 
Methodology 
A single arm phase II study will enroll 41 patients over 2 years. Patients will 
be followed for an additional 3 months after enrollment has ended. At the 
final analysis there will be 80% power to detect an improvement in median 
progression-free survival from 6 months (historical rate) to 10 months, 
assuming exponential survival and 1-sided 5% significance level.  Median 
progression-free survival and overall survival will be estimated by the 
Kaplan-Meier method. 
 


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1 Introduction 
 
This document is a protocol for a human research study. This study is to be conducted according to 
US and international standards of Good Clinical Practice (FDA Title 21 part 312 and International 
Conference on Harmonization guidelines), applicable government regulations and Institutional 
research policies and procedures.  
1.1 Background 
Isolated local or regional recurrences of non-small cell lung cancer (NSCLC) in or near previously 
irradiated thoracic fields present a therapeutic challenge.  Rather than using systemic therapy alone, 
instituting localized therapy is appealing given our generally poor response rates to salvage 
chemotherapy, particularly in tumors that arise in previously irradiated fields. However, surgery and 
radiation therapy are both technically difficult and pose high toxicity risks in this setting. Conventionally 
fractionated thoracic reirradiation for recurrent lung cancer has yielded 1-year local progression-free 
survival (PFS) rates as high as 51% [1-6], but its widespread use has been limited by toxicities. Given 
these positive results, proton reirradiation has been utilized as a potential strategy to minimize harm to 
surrounding tissues while treating a local recurrence aggressively. A multicenter study presented at the 
2013 ASCO Annual Meeting reported encouraging early outcomes, with a median PFS of 14 months, 
and acceptable toxicity for proton reirradiation in an initial cohort of patients treated with low-volume 
clinical target volumes [7]. Since proton reirradiation is a promising new tactic to treat thoracic 
recurrences of NSCLC that can potentially minimize toxicities compared with photon reirradiation, 
additional strategies to improve outcomes with this modality are warranted.  
 
Pembrolizumab is an anti-PD-1 immunotherapy that has demonstrated activity in several different types 
of cancers, including lung cancer. Because of its potentially enhanced efficacy when used in minimal 
disease states, Pembrolizumab may be well suited as “consolidation” therapy for localized recurrences 
treated with chemoradiation [8]. The combination of radiation therapy and immunotherapy may improve 
treatment responses through several different mechanisms [8]. Preclinical studies in mice show that 
anti-PD1 therapy enhances the efficacy of radiation therapy via a T cell dependent cytotoxic mechanism 
[9]. Immune cell recognition of tumor cells may be increased after radiation therapy [10] due to the 
release of additional tumor specific antigens leading to a heightened T-cell immune response driven by 
antigen-presenting cells [8]. Radiation therapy can also decrease immune tolerance due to a large 
tumor burden [8, 11], potentially increasing the success of immune therapies. Recent parallel preclinical 
and clinical studies suggest that PD-L1 upregulation by cancer cells may emerge as a resistance 
mechanism after treatment with anti-CTLA4 therapy plus radiation. Adding anti- PD-L1/PD-1 therapy 
may be of benefit in this situation [12]. 
 
The cytotoxic effects of chemotherapy may potentially enhance the effects of immunotherapy in a 
similar fashion to radiation therapy. There is evidence supporting a potential advantage to sequential 
chemotherapy followed by immune therapy. In the clinical setting, NSCLC patients receiving 
Ipilimumab, an anti-CTLA4 monoclonal antibody, experienced improved immune related PFS when it 
was phased into treatment after 2 cycles of chemotherapy, compared to chemotherapy alone, 
potentially from the mechanisms proposed [13].   Conversely, those individuals who started Ipilimumab 
concurrently with chemotherapy during cycle #1 did not have a statistically significant PFS or overall 
survival (OS) advantage. 
 
Based on previous data strongly suggesting that Pembrolizumab may have its optimal benefit in states 
of minimal disease, and pre-clinical and clinical evidence that immunotherapies that target the CTLA4 
and PD-1 pathways can be used effectively with radiation therapy and chemotherapy and potentially 
work synergistically with these treatment modalities, we propose a phase II trial of consolidation 


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Pembrolizumab after concurrent chemotherapy and proton reirradiation for thoracic recurrences of 
NSCLC. PFS will be our main endpoint. 
1.2 Investigational Agent 
The programmed cell death 1 (PD-1) pathway represents a major immune control switch, which may 
be engaged by tumor cells to overcome active T-cell immune surveillance. Pembrolizumab is a potent 
humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) with high specificity of binding to the 
programmed cell death 1 (PD-1) receptor, thus inhibiting its interaction with programmed cell death 
ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-L2). Based on preclinical in vitro data, 
pembrolizumab has high affinity and potent receptor blocking activity for PD-1. This blockade enhances 
functional activity of the target lymphocytes to facilitate tumor regression and ultimately immune 
rejection.  
1.3 Preclinical Data 
The importance of intact functions of immune surveillance in controlling outgrowth of neoplastic 
transformations has been known for decades [14]. Accumulating evidence shows a correlation between 
tumor-infiltrating lymphocytes in cancer tissue and favorable prognosis in various malignancies. In 
particular, the presence of CD8+ T-cells and the ratio of CD8+effector T-cells/FoxP3+ regulatory T-
cells (T-regs) correlates with improved prognosis and long-term survival in solid malignancies, such as 
ovarian, colorectal, and pancreatic cancer; hepatocellular carcinoma; malignant melanoma; and renal 
cell carcinoma. Tumor-infiltrating lymphocytes can be expanded ex vivo and re-infused, inducing 
durable objective tumor responses in cancers such as melanoma [15, 16]. 
 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control. The normal function of PD-1, expressed on the cell surface of activated T- cells under healthy 
conditions, is to down-modulate unwanted or excessive immune responses, including autoimmune 
reactions. PD-1 (encoded by the gene Pdcd1) is an immunoglobulin (Ig) superfamily member related 
to cluster of differentiation 28 (CD28) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) that 
has been shown to negatively regulate antigen receptor signaling upon engagement of its ligands (PD-
L1 and/or PD-L2) [17, 18]. The structure of murine PD-1 has been resolved [19]. PD-1 and family 
members are type I transmembrane glycoproteins containing an Ig Variable–type (IgV-type) domain 
responsible for ligand binding and a cytoplasmic tail responsible for the binding of signaling molecules. 
The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-
based inhibition motif, and an immunoreceptor tyrosine-based switch motif. Following T-cell stimulation, 
PD-1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, to the immunoreceptor tyrosine-based 
switch motif within its cytoplasmic tail, leading to the dephosphorylation of effector molecules such as 
CD3ζ, PKCθ, and ZAP70, which are involved in the CD3 T-cell signaling cascade [18, 20-22]. The 
mechanism by which PD-1 down-modulates T-cell responses is similar to, but distinct from, that of 
CTLA-4, because both molecules regulate an overlapping set of signaling proteins [23, 24]. PD-1 was 
shown to be expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B cells, 
T regs, and natural killer cells [25, 26]. Expression has also been shown during thymic development on 
CD4-CD8- (double negative) T-cells, as well as subsets of macrophages and dendritic cells [27]. The 
ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a variety of cell 
types including nonhematopoietic tissues and in various tumors [14, 24, 28-30]. Both ligands are type 
1 transmembrane receptors containing IgV-like and Ig constant–like (IgC-like) domains in the 
extracellular region and contain short cytoplasmic regions with no known signaling motifs. Binding of 
either PD-L1 or PD-L2 to PD-1 inhibits T-cell activation triggered through the T-cell receptor. PD-L1 is 
expressed at low levels on various nonhematopoietic tissues, most notably on vascular endothelium; 
whereas PD-L2 is only detectably expressed on antigen-presenting cells found in lymphoid tissue or 
chronic inflammatory environments. PD-L2 is thought to control immune T-cell activation in lymphoid 
organs, whereas PD-L1 serves to dampen unwarranted T-cell function in peripheral tissues [24]. 
Although healthy organs express little (if any) PD-L1, a variety of cancers were demonstrated to express 
abundant levels of this T-cell inhibitor. High expression of PD-L1 on tumor cells (and to a lesser extent 
of PD-L2) has been found to correlate with poor prognosis and survival in various cancer types, 
including renal cell carcinoma [31], pancreatic carcinoma [32], hepatocellular carcinoma [33], and 


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ovarian carcinoma [34]. Furthermore, PD-1 has been suggested to regulate tumor-specific T-cell 
expansion in subjects with melanoma [35]. 
 
The observed correlation of clinical prognosis with PD-L1 expression in multiple cancers suggests that 
the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and should be considered as an 
attractive target for therapeutic intervention. 
 
Therapeutic studies in mouse models show that administration of antibodies blocking PD-1/PD-L1 
interaction enhances infiltration of tumor-specific CD8+ T-cells and leads ultimately to tumor rejection, 
either as a monotherapy or in combination with other treatment modalities. Anti–mouse PD-1 and anti–
mouse PD-L1 have demonstrated antitumor responses as a monotherapy in models of squamous cell 
carcinoma, pancreatic carcinoma, melanoma, and colorectal carcinoma. Blockade of the PD-1 pathway 
effectively promoted CD8+ T-cell infiltration into the tumor and the presence of IFN-γ, granzyme B, and 
perforin, indicating that the mechanism of action involved local infiltration and activation of effector T-
cell function in vivo [32, 36-40]. In addition, the combination of gemcitabine and anti–PD-L1 mAb 
demonstrated synergy in the rejection of pancreatic mouse tumors [32]. In-house experiments have 
confirmed the in vivo efficacy of PD-1 blockade as a monotherapy as well as in combination with 
chemotherapy in syngeneic mouse tumor models. 
 
Pembrolizumab strongly enhances T-lymphocyte immune responses in cultured blood cells from 
healthy human donors, cancer subjects, and nonhuman primates. In T-cell activation assays using 
human donor blood cells, the half-maximal effective concentration (EC50) has been approximately 0.1 
to 0.3 nM. In addition to interleukin-2 (IL-2), tumor necrosis factor alpha (TNFα), interferon gamma 
(IFN), and levels of other cytokines were found to be modulated by pembrolizumab. The antibody 
potentiates existing immune responses only in the presence of antigen and does not nonspecifically 
activate T-cells. In the in vitro peripheral blood mononuclear cell (PBMC) and whole blood cytokine 
release assays, the cytokine levels induced by pembrolizumab were low and comparable to those 
induced by trastuzumab. Pembrolizumab does not induce antibody-dependent cell-mediated 
cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC). 
 
Using anti–murine PD-1 surrogate antibodies, PD-1 blockade has been shown to significantly inhibit 
tumor growth in a variety of syngeneic murine tumor models. In these experiments in mice, anti–PD-1 
therapy is synergistic with chemotherapeutic agents such as gemcitabine and 5-fluorouracil (5-FU), 
and combination therapy results in increased complete tumor regression rates in vivo. Studies also 
revealed that immunosuppressive doses of dexamethasone included in combination with agents used 
in standard-of-care treatment for NSCLC do not reduce the anti-tumor efficacy of an anti–murine PD-1 
surrogate antibody. 
1.4 Clinical Data to Date 
Immuno-modulatory agents recently showed promising efficacy in multiple cancer types. Two Phase III 
studies of IPI, an anti-CTL4 mAb, showed significant prolongation of OS in subjects with melanoma 
[41, 42]. Recent data with anti–PD-1 antibodies have validated PD-1 as an attractive target for clinical 
intervention [43-45]. Importantly, responses have been of long duration and pembrolizumab is generally 
well tolerated. Based on these data and considerations, the anti–PD-1 antibody, pembrolizumab, 
appears to be an attractive candidate for continued clinical development in cancer. 
 
As of the data cutoff dates for Merck’s most recent Investigator’s Brochure, the safety and efficacy of 
pembrolizumab treatment in subjects with hematologic malignancies and solid tumors have been 
evaluated in 18 ongoing, Merck-sponsored clinical trials (please refer to the Investigator’s Brochure for 
details).  
1.5 Dose Rationale and Risk/Benefits 
An open-label Phase I trial (Protocol 001) evaluating Pembrolizumab at 1 mg/kg, 3 mg/kg, and 10 
mg/kg, administered every 2 weeks revealed no dose-limiting toxicities and showed objective evidence 
of tumor size reduction at all dose levels. Recent data from other clinical studies in the Pembrolizumab 


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Version 4.6.22 
 
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program have shown that a lower dose of Pembrolizumab and a less frequent schedule may be 
sufficient for target engagement and clinical activity. 
 
A population pharmacokinetic analysis has been performed using serum concentration time data from 
476 patients. Within the resulting population PK model, clearance and volume parameters of 
Pembrolizumab were found to be dependent on body weight. The relationship between clearance and 
body weight, with an allometric exponent of 0.59, is within the range observed for other antibodies and 
would support both body weight normalized dosing or a fixed dose across all body weights. 
Pembrolizumab has been found to have a wide therapeutic range based on the melanoma indication. 
The differences in exposure for a 200 mg fixed dose regimen relative to a 2 mg/kg every 3 weeks body 
weight based regimen are anticipated to remain well within the established exposure margins of 0.5 – 
5.0 for Pembrolizumab in the melanoma indication. The exposure margins are based on the notion of 
similar efficacy and safety in melanoma at 10 mg/kg every 3 weeks vs. the dose regimen of 2 mg/kg 
every 3 weeks (i.e. 5-fold higher dose and exposure). The population PK evaluation revealed that there 
was no significant impact of tumor burden on exposure. In addition, exposure was similar between the 
NSCLC and melanoma indications. Therefore, there are no anticipated changes in exposure between 
different indication settings, and this trial will use the 200 mg every 3 weeks fixed dose regimen. 
2 Study Objectives 
Primary Objective 
1.) To assess PFS in subjects treated with consolidation Pembrolizumab after concurrent 
chemotherapy and proton reirradiation for thoracic recurrences of NSCLC. 
 
Secondary Objective 
1.) To assess OS in subjects treated with consolidation Pembrolizumab after concurrent chemotherapy 
and proton reirradiation for thoracic recurrences of NSCLC. 
 
2.) To determine toxicities (Common Terminology Criteria for Adverse Events (CTCAE) v5.0 scoring) 
of consolidation Pembrolizumab after concurrent chemotherapy and proton reirradiation 
 
4.) To evaluate PFS and OS as a function of PD-L1 expression, as well as other emerging indices of 
benefit. 
3 Study Design 
3.1 General Design 
This is a phase II, single arm, unblinded trial of about 12 months of consolidation Pembrolizumab 
after proton reirradiation with or without concurrent chemotherapy for isolated local and regional 
thoracic recurrences of NSCLC.  Forty-one patients will be treated with re-irradiation with or without 
standard concurrent chemotherapy to all gross disease with proton beam therapy. The intended 
radiation dose should be at least 60 Gy of reirradiation in 1.8-2.0 Gy fractions with or without 
concurrent chemotherapy or in 4.0 Gy fractions without chemotherapy, at the provider’s discretion. 
This corresponds to daily fractionated radiation over a period of approximately 3-8 weeks. Four to 12 
weeks after completing reirradiation, patients will begin Pembrolizumab consolidation. 
Pembrolizumab will be given at a fixed dose of 200 mg intravenously approximately every 21 days for 
17 cycles (about 12 months) if there is no evidence of progressive disease or intolerable side effects. 
 
Subjects will be evaluated approximately 30 days prior to consolidation Pembrolizumab and every 12 
weeks (1 day after until the day of the next infusion) while on Pembrolizumab with radiographic 
imaging to assess disease status. If new signs or symptoms of progression occur between scheduled 
scans, directed imaging will be obtained at the clinically appropriate time point to document disease 
status. Investigators will make all treatment-based decisions using RECIST 1.1. Adverse events will 
be monitored upon initiation of Pembrolizumab treatment and continue throughout the trial and 
graded in severity according to the National Cancer Institute (NCI) CTCAE version 5.0. For the 


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Pembrolizumab phase, all treatment-related toxicities will be recorded.  
Treatment with Pembrolizumab will continue for 17 cycles (about 12 months) in the absence of (1), 
documented disease progression, (2) unacceptable adverse event(s), (3) intercurrent illness that 
prevents further administration of treatment, (4) investigator’s decision to withdraw the subject, (5) 
subject withdrawal of consent, (6) pregnancy of the subject, (7) noncompliance with trial treatment or 
procedure requirements, (8) institution of alternative systemic treatment, or (9) other administrative 
reasons. After the end of treatment, each subject will be followed for a minimum of 30 days for adverse 
event monitoring (serious adverse events will be collected for up to 90 days after the end of treatment). 
Subjects will have post-treatment follow-up for disease status until one of the following events: (1) 
disease progression; (2) initiation of non-study cancer treatment; (3) withdrawal of study consent; (4) 
loss to follow-up or (5) death. In addition, survival status beyond the establishment of PD or initiation of 
subsequent therapies will be documented.  
 
The primary objective of the trial includes determination of PFS per RECIST 1.1. Secondary objectives 
include OS and safety/toxicity determination as assessed by a variety of parameters of adverse events 
(AEs), including incidence and time to first Grade 3-5 AE. Pre-specified adverse events of clinical 
interest during the Pembrolizumab phase include the following events: 1) Grade ≥ 3 diarrhea 2) Grade 
≥ 2 colitis, 3) Grade ≥ 2 pneumonitis, 4) Grade ≥ 3 hypo- or hyperthyroidism, 5) Grade ≥ 2 hypophysitis, 
6) Grade ≥ 2 uveitis, and 7) Grade ≥ 2 nephritis. Participation in this trial will encourage supplying tumor 
tissue from either a newly obtained formalin-fixed specimen (preferred) or an older formalin-fixed, 
paraffin-embedded specimen, from locations not radiated prior to biopsy. The specimen will be 
evaluated at a central laboratory facility for expression status of PD-L1 in a retrospective manner. 
Eligibility for the trial will not be dependent upon PD-L1 expression status, but the sponsor may amend 
the trial in the future if new data arise regarding the predictive value of PD-L1 expression. Any patient 
enrolled on the study prior to such an amendment, however, will remain on study. 
3.2 Primary Study Endpoints 
The primary endpoint is PFS, which measures the length of time from the first day of proton reirradiation 
+/- concurrent chemoradiation until progressive disease, death from any cause, or last patient contact. 
 
3.3 Secondary Study Endpoints 
Secondary endpoints include the following: 
 
1. OS: measures the length of time from the first day of proton reirradiation +/- concurrent 
chemoradiation to death from any cause or last patient contact. 
 
2. Toxicity: CTCAE v5.0 scoring 
 
Exploratory analysis of PDL-1 expression and other biomarkers in this setting will also be performed.  
3.4 Primary Safety Endpoints 
The safety and tolerability of consolidation Pembrolizumab after concurrent chemotherapy and proton 
reirradiation will be evaluated. Clinical assessment and laboratory evaluation of Adverse Events and 
Dose Limiting Toxicities will be done according to the CTCAE, version 5.0 of the NCI Cancer Therapy 
Evaluation Program (CTEP). 
4 Subject Selection and Withdrawal 
4.1 Inclusion Criteria 
1. Histologic or cytologic diagnosis of NSCLC who have received previous intrathoracic radiation 
therapy with definitive intent and have a tumor recurrence in or near the prior irradiation fields. 


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Re-biopsy of the recurrence is not required and is left to the discretion of the treating physician, 
although every effort should be made to confirm recurrence pathologically.   
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 
3. Age 18 or greater 
4. Patients with prior invasive malignancies are allowed, provided they have been treated with 
definitive intent and have no evidence of active disease requiring treatment in the past 2 years. 
5. Patients must be capable of giving informed consent and be willing and able to comply with 
schedule. 
6. Serum total bilirubin ≤ 1.5 X upper limit of normal (ULN) OR Direct bilirubin ≤ ULN for subjects 
with total bilirubin levels > 1.5 ULN prior to Pembrolizumab treatment. 
7. Platelets >100,000 cells/mm3 and ANC > 1,250 cells/mm3 prior to Pembrolizumab treatment. 
8. Creatinine ≤ 1.5 X ULN OR measured or calculated creatinine clearance ≥50 mL/min for subject 
with creatinine levels > 1.5 X institutional ULN. (GFR can also be used in place of creatinine or 
CrCl) prior to Pembrolizumab treatment 
9. Clinical target volume (CTV) size must be <250 cc, no more than 74 Gy of prior radiation in 2 
Gy fractions previously administered. 
4.2 Exclusion Criteria 
 
1. Allergy to Pembrolizumab or related compounds 
2. History of symptomatic CTCAEv5 grade ≥3 pneumonitis following the initial course of definitive 
radiation therapy 
3. History of symptomatic idiopathic pulmonary fibrosis or interstitial lung disease  
4. Use of continuous oxygen 
5. Diagnosis of immunodeficiency or exposure to systemic steroid therapy or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of trial treatment. (Nasal or 
oral inhalers are permissible).  
6. Active autoimmune disease requiring systemic treatment within the past 3 months or a 
documented history of clinically severe autoimmune disease, or a syndrome that requires 
systemic steroids or immunosuppressive agents. Subjects with vitiligo or resolved childhood 
asthma/atopy are an exception to this rule. Subjects that require intermittent use of 
bronchodilators or local steroid injections are not excluded from the study. Subjects with 
hypothyroidism stable on hormone replacement or Sjorgen’s syndrome are not excluded from 
the study. 
7. History of allogenic tissue or solid organ transplant 
8. Prior immunotherapy less than 30 days from the planned start of reirradiation 
9. Patients with known extrathoracic metastases, including brain metastases, or known malignant 
pleural or pericardial effusion  
10. Prior radiation treatment less than 6 months from the planned start of reirradiation of any part 
of the intended treatment volume 
11. Pregnant or breast-feeding patients. Men and women of reproductive potential may not 
participate in this study unless they have agreed to use an effective contraceptive method while 
in this study. 
12. Known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
13. Known active Hepatitis B (e.g., HBsAg positive or HBV DNA detectable) or Hepatitis C (e.g., 
HCV RNA [qualitative] is detected). 
4.3 Subject Recruitment and Screening 
 
Subjects will be recruited for this study from the clinical practices of the Abramson Cancer Center at 
the University of Pennsylvania and Penn Presbyterian Medical Center.  Subjects will be required to 
give written informed consent to participate in the study before any screening tests or evaluations are 
conducted that are not part of standard care.  


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4.4 Early Withdrawal of Subjects 
4.4.1 When and How to Withdraw Subjects 
Subjects who do not complete the study protocol will be considered to have prematurely discontinued 
the study. The reasons for premature discontinuation (for example, voluntary withdrawal, toxicity, 
death) must be recorded on the case report form (CRF). Final study evaluations will be completed at 
the time of discontinuation. Reasons for withdrawal include, but are not limited to, the following: 
 
1. Inter-current illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree or require discontinuation of study drugs; 
2. Unacceptable toxicity: Patients will be followed until resolution or stabilization; 
3. Disease progression; 
4. Withdrawal of patient consent; 
5. Patient opting out of further treatment in the absence of progressive disease or significant 
comorbidity but still willing to have follow up regarding disease status; 
6. Treatment delay greater than four weeks beyond the schedule for any toxicity 
7. Non- compliance with study procedures that cannot be resolved; 
8. Major protocol violations, including, but not limited to: 
1. failure to meet inclusion/exclusion criteria; 
2. failure to complete evaluations as required by protocol; 
3. use of concomitant therapies other than specified above. 
The reason(s) for withdrawal should be noted in the case report form and in the patient’s medical record.  
Standard supportive therapy should be maintained for subjects withdrawn from active treatment.  Long-
term follow-up data, including survival and progression data, will be collected.   
 
4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
Patients taken off study due to toxicity will be followed until resolution or stabilization. All patients 
will be followed for PFS and OS data. 
5 Study Drug  
5.1 Description 
Pembrolizumab is a humanized anti–programmed cell death 1 (anti–PD-1) monoclonal antibody (mAb) 
of the immunoglobulin G4 (IgG4)/kappa isotype with a stabilizing S228P sequence alteration in the 
fragment crystallizable (Fc) region. Pembrolizumab binds to human PD-1 and blocks the interaction 
between PD-1 and its ligands. The theoretical molecular weight of the polypeptide is 146,288 daltons 
(Da) and its theoretical isoelectric point (pI) is 7.5. The parental murine anti–human PD-1 antibody 
(hPD-1.09Ǻ) was produced by immunizing mice with hPD-1 DNA. The pembrolizumab antibody was 
generated by humanization of the parental antibody by the Medical Research Council (Cambridge, UK) 
using complementarity determining region grafting technology (U.S. Patent No. 5,225,539). The gene 
segments encoding the variable heavy and light chains of pembrolizumab, as well as human IgG4, 
were codon-optimized, synthesized, and ligated into a vector. 
 
A single expression plasmid, pAPD11V1-GA, was constructed for the expression of both the heavy and 
light antibody chains of pembrolizumab. The nucleotide sequences encoding the heavy and light 
chains, along with their respective promoters and poly A signal sequences, have been confirmed by 


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DNA sequence analysis. The pAPD11V1-GA expression vector was subsequently used to transfect 
CHO-DXB-11 cells for the development of the pembrolizumab-producing cell line. 
 
5.2 Treatment Regimen 
Patients will be treated with reirradiation with or without standard concurrent chemotherapy to all 
gross disease with proton beam therapy. The intended radiation dose should be at least 60 Gy of 
reirradiation in 1.8-2.0 Gy fractions with or without concurrent chemotherapy or in 4.0 Gy fractions 
without chemotherapy, at the provider’s discretion. This corresponds to daily fractionated radiation 
over a period of approximately 3-8 weeks. The decision to use concurrent chemotherapy, and which 
regimen to utilize, are left to the discretion of the treating oncologist. The chemotherapy regimen and 
doses will be recorded in the patient record. 
 
Pembrolizumab will be started 4 to 12 weeks after completion of reirradiation. Pembrolizumab will be 
given at a dose of 200 mg intravenously approximately every 21 days for 17 cycles (about 12 months) 
if there is no evidence of progressive disease or intolerable side effects.   
 Dose Modifications (Escalation/Titration/Other) 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These adverse events may occur shortly after the first dose or 
several months after the last dose of treatment. Pembrolizumab must be withheld for drug-related 
toxicities and severe or life-threatening AEs as per 3 below. See Section 5.6 for supportive care 
guidelines, including use of corticosteroids. 
Table 1: Dose Modification Guidelines for Drug-Related Adverse Events 
 
Toxicity 
Hold 
Treatmen
t For 
Grade 
Timing for Restarting Treatment 
Treatment Discontinuation 
Diarrhea/Colitis 
2-3 
 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or 
Increased 
Bilirubin 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose 
3-4 
Permanently discontinue 
(see exception below)a 
Permanently discontinue 
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia 
T1DM or  
3-4 
Hold pembrolizumab for new onset 
Type 1 diabetes mellitus or Grade 3-4 
hyperglycemia associated with 
evidence of beta cell failure 
Resume pembrolizumab when patients are clinically and 
metabolically stable 
Hypophysitis 
2-4 
Toxicity resolves to Grade 0-1. 
Therapy with pembrolizumab can be 
continued while endocrine 
replacement therapy is instituted 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
Hyperthyroidism  
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Hypothyroidism 
 
Therapy with pembrolizumab can be 
continued while thyroid replacement 
therapy is instituted 
Therapy with pembrolizumab can be continued while thyroid 
replacement therapy is instituted 
 
Infusion Reaction 
2b 
Toxicity resolves to Grade 0-1  
Permanently discontinue if toxicity develops despite adequate 
premedication  
3-4 
Permanently discontinue 
Permanently discontinue 


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Toxicity 
Hold 
Treatmen
t For 
Grade 
Timing for Restarting Treatment 
Treatment Discontinuation 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug-
Related Toxicityc 
3 or Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event. 
a For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% relative 
to baseline and lasts for at least 1 week then patients should be discontinued. 
b If symptoms resolve within one hour of stopping drug infusion, the infusion may be restarted at 50% of the original infusion rate   (e.g., from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be held until symptoms resolve and the subject should be premedicated  for the next scheduled dose; 
Refer to Infusion Treatment Guidelines for further management details. 
c Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  Permanently discontinue study 
drug for persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 within 12 
weeks of the last dose. 
 
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons not 
related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, and/or 
holidays). Subjects should be placed back on study therapy within 3 weeks of the scheduled 
interruption, unless otherwise discussed with the Sponsor. The reason for interruption should be 
documented in the patient's study record. 
5.3 Preparation and Administration of Study Drugs 
 
A research supply of Pembrolizumab will be supplied by Merck. It will be shipped to, stored and 
dispensed from Investigational Drug Services (IDS) of the Hospital of the University of Pennsylvania 
and Penn Presbyterian Medical Center for patients enrolled at that site. The drug preparation will be 
done in the pharmacy.  
 
The investigator shall take responsibility for and shall take all steps to maintain appropriate records and 
ensure appropriate supply, storage, handling, distribution and usage of investigational product in 
accordance with the protocol and any applicable laws and regulations. 
 
Clinical Supplies will be provided by Merck as summarized in Table 2.  
 
Table 2: Product Descriptions 
 
Product Name and Potency 
Dosage Form 
Pembrolizumab 100 mg/4mL 
Solution for injection 
 
 
Study Medication Administration 
Pembrolizumab will be administered as a 30 minute intravenous infusion (treatment cycle intervals may 
be increased due to toxicity as described in Table 1). Sites should make every effort to target infusion 
timing to be as close to 30 minutes as possible. However, given the variability of infusion pumps from 
site to site, a window of -5 minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 
min/+10 min). 
 


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Pembrolizumab Premedication 
Patients do not require premedication prior to Pembrolizumab administration, as hypersensitivity 
reactions are rare.  
5.4 Subject Compliance Monitoring 
The study team will track subject compliance with the treatment regimen at each visit and note the 
dose, date, and time of study medication administration on the case report form. If there are any 
significant irregularities in compliance (in the opinion of the investigator), the subject should be 
withdrawn from the study. Interruptions from the protocol specified treatment plan for greater than 12 
weeks between Pembrolizumab doses due to toxicity will require consultation between the investigator 
and the medical monitor and written documentation of the collaborative decision on subject 
management. 
 
5.5 Prior and Concomitant Therapy 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during the 
ongoing trial.  If there is a clinical indication for one of these or other medications or vaccinations 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may be required.  
The investigator should discuss any questions regarding this with the Sponsor.  The final decision on 
any supportive therapy or vaccination rests with the investigator and/or the subject's primary physician.  
However, the decision to continue the subject on trial therapy or vaccination schedule requires the 
mutual agreement of the Investigator, the Sponsor, and the subject.  
5.5.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be administered at 
the discretion of the investigator in keeping with the community standards of medical care.  All 
concomitant medications will be recorded in the subject’s medical record 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 in the 
medical record.  Examples of acceptable concomitant medications include zoledronic acid, denosumab, 
megestrol acetate, and cannabinoids. 
All concomitant medications received within 28 days before the first dose of trial treatment and 30 days 
after the last dose of trial treatment should be recorded.  Concomitant medications administered after 
30 days after the last dose of trial treatment should be recorded for SAEs and ECIs. 
5.5.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Pre-Pembrolizumab Screening 
and Pembrolizumab Treatment Phase of this trial: 
 
Anti-cancer systemic chemotherapy or biological therapy  
 
Immunotherapy not specified in this protocol 
 
Investigational agents other than Pembrolizumab 
 
Radiation therapy  
o 
Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may be allowed 
after consultation with Sponsor, but would be regarded as a disease progression event 
for the primary outcome. 
 
Live vaccines within 30 days prior to the first dose of trial treatment and while participating in 
the trial.  Examples of live vaccines include, but are not limited to, the following: measles, 
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influenza vaccines for injection are generally killed virus vaccines and are allowed; however 
intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated vaccines and are not allowed.  
 
Glucocorticoids for any purpose other than an abbreviated course to modulate symptoms from 
an event of clinical interest of suspected immunologic etiology.  The use of physiologic 
replacement doses of corticosteroids may be approved after consultation with the Sponsor.  
Subjects who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the trial.  Subjects may receive other 
medications that the investigator deems to be medically necessary. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.6 Rescue Medications and Supportive Care 
5.6.1 Supportive Care Guidelines  
Subjects should receive appropriate supportive care measures as deemed necessary by the treating 
investigator.  Suggested supportive care measures for the management of adverse events with 
potential immunologic etiology are outlined below. Where appropriate, these guidelines include the use 
of oral or intravenous treatment with corticosteroids as well as additional anti-inflammatory agents if 
symptoms do not improve with administration of corticosteroids.   Note that several courses of steroid 
tapering may be necessary as symptoms may worsen when the steroid dose is decreased. For each 
disorder, attempts should be made to rule out other causes such as metastatic disease or bacterial or 
viral infection, which might require additional supportive care. The treatment guidelines are intended to 
be applied when the investigator determines the events to be related to pembrolizumab.  
Note: if after the evaluation the event is determined not to be related, the investigator does not need to 
follow the treatment guidance (as outlined below). Refer to Section 5.2.1 for dose modification.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event.  
 
Pneumonitis:  
o 
For Grade 2 events, treat with systemic corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 
weeks. 
o 
For Grade 3-4 events, immediately treat with intravenous steroids.  Administer 
additional anti-inflammatory measures, as needed. 
o 
Add prophylactic antibiotics for opportunistic infections in the case of prolonged steroid 
administration. 
 
Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus).   
o 
All subjects who experience diarrhea/colitis should be advised to drink liberal quantities 
of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and electrolytes should 
be substituted via IV infusion.  For Grade 2 or higher diarrhea, consider GI consultation 
and endoscopy to confirm or rule out colitis. 
o 
For Grade 2 diarrhea/colitis, administer oral corticosteroids.  
o 
For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids followed by high 
dose oral steroids.   
o 
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 


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


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The table below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab (MK-3475). 
Table 1 Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of the 
investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated 
for < =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of the 
investigator. 
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate 
(e.g., from 100 mL/hr to 50 mL/hr).  
Otherwise dosing will be held until symptoms 
resolve and the subject should be 
premedicated for the next scheduled dose. 
Subjects who develop Grade 2 toxicity 
despite adequate premedication should 
be permanently discontinued from further 
trial treatment administration. 
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab (MK-
3475) with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of 
antihistamine). 
 
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief interruption 
of infusion); recurrence of 
symptoms following initial 
improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of the 
investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from 
further trial treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period 
of drug administration. 
 
 
 
5.6.1.1 Supportive Care Guidelines for Events of Clinical Interest and Immune-
related Adverse Events (irAEs) 
Events of clinical interest of a potential immunologic etiology (irECIs) may be defined as an adverse 
event of unknown etiology, associated with drug exposure and consistent with an immune 


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phenomenon.  irAEs may be predicted based on the nature of Pembrolizumab, its mechanism of action, 
and reported experience with immunotherapies that have a similar mechanism of action.  Special 
attention should be paid to AEs that may be suggestive of potential irAEs.  An irAE can occur shortly 
after the first dose or several months after the last dose of treatment.   
 
If an irAE is suspected, efforts should be made to rule out neoplastic, infectious, metabolic, toxin or 
other etiologic causes prior to labeling an adverse event as an irAE.  Information on how to identify and 
evaluate irAEs has been developed.  Subjects who develop a Grade 2 or higher irAE should be 
discussed immediately with the Sponsor.   
 
Recommendations to managing irAEs not detailed elsewhere in the protocol are detailed in Table 4 
and the irAE guidance document (attached Appendix). 
Table 4: General Approach to Handling irAEs 
irAE 
Withhold/Discontinue 
Pembrolizumab? 
Supportive Care 
Grade 1 
No action 
Provide symptomatic treatment 
Grade 2 
May withhold 
Pembrolizumab 
Consider 
systemic 
corticosteroids 
in 
addition 
to 
appropriate 
symptomatic 
treatment 
Grade 3 and Grade 4 
Withhold Pembrolizumab 
Discontinue if unable to 
reduce corticosteroid 
dose to < 10 mg per day 
prednisone equivalent 
within 12 weeks of 
toxicity 
Systemic corticosteroids are indicated in 
addition 
to 
appropriate 
symptomatic 
treatment.  May utilize 1 to 2 mg/kg 
prednisone or equivalent per day. 
Steroid taper should be considered once 
symptoms improve to Grade 1 or less and 
tapered over at least 4 weeks. 
 
5.6.1.2 Supportive Care Guidelines for Pneumonitis 
Subjects with symptomatic pneumonitis should immediately stop receiving Pembrolizumab and have 
an evaluation.  The evaluation may include bronchoscopy and pulmonary function tests to rule out other 
causes such as infection.  If the subject is determined to have study drug associated pneumonitis, the 
suggested treatment plan is detailed in Table 5. 
Table 5: Recommended Approach to Managing Pneumonitis 
Study drug 
associated 
pneumonitis 
Withhold/Discontinue 
Pembrolizumab? 
Supportive Care 
Grade 1 
(asymptomatic) 
No action 
Intervention not indicated 
Grade 2 
Withhold 
Pembrolizumab, may 
resume treatment if 
improves to Grade 1 or 
resolves within 12 weeks 
Systemic corticosteroids are indicated.  
Taper if necessary. 


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Grade 3 and Grade 4 
Permanently discontinue 
Pembrolizumab 
Systemic corticosteroids are indicated. The 
use of infliximab may be indicated as 
appropriate. 
 
For Grade 2 pneumonitis that improves to ≤ Grade 1 within 12 weeks, the following rules should apply: 
 
First episode of pneumonitis 
o 
May increase dosing interval by one week in subsequent cycles 
 
Second episode of pneumonitis – permanently discontinue Pembrolizumab if upon rechallenge 
subject develops pneumonitis  Grade 2 
5.7 Contraception and Pregnancy  
5.7.1 Contraception 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
Pembrolizumab has transient adverse effects on the composition of sperm.  Non-pregnant, non-breast-
feeding women may be enrolled if they are willing to use 2 methods of birth control or are considered 
highly unlikely to conceive.  Highly unlikely to conceive is defined as 1) surgically sterilized, or 2) 
postmenopausal (a woman who is ≥45 years of age and has not had menses for greater than 1 year 
will be considered postmenopausal), or 3) not heterosexually active for the duration of the study.  The 
two birth control methods can be either two barrier methods or a barrier method plus a hormonal method 
to prevent pregnancy. Subjects should start using birth control from study Visit 1 throughout the study 
period up to 120 days after the last dose of study therapy.  
The following are considered adequate barrier methods of contraception: diaphragm, condom (by the 
partner), copper intrauterine device, sponge, or spermicide.  Appropriate hormonal contraceptives will 
include any registered and marketed contraceptive agent that contains an estrogen and/or a 
progestational agent (including oral, subcutaneous, intrauterine, or intramuscular agents). 
Subjects should be informed that taking the study medication may involve unknown risks to the fetus 
(unborn baby) if pregnancy were to occur during the study.  In order to participate in the study they 
must adhere to the contraception requirement for the duration of the study and during the follow-up 
period. If there is any question that a subject will not reliably comply with the requirements for 
contraception, that subject should not be entered into the study. 
5.7.2 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with Pembrolizumab, the subject will 
immediately be removed from the study.  The site will contact the subject at least monthly and document 
the subject’s status until the pregnancy has been completed or terminated.  The outcome of the 
pregnancy will be reported to the Sponsor without delay and within 24 hours if the outcome is a serious 
adverse experience (e.g., death, abortion, congenital anomaly, or other disabling or life-threatening 
complication to the mother or newborn).  The study investigator will make every effort to obtain 
permission to follow the outcome of the pregnancy and report the condition of the fetus or newborn to 
the Sponsor.   If a male subject impregnates his female partner the study personnel at the site must be 
informed immediately and the pregnancy reported to the Sponsor and followed as described above and 
in Section 8.2.2. 
 


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5.7.3 Use in Nursing Women 
It is unknown whether Pembrolizumab is excreted in human milk.  Since many drugs are excreted in 
human milk, and because of the potential for serious adverse reactions in the nursing infant, subjects 
who are breast-feeding are not eligible for enrollment. 
5.8 Subject Withdrawal/Discontinuation Criteria 
 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the discretion 
of the investigator should any untoward effect occur.  In addition, a subject may be withdrawn by the 
investigator or the Sponsor if enrollment into the trial is inappropriate, the trial plan is violated, or for 
administrative and/or other safety reasons.   
 
A subject must be discontinued from the trial for any of the following reasons: 
 
 
Withdrawal of consent. 
 
Confirmed radiographic disease progression 
Note: A subject may be granted an exception to continue on treatment with confirmed 
radiographic progression if clinically stable or clinically improved, as consistent with irRC. 
 
 
Unacceptable adverse experiences or toxicities 
 
Intercurrent illness that prevents further administration of treatment 
 
Investigator’s decision to withdraw the subject 
 
Confirmed positive serum pregnancy test and unwillingness to abort pregnancy 
 
Noncompliance with trial treatment or procedure requirements 
 
Loss to follow-up 
 
Completion of 17 cycles (about 12 months) of treatment with Pembrolizumab 
 
Other Administrative reasons 
The End of Treatment and Follow-up visit procedures are listed in Section 7 (Protocol Flow Chart).  
After the end of treatment, each subject will be followed for 30 days for adverse event monitoring 
(serious adverse events will be collected for 90 days after the end of treatment).  Subjects who 
discontinue for reasons other than progressive disease will have post-treatment follow-up for disease 
status until disease progression, initiation of non-study cancer treatment, withdrawal of consent or loss  
to follow-up.  After documented disease progression each, subject will be followed by telephone or 
chart review for overall survival until death, withdrawal of consent, or the end of the study, whichever 
occurs first.  All subsequent therapies will be recorded, if feasible. 
5.9 Subject Replacement Strategy 
Subjects who receive at least 1 dose of proton reirradiation will be considered evaluable and will not be 
replaced. 


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5.10 Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential health 
hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
In the event of Merck decision to no longer supply study drug, ample notification will be provided so 
that appropriate adjustments to subject treatment can be made. 
 
6  Labeling, Packaging, Storage and Return of Clinical Supplies 
6.1 Labeling 
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements.  This 
trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or designee are not 
blinded to treatment. Drug identity (name, strength) is included in the label text; random 
code/disclosure envelopes or lists are not provided. 
6.2 Storage and Handling Requirements 
 
Clinical supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label.  They will be stored in the Investigational Drug Pharmacy as part of the Abramson 
Cancer Center. 
 
Receipt and dispensing of trial medication must be recorded by an authorized person at the trial site. 
 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
 
6.3 Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received from Merck 
or designee, the amount dispensed to and returned by the subjects and the amount remaining at the 
conclusion of the trial.  
 
Upon completion or termination of the study, all unused and/or partially used investigational product 
will be destroyed at the site per institutional policy. It is the Investigator’s responsibility to arrange 
for disposal of all empty containers, provided that procedures for proper disposal have been 
established according to applicable federal, state, local and institutional guidelines and procedures, 
and provided that appropriate records of disposal are kept. 


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7 TRIAL FLOW CHART 
7.1 Trial Flow Chart 
Table 6: Study procedures by visit 
Trial Period: 
Screening 
Phase 
Proton 
Reirrad-
iation +/- 
Chemo-
therapy 
Pembrolizumab Treatment Cycles* 
Post-Treatment 
Treatment Cycle 
/Title: 
Screening  
 
Reirradi-
ation 
1/9 
2/10  
3/11 
4/12 
5/13 
6/14 
7/15 
8/16 
 
 
 
17 
Safety 
Follow-up 
Follow Up Visits  
Scheduling 
Window (Days): 
-28 to -1 
Daily 
protons for 
3-8 weeks 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
 
At last 
treat-
ment 
30 days 
post 
tx/discon 
Every  3 months 
for 2 yrs 
Administrative Procedures 
 
 
 
 
 
 
 
 
 
 
 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusi
on Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
and Medical 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and 
Concomitant 
Medication 
Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
Trial Treatment 
Administration 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
Post-study 
anticancer 
therapy status 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Survival Status 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Procedures/Assessments 
 
Review Adverse 
Events** 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Full Physical 
Examination 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
Directed 
Physical 
Examination 
 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
 
 
Vital Signs and 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG 
Performance 
Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 
 
 
Pregnancy Test 
– Urine or 
Serum β-HCG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
PT/INR and 
aPTT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with 
Differential 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Comprehensive 
Serum 
Chemistry  
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Trial Period: 
Screening 
Phase 
Proton 
Reirrad-
iation +/- 
Chemo-
therapy 
Pembrolizumab Treatment Cycles* 
Post-Treatment 
Treatment Cycle 
/Title: 
Screening  
 
Reirradi-
ation 
1/9 
2/10  
3/11 
4/12 
5/13 
6/14 
7/15 
8/16 
 
 
 
17 
Safety 
Follow-up 
Follow Up Visits  
Scheduling 
Window (Days): 
-28 to -1 
Daily 
protons for 
3-8 weeks 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
 
At last 
treat-
ment 
30 days 
post 
tx/discon 
Every  3 months 
for 2 yrs 
Urinalysis 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
T3, FT4 and 
TSH 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
Efficacy Measurements 
Tumor Imaging  
X*** 
X 
X 
 
 
 
X, X 
 
 
 
X 
 
X 
Tumor Biopsies/Archival Tissue Collection/Correlative Blood Studies 
Archival or 
Newly Obtained 
Tissue 
Collection  
(optional) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Correlative 
Studies Blood 
Collection 
X 
 
 
X 
 
 
 
 
X 
 
X 
X 
X 
 
 
 
 
For the Pembrolizumab phase, we will report all treatment-related toxicities. 
*The Pre-Screening visit and Main Study Screening visit may be combined to one Study Screening visit in some patient circumstances 
*Cycles 9-17 are to be repeated using same trial flow chart as cycles 1-8 
**AEs will be monitored for one year following treatment for patients who complete all 17 cycles of Pembrolizumab. AEs will be followed 
for 30 days, and SAEs for 90 days, for patients who discontinue the study early for any reason. 
***Baseline tumor imaging may occur up to 42 days before starting standard of care treatment 
 
 
8 TRIAL PROCEDURES 
8.1 Trial Procedures 
The Trial Flow Chart (Table 6) summarizes the trial procedures to be performed at each visit.  Individual 
trial procedures are described in detail below.  It may be necessary to perform these procedures at 
unscheduled time points if deemed clinically necessary by the investigator. If a procedure is performed 
according to institutional standard of care, it will fall under SOC guidelines and not this protocol. 
 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor for reasons 
related to subject safety. In these cases, such evaluations/testing will be performed in accordance 
with those regulations. 
8.1.1 Administrative Procedures 
 
8.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to participating in 
a clinical trial.  Documentation of the informed consent process must be placed in the electronic medical 
record. We will also utilize Telemedicine for consenting patients and obtain electronic signatures. 


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Consent must be documented by the subject’s dated signature or by the subject’s legally acceptable 
representative’s dated signature on a consent form along with the dated signature of the person 
conducting the consent discussion.  
 
A copy of the signed and dated consent form should be given to the subject before participation in the 
trial. 
 
For Telemedicine consent, the staff will have access to a computer with a camera and a dedicated and 
private room for all telemedicine encounters.  It will be pre-determined that the potential subject has 
access to a computer, iPad, or phone with a camera and a My Penn Medicine account.  Consent forms 
will be sent prior to the telemedicine encounter.  Subjects can e-sign the document, at which point the 
consent form becomes part of their EMR, and they can print it from My Penn Medicine. 
 
The initial informed consent form, any subsequent revised written informed consent form and any 
written information provided to the subject must receive the IRB/ERC’s approval/favorable opinion in 
advance of use.  The subject or his/her legally acceptable representative should be informed in a timely 
manner if new information becomes available that may be relevant to the subject’s willingness to 
continue participation in the trial.  The communication of this information will be provided and 
documented via a revised consent form or addendum to the original consent form that captures the 
subject’s dated signature or by the subject’s legally acceptable representative’s dated signature. 
 
Specifics about a trial and the trial population will be added to the consent form template at the protocol 
level.   
 
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations and 
Sponsor requirements. 
 
8.1.1.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee to ensure 
that the subject qualifies for the trial.  Waivers will not be granted without the explicit approval of the 
study medical monitor and IRB/CTSRMC.  
8.1.1.3 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history will include 
all active conditions, and any condition diagnosed within the prior 10 years that are considered to be 
clinically significant by the Investigator.  Details regarding the disease for which the subject has enrolled 
in this study will be recorded separately and not listed as medical history.   
8.1.1.4 Prior and Concomitant Medications Review 
8.1.1.4.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any protocol-specified 
washout requirement, and record prior medication taken by the subject within 28 days before starting 
the trial.  Treatment for the disease for which the subject has enrolled in this study will be recorded 
separately and not listed as a prior medication.  
 
8.1.1.4.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject during the 
trial.  All medications related to reportable SAEs and ECIs should be recorded as defined in Section 
8.2. 


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8.1.1.5 Disease Details and Treatments 
8.1.1.5.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease status.  
 
8.1.1.5.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including systemic 
treatments, radiation and surgeries. 
 
8.1.1.5.3 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after the last 
dose of trial treatment.  If a subject initiates a new anti-cancer therapy within 30 days after the last dose 
of trial treatment, the 30 day Safety Follow-up visit must occur before the first dose of the new therapy.  
Once new anti-cancer therapy has been initiated the subject will move into survival follow-up.  
8.1.1.6 Trial Compliance (Medication/Diet/Activity/Other) 
Interruptions from the protocol specified treatment plan for greater than 12 weeks between 
Pembrolizumab doses due to toxicity will require consultation between the investigator and the 
medical monitor and written documentation of the collaborative decision on subject management.  
8.1.2 Clinical Procedures/Assessments 
 
8.1.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Trial Flow Chart and more frequently if clinically indicated.  Adverse 
experiences will be graded and recorded after the start of Pembrolizumab and during the follow-up 
period according to NCI CTCAE Version 5.0. Toxicities will be characterized in terms regarding 
seriousness, causality, toxicity grading, and action taken with regard to trial treatment.  
All AEs of unknown etiology associated with Pembrolizumab exposure should be evaluated to 
determine if it is possibly an event of clinical interest (ECI) of a potentially immunologic etiology (irAE).  
See Section 5.7.1.1 and the irAE guidance document (attached Appendix) regarding the identification, 
evaluation and management of AEs of a potential immunological etiology.   
Please refer to section 8.2 for detailed information regarding the assessment and recording of AEs.   
8.1.2.2 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. 
8.1.2.3 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.   


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8.1.2.4 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the administration of 
each dose of trial treatment and at treatment discontinuation as specified in the Trial Flow Chart 
(Section 7.0).  Vital signs should include temperature, pulse, respiratory rate, weight and blood 
pressure.  Height will be measured at screening only. 
8.1.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 12.1) at screening, prior 
to the administration of each dose of trial treatment and discontinuation of trial treatment as specified 
in the Trial Flow Chart.   
8.1.2.6 
Tumor Imaging and Assessment of Disease 
The initial tumor imaging will be performed within 42 days prior to the first day of proton reirradiation 
or as indicated according to standard of care. Scans performed as part of routine clinical 
management are acceptable for use as the screening scan if they are of diagnostic quality and 
performed within 30 days prior to the first day of treatment. Tumor imaging will be repeated at the 
conclusion of chemoradiation and within approximately 30 days prior to the first dose of 
pembrolizumab. Imaging while on pembrolizumab will be performed every 12 weeks (1 day before 
Pembrolizumab up until the day of the next infusion) after the first dose of pembrolizumab or more 
frequently if clinically indicated. Tumor imaging timing should follow calendar days and should not be 
adjusted for delays in cycle starts or extension of Pembrolizumab cycle frequencies. This image 
schedule will also be adjusted per subject’s insurance coverage.  
 
For patients that receive at least one dose of Pembrolizumab, after the first documentation of 
progression (if the subject is clinically stable) confirmatory scans may be performed as early as 28 
days later; alternately, the scan performed at the next scheduled time point (e.g. every 84 ±7 days) 
may be used as confirmation. 
 
After the first documentation of progression, it is at the discretion of the investigator either to verify 
true PD, to keep a clinically stable subject on trial treatment or to stop trial treatment until repeat 
imaging performed at least 28 days later confirms progression. Clinical Stability is defined as: 
 
1) Absence of symptoms and signs indicating clinical significant progression of disease (including 
worsening of laboratory values) indicating disease progression. 
2) No decline in ECOG performance status. 
3) Absence of rapid progression of disease or progressive tumor at critical anatomical sites (e.g., cord 
compression) requiring urgent alternative medical intervention. 
 
Subjects who are deemed clinically unstable are not required to have repeat imaging for 
confirmation. If progression is confirmed, then the subject will be discontinued from trial treatment. If 
progression is not confirmed, then the subjects should resume/continue trial treatment and have their 
next scan after two more cycles of treatment which would be approximately 6 weeks from the date of 
the scan that first showed progression. When feasible, subjects should not be discontinued until 
progression is confirmed. 
 
For subjects who complete all treatment cycles, imaging during the follow-up period should be 
repeated approximately every 3 months for up to two years or until confirmation of progressive 
disease. Imaging during the follow-up period is to be repeated approximately every 3 months for 
subjects who discontinue trial treatment for reasons other than disease progression until the subject 
experiences confirmed disease progression or starts a new antineoplastic therapy. 
 
The same imaging techniques should be used in a subject throughout the trial.  For patients with 


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brain metastases, MRI brain should be included in the imaging follow up prior to treatment and at any 
time when a patient develops new neurologic symptoms. Ideally, CT scans should be used in lieu of 
PET imaging as the means of determining tumor status.  But PET imaging may be used to confirm 
PD, if suspected, but not yet clear. 
8.1.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are provided 
below.  The total amount of blood/tissue to be drawn/collected over the course of the trial (from pre-trial 
of Pembrolizumab to post-trial of Pembrolizumab visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per subject may vary depending upon clinical course of the 
subject and length of time on trial.  
 
8.1.3.1 Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 7.  The total 
amount of blood/tissue to be drawn/collected over the course of the trial (from pre-trial of 
Pembrolizumab to post-trial of Pembrolizumab visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per subject may vary depending upon clinical course of the 
subject and length of time on trial. Blood testing done during the   reirradiation +_/-chemo phase will be 
done per standard of care. 


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Table 7:  Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human 
chorionic 
gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase 
(ALT) 
Protein 
PT (INR) 
WBC (total and differential) 
Aspartate aminotransferase 
(AST) 
Specific gravity  
aPTT 
Red Blood Cell Count 
 
Microscopic exam (If 
abnormal)  
Total 
thriiodothyronine 
(T3) 
Absolute Neutrophil Count 
Carbon Dioxide  
results are noted 
Free tyroxine (T4) 
 
  (CO2 or biocarbonate) 
Urine pregnancy test † 
Thyroid stimulating 
hormone (TSH) 
 
Calcium 
 
 
 
Chloride 
 
Blood for correlative 
studies 
 
Glucose 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin 
is elevated above the upper 
limit of normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a 
serum pregnancy test will be required.   
 
After Cycle 1, pre-dose laboratory procedures can be conducted up to 72 hours prior to dosing.  Results 
must be reviewed by the investigator or qualified designee and found to be acceptable prior to each 
dose of Pembrolizumab.  
 
8.1.3.1.1 Blood Collection for Additional Correlative Samples  
Sample collection, storage and shipment instructions for blood samples may vary.  Correlative samples 
will be used to examine Anti-Pembrolizumab Antibodies, inflammatory markers, circulating tumor cells 
and genetic analysis. These studies will be done upon receipt of additional funding; until that time 
samples will be stored as per local policy. 
8.1.4 Other Procedures 
 


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8.1.4.1 Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities scheduled for 
the final trial visit should be performed at the time of discontinuation when possible.  Any adverse events 
which are present at the time of discontinuation/withdrawal should be followed in accordance with the 
safety requirements outlined in Section 8.2 - Assessing and Recording Adverse Events. After 
discontinuing treatment, these subjects should return to the site for a Safety Follow-up Visit (described 
in Section 8.1.5.4) and then proceed to the Follow-Up Period of the study (described in Section 8.1.5.5). 
 
8.1.5 
Visit Requirements 
Visit requirements are outlined in Section 7.0 - Trial Flow Chart.    
 
8.1.5.1 Screening 
Visit requirements are outlined in Section 7.0 - Trial Flow Chart.  
 
Prior to treatment initiation of Pembrolizumab, potential subjects will be evaluated to determine that 
they fulfill the entry requirements. Screening procedures may be repeated. 
 
Written informed consent must be obtained prior to performing any protocol specific procedure. 
 
Results of a test performed prior to the subject signing consent as part of routine clinical management 
are acceptable in lieu of a screening test if performed within the specified time frame. Screening 
procedures are to be completed within 42 days prior to the first dose of trial treatment of 
Pembrolizumab except for the following: 
 
 
Laboratory tests are to be performed within 10 days prior to the first dose of trial treatment of 
Pembrolizumab. 
 
For women of reproductive potential, a urine pregnancy test will be performed within 72 hours 
prior to first dose of trial treatment. If urine pregnancy results cannot be confirmed as 
negative, a serum pregnancy test, performed by the local study site laboratory, will be 
required. 
 
Subjects may be rescreened after initially failing to meet the inclusion/exclusion criteria. Results from 
assessments performed during the initial screening period are acceptable in lieu of a repeating a 
screening test if performed within the specified time frame and the results meet the 
inclusion/exclusion criteria. 
 
8.1.5.2 Proton Reirradiation +/- Chemotherapy 
Subjects will be treated with proton re-irradiation with or without standard concurrent chemotherapy to 
all gross disease. The chemotherapy regimen and doses will be recorded.  
 
Visit requirements are outlined in Section 7.0 - Trial Flow Chart. 
 
 
8.1.5.3 Pre-Pembrolizumab Screening  
Visit requirements are outlined in Section 7.0 - Trial Flow Chart. 
 
Subjects will be eligible to move on to pembrolizumab treatment cycles if they received at least 50 Gy 
of reirradiation, if they have no progressive disease on tumor imaging, and if they do not have 
symptomatic CTCAEv5 grade ≥3 pneumonitis.  


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8.1.5.4 Pembrolizumab Treatment Cycles 
Visit requirements are outlined in Section 7.0 - Trial Flow Chart. 
 
8.1.5.5 Post-Treatment Visits 
Visit requirements are outlined in Section 7.0 - Trial Flow Chart. Patients will be followed for up to 5 
years for both PFS and OS status. After the completion of all therapy, subjects should be followed for 
up to 5 years, with no option for retreatment with Pembrolizumab on study. 
 
8.1.5.6 Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the last dose 
of trial treatment or before the initiation of a new anti-cancer treatment, whichever comes first.  All AEs 
that occur prior to the Safety Follow-Up Visit should be recorded.  Subjects with an AE of Grade > 1 
will be followed until the resolution of the AE to Grade 0-1 or until the beginning of a new anti-neoplastic 
therapy, whichever occurs first.  SAEs that occur within 90 days of the end of treatment or before 
initiation of a new anti-cancer treatment should also be followed and recorded.   
8.1.5.7 Follow-up Visits 
Subjects who discontinue trial treatment for a reason other than disease progression will move into the 
Follow-Up Phase and should be assessed approximately every 3 months by radiologic imaging to 
monitor disease status.  Every effort should be made to collect information regarding disease status 
until disease progression, death, or end of the study.  Information regarding post-study anti-neoplastic 
treatment will be collected if new treatment is initiated. 
 
8.1.5.8 Survival Follow-up 
Once a subject experiences confirmed disease progression, the subject moves into the survival follow-
up phase and should have their medical record reviewed  every 12 weeks to assess for survival status 
until death, withdrawal of consent, or the end of the study, whichever occurs first. A patient who has 
not experienced disease progression 3 years after enrollment may have his/her follow up visits and 
scans spaced out to every 6 months (24 weeks), at the discretion of the treating oncologist. 
8.2 Assessing and Recording Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. An adverse event can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of a medicinal product or protocol-specified procedure, whether or not 
considered related to the medicinal product or protocol-specified procedure.  Any worsening (i.e., any 
clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is 
temporally associated with the use of the Merck’s product, is also an adverse event. 
 
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. 
 


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Adverse events may occur during the course of the use of Merck product in clinical trials or within the 
follow-up period specified by the protocol, or prescribed in clinical practice, from overdose (whether 
accidental or intentional), from abuse and from withdrawal. 
 
All adverse events will be recorded from beginning with cycle 1 of Pembrolizumab through 30 days 
following cessation of treatment and at each examination on the Adverse Event case report 
forms/worksheets. Laboratory AE’s will also start being recorded beginning with cycle 1 of 
Pembrolizumab. The reporting timeframe for adverse events meeting any serious criteria is described 
in section 8.2.3.1. 
 
 
Applicable reporting to DSMC will occur as follows: 
 
On-Site subjects (this includes any subjects enrolled at other sites on an in-house study) 
 
     1. All grade 3 or higher events (AE or SAE) within five business days of knowledge. 
     2. All unexpected deaths within 24 hours of knowledge. 
     3. All others deaths within 30 days of knowledge. Deaths of subjects off-study for greater 
  
than 30 days from the last study treatment/intervention are not reportable with the 
 following exceptions: 
 
Study Exceptions the CTSRMC will not Approve: 
 
Exceptions to eligibility, treatment/dosing, contraindicated treatment/therapies/interventions or safety 
tests will not be approved for any of the following types of studies: 
 
1. Any investigator-initiated treatment study. 
2. Any investigator-initiated study utilizing an intervention with therapeutic intent. 
3. Any Phase III study, regardless of sponsor (in-house, cooperative group, industry, consortium, 
etc.). 
4. Any study involving on-campus manufacturing of any component, regardless of sponsor. 5. Any 
first in-human study. 
Requests that fall into any of the above categories will receive an automatic rejection "The DSMC has 
rejected this request." 
 
Exception 
 
A one time, intentional action or process that departs from the IRB and CTSRMC approved study 
protocol, intended for one occurrence. If the action disrupts the study progress, such that the study 
design or outcome (endpoints) may be compromised, or the action compromises the safety and 
welfare of study subjects, advance documented IRB and DSMC approval is required. 
 
  • For exceptions on Industry or Cooperative group sponsored protocols, written approval must be 
obtained from the Sponsor prior to submitting the exception request to the DSMC. 
  • For in-house studies with a Medical Monitor or Safety Monitoring Committee (not DSMB), approval 
must be obtained from the Medical Monitor or Safety Monitoring Committee prior to submitting the 
exception request to the DSMC. 
 
Deviation 
 
A one time, unintentional action or process that departs from the IRB and DSMC approved study 
protocol, involving one incident and identified retrospectively, after the event occurred. If the impact 
on the protocol disrupts the study design, may affect the outcome (endpoints) or compromises the 
safety and welfare of the subjects, the deviation must be reported to the DSMC within 5 business 
days and the IRB within 10 business days. 
 


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Events Requiring Prompt Reporting to the IRB including Unanticipated Problem Involving Risks to 
Subjects or Others Reporting Requirements 
 
Federal Regulation 21CFR §56.108(b)(1) and 45 CFR 46.103(b)(5) require the IRB to "follow written 
procedures for ensuring prompt reporting to the IRB…any unanticipated problems involving risk to 
human subjects or others."   
 
In alignment with 21 CFR 312, investigators are required to promptly report to the IRB: 
 
 (1) Unanticipated problems including suspected adverse reactions and adverse reactions. 
 
 
An event is considered a “suspected adverse reaction” when there is reasonable possibility that 
the 
drug/investigational 
product 
caused 
the 
adverse 
event.  For 
these 
reporting 
purposes, reasonable possibility means there is evidence to suggest a causal relationship 
between the drug/investigational product and the event. 
 
For University of Pennsylvania IRB reporting, this means an event should be considered 
probably or definitely related to the research procedures. 
 
An event is “unexpected” if it is not listed in the investigator’s brochure/package insert, or, is 
not listed at the specificity or severity that has previously been observed with the specific 
drug/investigational product; if an investigator’s brochure/package insert is not available, is not 
consistent with the risk information described in the general investigational plan.) 
 
“Unexpected” also refers to events that are mentioned in the investigator’s brochure/package 
insert as occurring with a class of drugs or as anticipated, but, are not mentioned as to have 
been occurring (have been seen) with the particular drug/investigational product under study.  
  
(2) Unanticipated adverse device reaction. Any serious adverse effect on health or safety or any life-
threatening problem or death caused by, or associated with, a device, if that effect, problem, or death 
was not previously identified in nature, severity, or degree of incidence in the investigational plan or 
application (including a supplementary plan or application, or any other unanticipated serious problem 
associated with a device that relates to the rights, safety, or welfare of subjects. 
 
 
For drug/investigational product and device events, “serious” is defined as any death, life-
threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, 
a persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions, or a congenital anomaly/birth defect.  Other events that may be considered 
“serious” but not meet the prior criteria include: those events that may jeopardize the patient 
or subject and may require medical or surgical intervention to prevent one of the outcomes 
noted above. 
  
(3) In addition to unanticipated problems, the IRB also requires prompt reporting of the following events: 
 
 
Complaint of a participant when the complaint indicates unexpected risks or the complaint 
cannot be resolved by the research team. 
 
Violation or deviation (meaning an accidental or unintentional change to the IRB approved 
protocol) only when: one or more participants were placed at increased risk of harm, or, the 
event has the potential to occur again, the event represents serious or continuing 
noncompliance.  


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 (4)  Breach of confidentiality. 
 
 (5) Incarceration of a participant when the research was not previously approved under Subpart C and 
the investigator believes it is in the best interest of the subject to remain on the study. 
This study will be monitored in accordance with the DSMC monitoring plan.  Dr. Dan Vogl will serve as 
medical monitor and will consult on decisions made as a part of this trial as noted above. 
8.2.1 Definition of an Overdose for This Protocol and Reporting 
of Overdose to the Sponsor 
 
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed dose for 
Pembrolizumab by 20% over the prescribed dose. No specific information is available on the treatment 
of overdose of Pembrolizumab. In the event of overdose, Pembrolizumab should be discontinued and 
the subject should be observed closely for signs of toxicity.  Appropriate supportive treatment should 
be provided if clinically indicated. 
 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the adverse 
event(s) is reported as a serious adverse event, even if no other seriousness criteria are met. 
 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any associated 
clinical symptoms or abnormal laboratory results, the overdose is reported as a non-serious Event of 
Clinical Interest (ECI), using the terminology “accidental or intentional overdose without adverse effect.” 
 
All reports of overdose with and without an adverse event must be reported within 24 hours to the 
Sponsor and within 2 working days’ hours to Merck Global Safety. (Attn: Worldwide Product Safety; 
FAX 215 993-1220) 
8.2.2 Reporting of Pregnancy and Lactation to the Sponsor  
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject (spontaneously 
reported to them), including the pregnancy of a male subject's female partner that occurs during the 
trial or within 120 days of completing the trial.  All subjects and female partners of male subjects who 
become pregnant must be followed to the completion/termination of the pregnancy.  Pregnancy 
outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal 
death, intrauterine death, miscarriage and stillbirth must be reported as serious events (Important 
Medical Events).  If the pregnancy continues to term, the outcome (health of infant) must also be 
reported. 
Such events must be reported within 24 hours to the Sponsor and within 2 working days to Merck 
Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
8.2.3 Immediate Reporting of Adverse Events to the Sponsor  
 
8.2.3.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck’s 
product that: 
 
Results in death; 
 
Is life threatening; 
 
Results in persistent or significant disability/incapacity; 
 
Results in or prolongs an existing inpatient hospitalization; 
 
Is a congenital anomaly/birth defect; 
 
Is a new cancer (that is not a condition of the study); 
 
Is associated with an overdose; 
 
Is another important medical event  


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SAE reports and any other relevant safety information are to be forwarded to the Merck Global Safety 
facsimile number:  +1-215-993-1220 within two (2) business days of learning of the information. 
 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local regulators. 
Investigators will cross reference this submission according to local regulations to the Merck 
Investigational Compound Number (IND, CSA, etc.) at the time of submission.  Additionally, 
investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: Worldwide Product Safety; 
FAX 215 993-1220) at the time of submission to FDA. 
 
All subjects with serious adverse events must be followed up for outcome. 
 
8.2.3.2 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 24 hours to the Sponsor and within 2 working days to Merck Global Safety. 
(Attn: Worldwide Product Safety; FAX 215 993-1220). 
 
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 subject must be reported within 24 hours to the 
Sponsor and within 2 working days to Merck Global Safety if it causes the subject to be excluded from 
the trial, or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure. 
For the time period beginning at treatment allocation/randomization through 90 days following cessation 
of treatment, or 30 days following cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier, any ECI, or follow up to an ECI, whether or not related to Merck product, must be 
reported within 24 hours to the Sponsor and within 24 hours to Merck Global Safety. 
Events of clinical interest for this trial include: 
1.  an overdose of Merck product, as defined in Section 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.  
 
8.2.4 Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to the NCI 
CTCAE, version 5.0. 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 8: Evaluating Adverse Events 
An investigator who is a qualified physician, will evaluate all adverse events as to:  
 
 
V5.0 CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-
threatening; hospitalization or prolongation or hospitalization 
indicated; disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness A serious adverse event is any adverse event occurring at any dose or during any 
use of Merck product that: 
†Results in death; or 
†Is life threatening; or places the subject, in the view of the investigator, at 
immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused 
death.); or 
†Results in a persistent or significant disability/incapacity (substantial 
disruption of one’s ability to conduct normal life functions); or 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is 
defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization [including hospitalization for an elective procedure] for a preexisting 
condition which has not worsened does not constitute a serious adverse event.); or 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product 
regardless of time to diagnosis);or 
Is a new cancer; (that is not a condition of the study) or 
Is an overdose (whether accidental or intentional).  Any adverse event associated 
with an overdose is considered a serious adverse event. An overdose that is not 
associated with an adverse event is considered a non-serious event of clinical 
interest and must be reported within 24 hours. 
Other important medical events that may not result in death, not be life 
threatening, or not require hospitalization may be considered a serious adverse 
event when, based upon appropriate medical judgment, the event may jeopardize 
the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the 
appropriate length of time and units 
Action taken  Did the adverse event cause the Merck product to be discontinued? 
Relationship 
to test drug 
Did the Merck product cause the adverse event? The determination of the likelihood 
that the Merck product caused the adverse event will be provided by an investigator 
who is a qualified physician. The investigator’s signed/dated initials on the source 
document or worksheet that supports the causality noted on the AE form, ensures 
that a medically qualified assessment of causality was done. This initialed document 
must be retained for the required regulatory time frame. The criteria below are 


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intended as reference guidelines to assist the investigator in assessing the likelihood 
of a relationship between the test drug and the adverse event based upon the 
available information.  
The following components are to be used to assess the relationship between 
the Merck product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the Merck 
product caused the adverse event (AE): 
Exposure 
Is there evidence that the subject was actually exposed to the Merck 
product such as: reliable history, acceptable compliance assessment 
(pill count, diary, etc.), expected pharmacologic effect, or measurement 
of drug/metabolite in bodily specimen? 
Time 
Course 
Did the AE follow in a reasonable temporal sequence from 
administration of the Merck product?  
Is the time of onset of the AE compatible with a drug-induced effect 
(applies to trials with investigational medicinal product)? 
Likely 
Cause 
Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or 
environmental factors 
 
 
Relationship 
to Merck 
product 
(continued)  
The following components are to be used to assess the relationship between 
the test drug and the AE: (continued) 
Dechallenge Was the Merck product discontinued or dose/exposure/frequency 
reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative 
dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death 
or permanent disability; (2) the AE resolved/improved despite 
continuation of the Merck product; or (3) the trial is a single-dose 
drug trial); or (4) Merck product(s) is/are only used one time.) 
Rechallenge Was the subject re-exposed to the Merck product in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative 
rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in 
death or permanent disability, or (2) the trial is a single-dose drug 
trial); or (3) Merck product(s) is/are used only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE 
EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE MERCK PRODUCT, OR IF REEXPOSURE TO 
THE MERCK PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE 
RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE 
U.S. CLINICAL MONITOR AS PER DOSE MODIFICATION 
GUIDELINES IN THE PROTOCOL. 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with 
previous knowledge regarding the Merck product or drug class 
pharmacology or toxicology? 


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The assessment of relationship will be reported on the case report forms /worksheets by an 
investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements. 
Record one of 
the following 
Use the following scale of criteria as guidance (not all criteria must be 
present to be indicative of a Merck product relationship). 
Yes, there is a 
reasonable 
possibility of 
Merck product 
relationship. 
There is evidence of exposure to the Merck product.  The temporal sequence of 
the AE onset relative to the administration of the Merck product is reasonable.  
The AE is more likely explained by the Merck product than by another cause. 
No, there is not 
a reasonable 
possibility 
Merck product 
relationship 
Subject did not receive the Merck product OR temporal sequence of the AE 
onset relative to administration of the Merck product is not reasonable OR there 
is another obvious cause of the AE.  (Also entered for a subject with overdose 
without an associated AE.) 
 
8.2.5 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.  
 
8.2.6 Tumor Biopsies/Archival Tissue Collection  
Provision of tissue from an archival tissue sample or newly obtained core or excisional biopsy of a tumor lesion will 
be encouraged.  
a. For archival tissue, 10 unstained slides of 4-5 micron thickness on positively charged slides are required. 
b. Tumor tissue may be from a diagnostic biopsy or a portion of a surgical specimen, if surgery is a 
component of definitive intent therapy. 
c. Formalin fixed paraffin embedded (FFPE) tissue samples are acceptable; a fine needle aspirate, frozen 
sample, plastic embedded sample, cell block, clot, bone, bone marrow or cytologic specimen will not be 
acceptable for IHC analysis. 
d. It is recommended that FFPE blocks be sectioned fresh (within 7 days of sectioning and sending for 
PD-L1 analysis) onto positively charged slides; slides should be stored and shipped (and stored upon 
receipt at Qualtek) at 2-8C in the dark. 
e. Recommended fixation time for samples is 24 hours to 48 hours in 10% neutral buffered formalin. 
9 Statistical Plan 
 
9.1 Statistical Analysis Plan Summary 
The statistical analysis of the data obtained from this study will be the responsibility of the Biostatistics Core 
Facility of the Abramson Cancer Center.  
 
Objectives of the study are stated in Section 3. 
9.2 Sample Size Determination 
The sample size will be 41 evaluable patients; i.e.: subjects who receive at least 1 dose of proton reirradiation. 
 


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9.3 Hypothesis/Evaluation 
 
This phase II study evaluates a multi-stage treatment plan for recurrent disease that is comprised of definitive 
therapy consisting of proton reirradiation with or without chemotherapy, followed by consolidation Pembrolizumab, 
for recurrent NSCLC. A total of 41 patients will be enrolled on the study. Between the end of definitive therapy and 
the start of Pembrolizumab, there is a 4-12 week rest period. The primary intent-to-treat analysis will estimate PFS 
from start of definitive therapy, regardless of whether consolidation Pembrolizumab was administered. A secondary 
proof of principle analysis will estimate PFS in the subgroup of patients who receive definitive therapy followed by 
consolidation Pembrolizumab. The benefit of adding Pembrolizumab after definitive therapy will be determined in 
this analysis, by testing whether PFS is improved as compared to a historical control population who received 
standard therapy only. For this proof of principle analysis, the null hypothesis is that the median PFS from start of 
therapy for a recurrence of NSCLC is 6 months as compared to the alternative hypothesis that the median PFS is 
increased to 10 months.  
9.3.1 Analysis Endpoints 
Primary 
 
Progression Free Survival (PFS) per RECIST 1.1 
Progression Free Survival is defined as the time from initiation of definitive therapy to the first documented disease 
progression per RECIST 1.1 based on radiologists’ review or death due to any cause, whichever occurs first, or 
last patient follow-up that documented lack of disease progression. Patients who have not had disease progression 
or who have died, will be censored on the most recent clinical evaluation date that documented that they were 
progression-free. 
 
Secondary 
 
Overall Survival 
 
Overall Survival (OS) is defined as the time from initiation of definitive therapy to death due to any cause or last 
patient contact alive. Subjects without documented death at the time of the final analysis will be censored at the 
date of the last follow-up. 
 
Toxicity Determination 
Tolerability of therapy will be determined on the basis of CTCAE adverse event reporting. Toxicity will be reported 
separately for definitive therapy and Pembrolizumab. For the definitive therapy phase, we will report on adverse 
events which are grade 3 or higher treatment-related toxicities or any grade of pneumonitis or esophagitis. For the 
Pembrolizumab phase, we will report all treatment-related toxicities.  
9.3.2 Efficacy Analysis Populations 
 
The analysis of primary efficacy endpoints is based on the intention-to-treat (ITT) population. All patients who 
enroll will be included, regardless of whether they receive consolidation Pembrolizumab. A secondary efficacy 
analysis will be conducted that excludes those patients who did not initiate consolidation Pembrolizumab after 
definitive therapy. At least 25 treatments of radiation should be delivered in order to be included in the analysis. 
9.3.3 Safety Analysis Populations 
 
The All Patients as Treated (APaT) population will be used for the analysis of safety data in this study. The APaT 
population consists of all enrolled subjects who received at least one dose of study treatment. At least one 
laboratory or vital sign measurement obtained subsequent to at least one dose of trial treatment is required for 


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inclusion in the analysis of each specific parameter. To assess change from baseline, a baseline measurement is 
also required. 
9.4 Statistical Methods 
 
Primary Objective 
 
1. 
The primary intent-to-treat analysis will estimate progression free survival from initiation of definitive 
therapy by the Kaplan-Meier method. Median PFS and 95% CI will be determined. A total of 41 patients 
will be enrolled on the study. 
2. 
A secondary proof of principle analysis will determine the clinical benefit of adding consolidation 
Pembrolizumab after definitive therapy. Only patients who receive consolidation Pembrolizumab are 
included in this analysis. It is expected that up to 15% of enrolled patients will have progressive disease or 
lingering toxicity and will not start Pembrolizumab after definitive therapy. Thus we anticipate that at least 
35 patients will be included.  
 
In this proof of principle analysis, we will compare progression free survival from initiation of definitive 
therapy to a historical control value. We assume the median PFS for the historical control population 
treated with standard therapy only is 6 months and the median PFS for the patients treated with definitive 
therapy and consolidation Pembrolizumab is 10 months. Assuming 35 patients are enrolled over 2 years 
and followed for an additional 3 months, the final analysis will have 80% power to detect an improvement 
in median PFS assuming exponential survival and 1-sided 5% significance level.  
 
Secondary Objectives 
 
1. Overall survival will be estimated by the Kaplan-Meier method. Median OS and 95% CI will be 
determined.  
2. Toxicities will be graded, categorized and tabled. For the definitive therapy phase, we will report on 
adverse events which are grade 3 or higher treatment-related toxicities or any grade of pneumonitis or 
esophagitis. For the Pembrolizumab phase, we will report all treatment-related toxicities. 
Exploratory Objective 
1. Biomarkers will be tested for association with PFS using log rank test for categorical biomarkers and 
Cox proportional hazards regression for continuous biomarkers. Biomarkers will be tested for 
association with graded toxicity (i.e., worse toxicity grade) for specific categories of toxicity using chi 
square test for categorical biomarkers and Spearman’s correlation for continuous biomarkers. 
 
10 ADMINISTRATIVE AND REGULATORY DETAILS 
10.1 Confidentiality 
10.1.1 Confidentiality of Data 
 
By signing this protocol, the investigator affirms to the Sponsor that information furnished to the investigator by 
the Sponsor will be maintained in confidence, and such information will be divulged to the institutional review 
board, ethics review committee (IRB/ERC) or similar or expert committee; affiliated institution and employees, 
only under an appropriate understanding of confidentiality with such board or committee, affiliated institution and 
employees. Data generated by this trial will be considered confidential by the investigator, except to the extent 
that it is included in a publication as provided in the Publications section of this protocol. 
10.1.2 Confidentiality of Subject Records 
 


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By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), IRB/ERC, or 
regulatory authority representatives may consult and/or copy trial documents in order to verify worksheet/case 
report form data. By signing the consent form, the subject agrees to this process. If trial documents will be 
photocopied during the process of verifying worksheet/case report form information, the subject will be identified 
by unique code only; full names/initials will be masked prior to transmission to the Sponsor. 
 
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in connection with 
this trial in accordance with all applicable privacy laws, rules and regulations. 
 
10.1.3 Confidentiality of Investigator Information 
 
By signing this protocol, the investigator recognizes that certain personal identifying information with respect to 
the investigator, and all subinvestigators and trial site personnel, may be used and disclosed for trial 
management purposes, as part of a regulatory submissions, and as required by law. This information may 
include: 
 
1. Name, address, telephone number and e-mail address; 
2. Hospital or clinic address and telephone number; 
3. Curriculum vitae or other summary of qualifications and credentials; and 
4. Other professional documentation. 
 
Consistent with the purposes described above, this information may be transmitted to the Sponsor, and 
subsidiaries, affiliates and agents of the Sponsor, in this and other countries, including countries that do not have 
laws protecting such information. 
 
Additionally, the investigator’s name and business contact information may be included when reporting certain 
serious adverse events to regulatory authorities or to other investigators. By signing this protocol, the investigator 
expressly consents to these uses and disclosures. 
 
10.2 Compliance with Financial Disclosure Requirements 
Financial Disclosure requirements are outlined in the US Food and Drug Administration Regulations, Financial 
Disclosure by Clinical Investigators (21 CFR Part 54). It is the Sponsor's responsibility to determine, based on 
these regulations, whether a request for Financial Disclosure information is required. It is the investigator's/ 
subinvestigator's responsibility to comply with any such request. 
 
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 CFR Part 54, to 
provide his/her financial interests in and/or arrangements with the Sponsor to allow for the submission of 
complete and accurate certification and disclosure statements. The investigator/subinvestigator(s) further agree 
to provide this information on a Certification/Disclosure Form, commonly known as a financial disclosure form, 
provided by the Sponsor or through a secure password-protected electronic portal provided by the Sponsor. The 
investigator/subinvestigator(s) also consent to the transmission of this information to the Sponsor in the United 
States for these purposes. This may involve the transmission of information to countries that do not have laws 
protecting personal data. 
 
10.3 Compliance with Law, Audit and Debarment 
By signing this protocol, the investigator agrees to conduct the trial in an efficient and diligent manner and in 
conformance with this protocol; generally accepted standards of Good Clinical Practice (e.g., International 
Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use 
Good Clinical Practice: Consolidated Guideline and other generally accepted standards of good clinical practice); 
and all applicable federal, state and local laws, rules and regulations relating to the conduct of the clinical trial. 
 


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The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory authority inspection of 
trial-related documents and procedures and provide for direct access to all trial-related source data and 
documents. 
 
The investigator agrees not to seek reimbursement from subjects, their insurance providers or from government 
programs for procedures included as part of the trial reimbursed to the investigator by the Sponsor. 
 
The investigator shall prepare and maintain complete and accurate trial documentation in compliance with Good 
Clinical Practice standards and applicable federal, state and local laws, rules and regulations; and, for each 
subject participating in the trial, provide all data, and, upon completion or termination of the clinical trial, submit 
any other reports to the Sponsor as required by this protocol or as otherwise required pursuant to any agreement 
with the Sponsor. 
 
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator upon request and also 
shall be made available at the trial site upon request for inspection, copying, review and audit at reasonable 
times by representatives of the Sponsor or any regulatory authorities. The investigator agrees to promptly take 
any reasonable steps that are requested by the Sponsor as a result of an audit to cure deficiencies in the trial 
documentation and worksheets/case report forms. 
 
The investigator must maintain copies of all documentation and records relating to the conduct of the trial in 
compliance with all applicable legal and regulatory requirements. This documentation includes, but is not limited 
to, the protocol, worksheets/case report forms, advertising for subject participation, adverse event reports, 
subject source data, correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or quality control 
procedures and laboratory director curriculum vitae. By signing this protocol, the investigator agrees that 
documentation shall be retained until at least 2 years after the last approval of a marketing application in an ICH 
region or until there are no pending or contemplated marketing applications in an ICH region or until at least 2 
years have elapsed since the formal discontinuation of clinical development of the investigational product. 
Because the clinical development and marketing application process is variable, it is anticipated that the retention 
period can be up to 15 years or longer after protocol database lock. The Sponsor will determine the minimum 
retention period and notify the investigator when documents may be destroyed. The sponsor also recognizes that 
documents may need to be retained for a longer period if required by local regulatory requirements. All trial 
documents shall be made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to discarding trial and/or subject files. 
 
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s primary physician 
about the subject’s participation in the trial if the subject has a primary physician and if the subject agrees to the 
primary physician being informed. 
 
The investigator will promptly inform the Sponsor of any regulatory authority inspection conducted for this trial. 
 
Persons debarred from conducting or working on clinical trials by any court or regulatory authority will not be 
allowed to conduct or work on this Sponsor’s trials. The investigator will immediately disclose in writing to the 
Sponsor if any person who is involved in conducting the trial is debarred or if any proceeding for debarment is 
pending or, to the best of the investigator’s knowledge, threatened. 
 
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will promptly notify that trial 
site’s IRB/IEC. 
 
10.4 Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the Food and Drug 
Administration Amendments Act (FDAAA), the Sponsor of the trial is solely responsible for determining whether 
the trial and its results are subject to the requirements for submission to the Clinical Trials Data Bank, 
http://www.clinicaltrials.gov.  Information posted will allow subjects to identify potentially appropriate trials for their 


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disease conditions and pursue participation by calling a central contact number for further information on 
appropriate trial locations and trial site contact information.    
  
10.5 Quality Management System 
By signing this protocol, the Sponsor agrees to be responsible for implementing and maintaining a quality 
management system with written development procedures and functional area standard operating procedures 
(SOPs) to ensure that trials are conducted and data are generated, documented, and reported in compliance 
with the protocol, accepted standards of Good Clinical Practice, and all applicable federal, state, and local laws, 
rules and regulations relating to the conduct of the clinical trial. 
 
10.6 Data Management 
The investigator or qualified designee is responsible for recording and verifying the accuracy of subject data. By 
signing this protocol, the investigator acknowledges that his/her electronic signature is the legally binding 
equivalent of a written signature. By entering his/her electronic signature, the investigator confirms that all 
recorded data have been verified as accurate. 
 
Detailed information regarding Data Management procedures for this protocol will be provided by the Sponsor. 
11 Publication Plan 
 
This trial is intended for publication, even if terminated prematurely. Publication may include any or all of the 
following: posting of a synopsis online, abstract and/or presentation at a scientific conference, or publication of a 
full manuscript. The Sponsor will work with the authors to submit a manuscript describing trial results within 12 
months after the last data become available, which may take up to several months after the last subject visit in 
some cases. However, manuscript submission timelines may be extended. 
 
These timelines may be extended for products that are not yet marketed, if additional time is needed for analysis, 
to protect intellectual property, or to comply with confidentiality agreements with other parties. Authors of the 
primary results manuscript will be provided the complete results from the Clinical Study Report, subject to the 
confidentiality agreement. When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of the manuscript. If the 
manuscript is subsequently accepted for publication, the Sponsor will allow the journal, if it so desires, to post on 
its website the key sections of the protocol that are relevant to evaluating the trial, specifically those sections 
describing the trial objectives and hypotheses, the subject inclusion and exclusion criteria, the trial design and 
procedures, the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections. The Sponsor reserves the right to redact proprietary information. 
 
Authorship credit should be based on 1) substantial contributions to conception and design, or acquisition of 
data, or analysis and interpretation of data; 2) drafting the article or revising it critically for important intellectual 
content; and 3) final approval of the version to be published. Authors must meet conditions 1, 2 and 3. Significant 
contributions to trial execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria. Although publication planning 
may begin before conducting the trial, final decisions on authorship and the order of authors’ names will be made 
based on participation and actual contributions to the trial and writing, as discussed above. The first author is 
responsible for defending the integrity of the data, method(s) of data analysis and the scientific content of the 
manuscript. 
 
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or presentations regarding 
this trial 45 days prior to submission for publication/presentation. Any information identified by the Sponsor as 
confidential must be deleted prior to submission; this confidentiality does not include efficacy and safety results. 
Sponsor review can be expedited to meet publication timelines.  


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Target meeting: ASCO annual meeting Spring 2018 
Target final manuscript: Journal of Clinical Oncology Jul 01, 2018 
12 Appendices  
 
12.1 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. 
 
12.2 Common Terminology Criteria for Adverse Events V5.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI CTCAE version 5.0 will be utilized for adverse event 
reporting. (http://ctep.cancer.gov/reporting/ctc.html) 
12.3 Response Evaluation Criteria in Solid Tumors (RECIST 1.1) Criteria for 
Evaluating Response in Solid Tumors  
 
RECIST version 1.1* will be used in this study for assessment of tumor response. While either CT or MRI may be 
utilized, as per RECIST 1.1, CT is the preferred imaging technique in this study. 
 
* As published in the European Journal of Cancer: 
 
 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. Arbuck, S. 
Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe, J. Verweij. New response 
evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
 


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Conference Presentation 
 
 
 
 
 
 
 


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