Quad-Shot Radiotherapy in Combination With Immune Checkpoint Inhibition for Advanced/Recurrent Head and Neck Cancer
Phase: PHASE2
Conditions: Advanced Head and Neck Squamous Cell Carcinoma, Recurrent Head and Neck Squamous Cell Carcinoma, Metastatic Head-and-neck Squamous-cell Carcinoma, Stage III Cutaneous Squamous Cell Carcinoma of the Head and Neck, Locally Advanced Head and Neck Squamous Cell Carcinoma, Stage IV Cutaneous Squamous Cell Carcinoma of the Head and Neck
Sponsor: Wake Forest University Health Sciences

 
Quad-Shot Radiotherapy in Combination with Immune Checkpoint Inhibition for 
Advanced/Recurrent Head and Neck Cancer 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC60320 
 
 
 
 
Principal Investigator: 
Name and Title 
Mercedes Porosnicu, MD 
Department / Section Name 
Department of Internal Medicine 
Section on Hematology/Oncology 
Email Address 
 
Phone Number 
 
 
Biostatistician: 
Name and Title 
Ralph B. D’Agostino Jr, PhD 
Department / Section Name 
Biostatistics and Data Science 
Email Address 
 
Phone Number 
 
Regulatory Contact: 
Name and Title 
Kim Sweat 
Email Address 
 
Phone Number 
 
 
 
 
Participating Institution(s):  
Wake Forest Baptist Comprehensive Cancer Center 
 
 
Version Date: 
 
 
07-15-2020 
 
Amended: 
 
 
 
02-23-21 
 
 
 
 
 
03-16-21 
 
 
 
 
 
05-14-21 
 
 
 
 
 
11-11-21 
 
 
 
 
 
12-21-21 
 
 
 
 
 
12-22-22 
 
 
 
 
 
03-17-23 
 
 
 
 
 
06-26-23 
 
 
Confidential

 
Quad-Shot Radiotherapy in Combination with Immune Checkpoint Inhibition for 
Advanced/Recurrent Head and Neck Cancer 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC60320 
 
 
 
 
Table of Contents 
SCHEMA .............................................................................................................................................................. 5 
1.0 
Introduction and Background .................................................................................................................... 6 
2.0 
Objectives ................................................................................................................................................. 9 
2.1 ..................................................................................................................................................... Primary Objective(s)
 .......................................................................................................................................................................... 9 
2.2 ................................................................................................................................................ Secondary Objective(s)
 .......................................................................................................................................................................... 9 
2.3 ................................................................................................................................................. Exploratory Objectives
 ........................................................................................................................................................................ 10 
3.0 
Patient Selection ..................................................................................................................................... 10 
3.1 ........................................................................................................................................................... Inclusion Criteria
 ........................................................................................................................................................................ 10 
3.2 .......................................................................................................................................................... Exclusion Criteria
 ........................................................................................................................................................................ 12 
3.3 ............................................................................................................................ Inclusion of Women and Minorities
 ........................................................................................................................................................................ 13 
4.0 
Methods .................................................................................................................................................. 14 
4.1 ................................................................................................................................................ Registration Procedure
 ........................................................................................................................................................................ 14 
4.2 ................................................................................................................................................................. Study Design
 ........................................................................................................................................................................ 14 
4.3 ................................................................................................................................................................. Radiotherapy
 ........................................................................................................................................................................ 16 
4.4 ............................................................................................................................................................. Immunotherapy
 ........................................................................................................................................................................ 18 
4.5 ................................................................................................................................... Other Non-study Treatments
 ........................................................................................................................................................................ 22 
5.0 
Study Outcomes and Study Measures ................................................................................................... 22 
5.1 .......................................................................................................................................................... Primary Outcome
 ........................................................................................................................................................................ 22 
5.2 ................................................................................................................................................... Secondary Outcomes
 ........................................................................................................................................................................ 22 

 
Quad-Shot Radiotherapy in Combination with Immune Checkpoint Inhibition for Advanced/Recurrent Head and 
Neck Cancer 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC60320 
 
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5.3 ................................................................................................................................................. Exploratory Objectives
 ........................................................................................................................................................................ 23 
6.0 
Treatment Plan ....................................................................................................................................... 24 
6.1 .............................................................................................................................................................. Study Calendar
 ........................................................................................................................................................................ 24 
6.2 Schedule of study procedures: follow-up for subjects who have completed treatment or have discontinued 
treatment due to toxicity .................................................................................................................................. 27 
6.3 .............................................................................................................................................Treatment Administration
 ........................................................................................................................................................................ 28 
6.4 ...................................................................................................................................................... Duration of Therapy
 ........................................................................................................................................................................ 28 
6.5 ................................................................................................................................................... Duration of Follow Up
 ........................................................................................................................................................................ 28 
6.6 ................................................................................................................................. Criteria for Removal from Study
 ........................................................................................................................................................................ 28 
7.0 
Measurement of Effect ............................................................................................................................ 29 
7.1 ................................................................................................................................. Antitumor Effect – Solid Tumors
 ........................................................................................................................................................................ 29 
7.1.1 
Definitions ..................................................................................................................................... 30 
7.1.2 
Methods for Evaluation of Measurable Disease ............................................................................ 31 
7.1.3 
Response Criteria ......................................................................................................................... 32 
7.1.4 
Duration of Response ................................................................................................................... 33 
7.1.5 
Survival Outcomes ........................................................................................................................ 33 
7.1.6 
Response Review ......................................................................................................................... 33 
8.0 
Adverse Events List and Reporting Requirements ................................................................................. 34 
8.1 ........................................................................................................................................................ Safety Parameters
 ........................................................................................................................................................................ 34 
8.2 .................................................................................................................................... Adverse Event Characteristics
 ........................................................................................................................................................................ 39 
8.3 ......................................................................................................................... STRC SAE Reporting Requirements
 ........................................................................................................................................................................ 40 
8.4 ................................................................................................................ WFUHS IRB AE Reporting Requirements
 ........................................................................................................................................................................ 40 
9.0 
Correlative/Special Studies ..................................................................................................................... 41 

 
Quad-Shot Radiotherapy in Combination with Immune Checkpoint Inhibition for Advanced/Recurrent Head and 
Neck Cancer 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC60320 
 
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9.1 ................................................................................................................................... Laboratory Correlative Studies
 ........................................................................................................................................................................ 41 
10.0 
Pharmaceutical Information .................................................................................................................... 44 
Pharmaceutical Accountability .................................................................................................................... 44 
11.0 
Statistical Considerations ........................................................................................................................ 45 
11.1 ................................................................................................................................... Analysis of Primary Objective
 ........................................................................................................................................................................ 45 
11.2 .............................................................................................................................. Analysis of Secondary Objective
 ........................................................................................................................................................................ 45 
11.3 .............................................................................................................................................Power and Sample Size
 ........................................................................................................................................................................ 45 
11.4 ............................................................................................................................................. Estimated Accrual Rate
 ........................................................................................................................................................................ 45 
11.5 ............................................................................................................................................. Estimated Study Length
 ........................................................................................................................................................................ 46 
12.0 Ethical and regulatory requirements ...................................................................................................... 46 
12.1 Ethical conduct of the study ................................................................................................................ 46 
12.2 Ethics and regulatory review ............................................................................................................... 46 
12.3 Informed consent .................................................................................................................................. 47 
12.4 Audits and inspections ......................................................................................................................... 47 
13.0 Study Management ................................................................................................................................... 48 
13.1 Training of study site personnel .......................................................................................................... 48 
13.2 Data Management ................................................................................................................................. 48 
13.3 Confidentiality and Privacy .................................................................................................................. 48 
13.4 Data Safety and Monitoring .................................................................................................................. 49 
13.5 Reporting of Unanticipated Problems, Adverse Events or Deviations ............................................ 49 
Appendix A – Eligibility Checklist ........................................................................................................................ 54 
Appendix B – Protocol Registration Form ........................................................................................................... 58 
Appendix C - Race & Ethnicity Verification Form ............................................................................................... 59 
Appendix D ......................................................................................................................................................... 60 
 

 
Quad-Shot Radiotherapy in Combination with Immune Checkpoint Inhibition for Advanced/Recurrent Head and Neck Cancer 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC60320 
 
Protocol version date 06-26-2023 
 
 
 
 
 
 
Page 5 of 67 
SCHEMA 
  

 
Quad-Shot Radiotherapy in Combination with Immune Checkpoint Inhibition for 
Advanced/Recurrent Head and Neck Cancer 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC60320 
 
Protocol version date 06-26-2023 
 
 
 
 
 
 
Page 6 of 67 
1.0 
Introduction and Background 
 
1.1 
Introduction 
 
Head and neck cancer is diagnosed in approximately 65,000 patients per year in the United 
States and causes over 14,000 deaths per year (1). Approximately 90% of all head and neck 
cancers are squamous cell carcinoma (SCC) of the autodigestive mucosal lining, with other 
histologies including cutaneous SCC/basal cell carcinoma, melanoma, salivary gland tumors, 
and others. Generally, 10% of patients have metastatic disease at presentation, 20-30% will 
develop metastatic disease after definitive treatment, and 40-60% of patients progress within 3-
years after curative therapy (2-7). Head and neck cancer is the cause of death in the majority of 
patients, whether locoregional disease (42.5%) or distant disease (17.9%) (8). Therefore, for 
those with recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC), 
there is strong rationale for the use of second line strategies aimed to: 1) impact disease control 
on a systemic level and 2) maximize local control at the primary site.  
 
Role for Immunotherapy in the Management of Head and Neck Cancer 
 
The first-line standard of care (SOC) management for patients with recurrent/metastatic HNSCC 
includes combination platinum-based chemotherapy plus cetuximab, platinum-based 
chemotherapy plus pembrolizumab, pembrolizumab alone (for those with combined positive 
score [CPS] ≥1) (9). Second-line systemic therapy regimens include immune checkpoint 
inhibitors (ICIs) such as nivolumab or pembrolizumab as single agents after progression on 
platinum-based therapy (10-14). However, overall response rates (ORR) remain low (Table 1). 
Additional interventions are direly needed to improve rates of disease response with ICI (with or 
without chemotherapy), particularly at the primary tumor site, progression of which often leads 
to significant morbidity and possibly mortality.  
 
Table 1: Overall Response Rates for Immunotherapy in R/M Head and Neck Squamous 
Cell Carcinoma 
Study 
Overall Response Rate 
Agent 
KEYNOTE-012 
18% 
Pembrolizumab 
KEYNOTE-040 
15% 
Pembrolizumab 
KEYNOTE-048 
17% 
36% 
Pembrolizumab 
Pembrolizumab + 
chemotherapy 
Checkmate 141 
13% 
Nivolumab 
 
 
Quad-Shot Palliative Radiotherapy for Head and Neck Cancer 
 
Palliative radiotherapy (RT) is a mainstay in the SOC treatment of recurrent or metastatic 
HNSCC (15). Palliative RT is primarily delivered using external-beam techniques over short 
courses using larger doses per fraction (≥3 Gy per fraction) than conventionally fractionated 
radiotherapy (1.8-2 Gy per fraction) in an attempt to effect local tumor regression and relief of 

 
Quad-Shot Radiotherapy in Combination with Immune Checkpoint Inhibition for 
Advanced/Recurrent Head and Neck Cancer 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC60320 
 
Protocol version date 06-26-2023 
 
 
 
 
 
 
Page 7 of 67 
malignancy-related morbidity while limiting acute toxicity. While various fractionations have been 
reported for this purpose, the quad-shot regimen is a commonly used SOC radiotherapy 
schedule derived from prior palliative experiences in advanced pelvic malignancy (16, 17). This 
regimen is comprised of four 3.5 to 3.7-Gy fractions delivered twice daily (BID) over the course 
of two consecutive days (17-22). This regimen is associated with favorable palliative response 
rates at the treated site (Table 2). It can also be given concurrently with cytotoxic chemotherapy 
as reported in two studies detailed in Table 2 (21, 23). Additionally, due to the nature of the 
hypofractionated regimen and its delivery in split-course cycles, acute toxicity is modest. 
 
Table 2: Quad-Shot Palliative Radiotherapy for Head and Neck Cancer 
Study 
Dose/Number 
of Fractions 
Response 
Rate 
Toxicity Rate 
Note 
Paris et al. 
(17) 
14.8 Gy / 4  
CR: 28% 
PR: 49% 
N/A 
1-3 cycles delivered 
with 3-4 weeks 
between cycles 
Corry et al. 
(19) 
14 Gy / 4 
CR: 6% 
PR: 47% 
Mucositis G1: 33%; 
G2: 11%; G3: 0% 
1-3 cycles delivered 
with 3-4 weeks 
between cycles 
Lok et al. 
(18) 
14.8 Gy / 4  
Pain 
response: 
66% 
Mucositis/dermatitis 
G3: 5% 
1-3 cycles delivered 
with 3-4 weeks 
between cycles 
Finnegan et 
al. (20) 
14.8 Gy / 4 
Pain CR: 39% 
Pain PR: 22% 
Mucositis/dermatitis 
G2+: 26%/17% 
1-3 cycles delivered 
with 3-4 weeks 
between cycles 
Chen et al. 
(22) 
14.8 Gy / 4 
Palliative 
response: 
83% 
G3+: 9% 
1-3 cycles delivered 
with 3-4 weeks 
between cycles. 
Carrascosa 
et al.  
14.8 Gy / 4 
CR: 14% 
PR: 71% 
Mucositis G3: 14% 
1-3 cycles delivered 
with 3-4 weeks 
between cycles. 
Concurrent paclitaxel 
administered 1 hour 
prior to the first 
fraction of each cycle. 
Gamez et 
al.  
14.8 Gy / 4 
CR: 24% 
PR: 62% 
Mucositis/xerostomia 
G2: 35% 
1-3 cycles delivered 
with 3-4 weeks 
between cycles. 
Concurrent 
carboplatin or 
cetuximab 
administered 1 hour 
prior to the first 
fraction of each cycle. 
 
However, the quad-shot regimen is not sufficient to provide a definitive dose for durable disease 
control. The equivalent dose in 2-Gy fractions (EQD2) (assuming α/β=10 [tumor]) for a single 
cycle is 16.9 Gy, 33.8 Gy for 2 cycles, and 50.7 Gy for 3 cycles. In prior studies, approximately 

 
Quad-Shot Radiotherapy in Combination with Immune Checkpoint Inhibition for 
Advanced/Recurrent Head and Neck Cancer 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC60320 
 
Protocol version date 06-26-2023 
 
 
 
 
 
 
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64% of patients are eligible to receive more than one quad-shot cycle, and palliative response 
rates correlate with number of cycles delivered: 55% for 1 cycle, 44% for 2 cycles, 88% for 3 
cycles (correlation coefficient 0.29, p=0.012) (18). Despite its fairly favorable rates of achieving 
palliation at the treated site, this palliative (rather than curative) regimen is insufficient for long-
term disease control at the target site. Duration of control (DOC) has been reported in a phase II 
study also included in Table 2 (19). Median DOC was 5.7 months at the primary and 5.2 months 
at nodal sites for those with CR/PR and 1.8 months at the primary and 9.5 months at nodal sites 
for those with stable disease. Considering that advancements in systemic therapy using ICI 
have prolonged median survival for this patient cohort to 12 months or more, most patients will 
experience local and/or regional progression that may result in significant morbidity or even 
mortality. Therefore, there is strong rationale for combination therapy with PRT + 
immunotherapy for both patients with recurrent, advanced, incurable local disease or metastatic 
disease with an untreated primary.  
 
Rationale for the Combination of Quad-Shot Radiotherapy and Immunotherapy 
 
The mechanism of conventionally-fractionated RT (1.8-2 Gy per fraction) is to induce clonogenic 
cell death in target cells by generating irreparable DNA damage. This is achieved indirectly 
through the generation of reactive oxygen species or directly by ionizing the DNA itself. For 
palliation, more hypofractionated regimens such as quad-shot are often utilized. It is now 
apparent in preclinical data that hypofractionated radiotherapy impacts many components of the 
tumor microenvironment including CD8 T-cells, dendritic cells/antigen-presenting cells, cytokine 
expression, MHC expression, regulatory T-cells, interferon-gamma expression, MHC 
expression, and others (24).  
 
Immune checkpoint inhibition has been studied in combination with radiotherapy in preclinical 
models with the goal of increasing efficacy through RT-mediated increase in tumor 
immunogenicity (25). The combination of hypofractionated radiotherapy with anti-CTLA-4 
antibodies or with PD-1 pathway blockade seems to enhance the effects of RT on tumor kill (26-
28). RT has been shown to induce a significant increase in major histocompatibility complex 
(MHC) molecular expression in tumor cell lines and may re-sensitize tumors resistant to anti-
PD-1 therapy causing regression in the target primary and non-irradiated (non-target) tumors 
(29). Additionally, tumor cells and other cells in the tumor microenvironment upregulate PD-L1 
expression after RT, and the combination of ICI and RT may increase tumor kill by enhancing 
the efficacy of established T-cell mediated tumor immunity (30).  
 
It appears that RT regimens using hypofractionated radiotherapy (a few fractions of doses 
higher than 2 Gy per fraction) improve tumor control when combined with ICI. Because T cells 
are sensitive to low doses of radiation, it is thought that conventionally fractionated radiotherapy 
over the course of several weeks may deplete the tumor immune response by local depletion of 
tumor-specific immune cells (31). In a mouse model, synergistic effects are increased when RT 
is given in the days prior to ICI or on the same day (32). Other preclinical evidence points to a 
benefit with ICI is administered prior to radiotherapy (30, 33). No clear clinical evidence exists to 
support the timing of ICI combined with RT, and currently, administration of ICI and radiotherapy 
on the same day is avoided given concerns for increased RT and immune-mediated adverse 
effects. It is worth noting that this practice is borne from an abundance of caution among 
oncologists and that it is not clear there is increased toxicity with concurrent administration of ICI 

 
Quad-Shot Radiotherapy in Combination with Immune Checkpoint Inhibition for 
Advanced/Recurrent Head and Neck Cancer 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC60320 
 
Protocol version date 06-26-2023 
 
 
 
 
 
 
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and RT—recent and ongoing clinical trials are testing the efficacy of conventionally fractionated 
concurrent with ICI (RTOG 3504: NCT02764593, HN-005: NCT03952585).  
 
Current standards of care for patients receiving palliative RT while on ICI or chemo-ICI is to 
deliver the RT between administrations of systemic therapy. The half-life of pembrolizumab is 
on the order of 14-27 days and reaches steady-state after approximately 6 every-3-weekly 
cycles (34). We hypothesize that this combination and the timing detailed in the schema will 
provide sufficient PD-L1 blockade at the time of quad-shot radiotherapy. It has been suggested 
that RT doses in the range of 14-24 Gy in 2-3 fractions with concurrent ICI may be the most 
appropriate to utilize in further study (25). It is important to note that the quad-shot regimen falls 
close to this optimal range (14.4 Gy in 4 fractions). Additionally, prior reports indicate this 
dosage may be able to produce an abscopal effect in patients treated with ICI in metastatic 
head and neck squamous cell carcinoma (35). In all, this regimen is well-established in the 
literature to be safe and effective for head and neck cancer, can be delivered safely as RT alone 
or in combination with cytotoxic chemotherapy.  
 
The combination of ICI with radiotherapy has been found to be safe for patients with 
intermediate- or high-risk squamous cell carcinoma of the head and neck in preliminary studies 
(36, 37). Early-phase studies have also demonstrated safety with hypofractionated (3 Gy per 
fraction) regimens and stereotactic body radiotherapy (SBRT), a technique which employs 
larger fraction sizes (8 Gy per fraction) (38, 39). The data presented herein provide strong 
rationale for further clinical study into the efficacy of quad-shot radiotherapy combined with ICI.  
2.0 
Objectives 
 
This pilot study aims to assess the efficacy and tolerability of short-course quad-shot 
radiotherapy in combination with immunotherapy. Both of these standard-of-care 
treatments have the potential to act synergistically to improve response rates to systemic 
therapy. This study will study the effects of combining these standard treatments in a 
novel sequence. For the purposes of this study, the term immunotherapy will be used to 
specifically reference the use of the immune checkpoint inhibitor pembrolizumab. 
 
The hypothesis is that the delivery of palliative quad-shot radiotherapy in combination 
with immunotherapy is feasible and improves the response rates at the treated site.  
 
2.1 
Primary Objective(s) 
 
2.1.1 Measure the overall response rate for immunotherapy given with quad-
shot radiotherapy 
 
2.2 
Secondary Objective(s) 
 
2.2.1 Measure the response rate at the target lesion. 
 

 
Quad-Shot Radiotherapy in Combination with Immune Checkpoint Inhibition for 
Advanced/Recurrent Head and Neck Cancer 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC60320 
 
Protocol version date 06-26-2023 
 
 
 
 
 
 
Page 10 of 67 
2.2.2 Measure the response rate at non-target sites in patients with non-target 
sites. 
 
2.2.3 Evaluate the durability of response at the target lesion. 
 
2.2.4 Evaluate progression-free survival. 
 
2.2.5 Evaluate overall survival. 
 
2.2.6 Assess the tolerability of the combination of quad-shot radiotherapy with 
immunotherapy in order to assess the feasibility of this treatment 
regimen.  
 
2.3 
Exploratory Objectives 
 
2.3.1   Evaluate the effect of quad- shot administration on increasing the immune 
activation by treatment with pembrolizumab and investigate possible 
mechanisms.  
3.0 
Patient Selection 
 
In this pilot study of quad-shot radiotherapy in combination with pembrolizumab 
immunotherapy, patients with advanced, recurrent or metastatic head and neck cancer 
will be enrolled. Participants will be identified and selected for eligibility screening during 
routine clinical practice in either the medical oncology or radiation oncology clinics at 
WFBCCC.  
 
3.1 
Inclusion Criteria  
 
3.1.1 Advanced, recurrent or metastatic head and neck squamous cell 
carcinoma, as defined by clinical or pathological diagnosis of any of the 
following: 
 
3.1.1.1 Locally advanced head and neck squamous cell carcinoma not 
suitable for curative local treatment. 
 
3.1.1.2 Locally recurrent head and neck squamous cell carcinoma not 
suitable for curative local treatment within or outside a previously 
irradiated tissue. 
 
3.1.1.3 Metastatic head and neck squamous cell carcinoma. 
 

 
Quad-Shot Radiotherapy in Combination with Immune Checkpoint Inhibition for 
Advanced/Recurrent Head and Neck Cancer 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC60320 
 
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3.1.2 Target site in the head and neck region amenable to quad-shot palliative 
radiotherapy, for which palliative radiotherapy is recommended, as 
determined by the treating radiation oncologist. 
 
3.1.3 Age 18 years or greater at time of registration 
 
3.1.4 ECOG Performance Status of 0-2. 
 
3.1.5 Women of child-bearing potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) 
prior to study entry and for the duration of study participation. Should a 
woman become pregnant or suspect she is pregnant while participating in 
this study, she should inform her treating physician immediately. 
 
3.1.6 Ability to understand and the willingness to sign an IRB-approved 
informed consent document (either directly or via a legally authorized 
representative). 
 
3.1.7 Willingness to provide blood and saliva samples for exploratory research 
purposes 
 
3.1.8 Organ and Marrow Function as defined below:  
 
3.1.8.1 Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 
 
3.1.8.2 Platelet count ≥ 100 x 109/L 
 
3.1.8.3 Hemoglobin ≥ 9.0 g/dL 
 
3.1.8.4 Serum bilirubin ≤ 1.5 x ULN (institutional upper limit of normal) 
 
3.1.8.5 AST and ALT ≤ 2.5 x ULN (institutional upper limit of normal) 
 
3.1.8.6 Serum creatinine CL>40 mL/min by the Cockcroft-Gault formula 
(Cockcroft and Gault 1976) or by 24-hour urine collection for 
determination of creatinine clearance: 
Males: 
 
 
Creatinine CL 
(mL/min) 
= 
Weight (kg) x (140 – Age)       . 
72 x serum creatinine (mg/dL) 
 
Females: 
 
 
Creatinine CL 
(mL/min) 
= 
Weight (kg) x (140 – Age)            x 0.85 
72 x serum creatinine (mg/dL) 
 

 
Quad-Shot Radiotherapy in Combination with Immune Checkpoint Inhibition for 
Advanced/Recurrent Head and Neck Cancer 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC60320 
 
Protocol version date 06-26-2023 
 
 
 
 
 
 
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3.2 
Exclusion Criteria  
 
3.2.1 Radiation therapy to the planned quad-shot radiotherapy target region 
within 30 days of registration.  
 
3.2.2 Prior radiotherapy to the head and neck that precludes safe delivery of 
study radiotherapy, as determined by the treating radiation oncologist. 
 
3.2.3 Active medical conditions that are contraindications to study radiotherapy 
(i.e. scleroderma), as determined by the treating radiation oncologist.  
 
3.2.4 Pregnant or lactating women are excluded from this study because 
radiotherapy is contraindicated in pregnancy and because there is an 
unknown but potential risk for adverse events in nursing infants 
secondary to treatment of the mother with immunotherapy. 
 
3.2.5 Participation in another clinical study with an investigational product 
during the last 3 months. 
 
3.2.6 Any previous treatment with a PD1 or PD-L1 inhibitor. 
 
3.2.7 Any anti-cancer therapy (chemotherapy, immunotherapy, endocrine 
therapy, targeted therapy, biologic therapy, tumor embolization, 
monoclonal antibodies, other investigational agent) within the last 30 
days. Note: this excludes palliative radiotherapy to the non-target site. 
 
3.2.8 Mean QT interval corrected for heart rate (QTc) ≥470 ms.except for 
patients with pacemaker who have a paced ventricular rhythm 
 
3.2.9 Current or prior use of immunosuppressive medication within 30 days, 
with exceptions of intranasal and inhaled corticosteroids, a brief, non-
sustained corticosteroids treatment for incidental problems such as 
allergies (at the discretion of the treating physician) or sustained  
systemic corticosteroids treatment at physiological doses, which are not 
to exceed 10 mg/day of prednisone, or an equivalent corticosteroid 
except for s short course of prednisone that is prescribed for acute 
allergic situations or for prevention of an allergy to contrast substance 
utilized for imaging studies. 
 
3.2.10 Any unresolved toxicity (>CTCAE grade > 2) from previous anti-cancer 
therapy. Subjects with irreversible toxicity that is not reasonably expected 
to be exacerbated by the investigational product may be included (e.g., 
hearing loss, peripherally neuropathy).  
 
3.2.11 Any prior Grade ≥3 immune-related adverse event (irAE) while receiving 
any previous immunotherapy agent, or any unresolved irAE >Grade 1. 
 

 
Quad-Shot Radiotherapy in Combination with Immune Checkpoint Inhibition for 
Advanced/Recurrent Head and Neck Cancer 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC60320 
 
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3.2.12 Active or prior documented autoimmune disease within the past 2 years 
NOTE: Subjects with vitiligo, Grave’s disease, or psoriasis not requiring 
systemic treatment (within the past 2 years) are not excluded. 
3.2.13 Active or prior documented inflammatory bowel disease (e.g., Crohn’s 
disease, ulcerative colitis). 
 
3.2.14 History of primary immunodeficiency. 
 
3.2.15 History of allogeneic organ transplant. 
 
3.2.16 History of hypersensitivity to any excipient in pembrolizumab. 
 
3.2.17 History of pneumonitis or interstitial lung disease. 
 
3.2.18 Subjects with uncontrolled seizures. 
 
3.2.19 Uncontrolled intercurrent illness including, but not limited to, ongoing or 
active infection, symptomatic congestive heart failure, uncontrolled 
hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, 
active peptic ulcer disease or gastritis, active bleeding diatheses, 
evidence of acute or chronic hepatitis B, hepatitis C or human 
immunodeficiency virus (HIV), or psychiatric illness/social situations that 
would limit compliance with study requirements or compromise the ability 
of the subject to give written informed consent. 
 
3.2.20 Known history of active tuberculosis. 
 
3.2.21 Receipt of live attenuated vaccination within 30 days prior to study entry 
or within 30 days of receiving pembrolizumab. 
 
3.2.22 Any condition that, in the opinion of the investigator, would interfere with 
evaluation of study treatment or interpretation of patient safety or study 
results. 
 
3.3 
Inclusion of Women and Minorities 
 
Men and women of all races and ethnicities who meet the above-described 
eligibility criteria are eligible to participate in this study.  
 
Based on WFBCCC population estimates, we expect approximately 30% of 
participants to be women. Similarly, we expect approximately 1% of study 
participants to be Hispanic/Latino. We plan to enroll at least 15% Black or African 
American.  Should we not meet or exceed these estimates, the PI will engage the 
Cancer Center Health Equity Advisory Group to discuss strategies to enhance 
recruitment in these target populations. 

 
Quad-Shot Radiotherapy in Combination with Immune Checkpoint Inhibition for 
Advanced/Recurrent Head and Neck Cancer 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC60320 
 
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4.0 
Methods 
 
4.1 
Registration Procedure 
 
All patients entered on any WFBCCC trial, whether treatment, companion, or cancer control 
trial, must be linked to the study in EPIC within 24 hours of Informed Consent. Patients must be 
registered prior to the initiation of treatment.   
 
You must perform the following steps in order to ensure prompt registration of your patient: 
 
1. Complete the Eligibility Checklist (Appendix A) 
2. Complete the Protocol Registration Form (Appendix B) 
3. Alert the Cancer Center registrar by phone, and then send the signed Informed 
Consent Form, Eligibility Checklist and Protocol Registration Form to the registrar, 
either by fax or e-mail. 
 
 
 
            
*Protocol Registration is open from 8:30 AM - 4:00 PM, Monday-Friday. 
 
4. Fax/e-mail ALL eligibility source documents with registration. Patients will not be 
registered without all required supporting documents. 
Note: If labs were performed at an outside institution, provide a printout of the results. 
Ensure that the most recent lab values are sent. 
 
To complete the registration process, the Registrar will:   
 
• 
assign a patient study number 
• 
register the patient on the study 
 
4.2 
Study Design 
 
This is a single-arm, non-randomized pilot study to evaluate the efficacy and tolerability of 
combination of two standard of care interventions (quad-shot palliative radiotherapy and 
pembrolizumab immunotherapy) for patients with advanced/recurrent/metastatic head and neck 
cancer.  
 
Fifteen patients will be enrolled who have no curative localized treatment options, are eligible for 
palliative immunotherapy (pembrolizumab), have a lesion that can be targeted by radiotherapy, 
and are eligible for palliative radiotherapy as recommended by their radiation oncologist.  
 

 
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Patients eligible for this study will be those scheduled to receive palliative immunotherapy with 
the immune checkpoint inhibitor pembrolizumab (which is standard of care) for advanced, R/M 
head and neck SCC according to standard of care practice. They will also be eligible for 
palliative quad-shot radiotherapy according to the standard of care for 
advanced/recurrent/metastatic HSNCC. Quad-shot radiotherapy will be applied between 
immunotherapy cycle 2-3 or between immunotherapy cycle 3-4, within the last week of the 
cycle, and not to be delivered on the same day as ICI administration. Up to two additional quad-
shot cycles will be delivered between cycles 6-7 or 7-8 (prior to cycle 8) and 11-12 or 12-13 
(prior to cycle 13) of immunotherapy. The additional quad-shot treatments will be delivered in a 
similar fashion, in the last week of the ICI cycle.  
 
Restaging imaging with CT, MRI or PET/CT will be obtained every 5-6 immunotherapy 
treatments. For the purposes of lesion measurements, follow-up imaging must be performed 
using the same modality (CT or MRI) as was used for initial baseline imaging. PET/CT may be 
utilized for follow-up imaging at the clinician’s discretion. The maximum response in the targeted 
lesion and in the non-targeted lesions will be assessed. Subsequent immunotherapy cycles will 
be delivered after quad-shot radiotherapy until tumor progression or treatment intolerance. 
 
Palliative local (non-systemic) interventions to other sites that are not quad-shot radiotherapy 
target sites is allowable while on study protocol treatment for the management of cancer 
symptoms. This should not be utilized for progression of disease at that site.   
 
The study treatment portion ends for all patients with the last administration of the 
immunotherapy.  
 
We will monitor and document clinical toxicity per NCI Common Terminology Criteria for 
Adverse Events version 5.0 during the treatment and for two additional visits 30 days apart from 
the end of treatment with immunotherapy. Subjects who decline to return to the site for 
evaluations will be offered follow-up by phone up to 2 months as an alternative and the PI will 
make every effort to collect toxicity data from medical records. 
 
Patients will be subsequently followed for progression-free survival and overall survival 
outcomes. Subsequent visits can be accomplished in person or over the phone and clinical and 
imaging data will be collected from medical records as available. 
 
Patient-reported outcomes will be obtained at each time point using a tailored checklist of PRO-
CTCAE head and neck cancer-specific items.  
 
Saliva and blood for correlative studies will be collected before each treatment with 
immunotherapy for the first 5 administrations and before the quad-shot administration. Saliva 
and blood samples will only need to be collected on the first day of Quadshot treatment. In the 
cases in which the patients will receive a 2nd quad-shot and possibly a third quad-shot, blood 
and saliva will be collected before the respective radiation treatments as well as before the 
immunotherapy cycles that proceed and follow the quad-shot treatments.   
 
PD-L1 receptors will be tested in all patients as per standard of care. Next generation 
sequencing is encouraged and will be done whenever possible from the blood or tumor if 
available.  

 
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If any patient does not complete the study treatment and investigations, the patient will be 
replaced. 
 
4.3 
Radiotherapy 
 
4.3.1 Patient Positioning and Simulation: Patients will be simulated using CT simulation with or 
without contrast at the discretion of the treating physician. Immobilization will be 
employed at the discretion of the treating radiation oncologist.  
 
4.3.2 Target Delineation:  
- 
Gross Tumor Volume (GTV): the target lesion will be identified and delineated as GTV.  
- 
Clinical Target Volume (CTV): areas at risk of subclinical disease around the GTV may 
be delineated at the discretion of the treating radiation oncologist.  
- 
Planning Target Volume (PTV): 0.3-1 cm isotropic expansion from the GTV or CTV (if 
present).  
- 
Diagnostic imaging including but not limited to CT, MR, and PET/CT imaging may be 
utilized to guide target delineation 
 
4.3.3 Radiotherapy Planning:  
- 
Each cycle of quad-shot radiotherapy will be comprised of 14.8 Gy in 4 fractions (3.7 Gy 
per fraction) delivered twice daily (at least 6 hours apart) over two consecutive days.  
- 
All patients will receive 1 cycle of quad-shot radiotherapy between ICI cycles 2-3. 
- 
Subsequent cycles may occur between immunotherapy cycles 6-7 and 11-12, if more 
than 1 cycle can be safely delivered at the discretion of the treating radiation oncologist. 
The eligibility for subsequent cycles will be at the discretion of the treating radiation 
oncologist. 
Therefore, the total prescription dose will be:  
o 14.8 Gy in 4 fractions for those that complete 1 cycle (all patients will receive 1 
cycle) 
o 29.6 Gy in 8 fractions for those that complete 2 cycles 
o 44.4 Gy in 12 fractions for those that complete 3 cycles 
- 
Upon planning the initial cycle of quad-shot radiotherapy, a composite plan will be 
generated to assess the total dose to the target/organs at risk (see below).  
o If deemed appropriate by the treating radiation oncologist, the same plan may be 
delivered for up to 3 cycles.  
o If deemed appropriate by the treating radiation oncologist, re-simulation may be 
performed in order to plan subsequent cycles. This may be necessary to account 
for anatomic changes that may have occurred in the interim (between quad-shot 
cycles) which would otherwise impact dose to the target or organs at risk.  
 
4.3.4 Organs at Risk (OAR): Organs at risk will vary depending on the location of the target 
lesion and will be delineated at the discretion of the treating radiation oncologist. No 
target or normal tissue constraints are mandated by this protocol. However, optional 
clinical goals are below:  
 

 
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Wake Forest Baptist Comprehensive Cancer Center 
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Structure 
Treatment Planning Goals 
Treatment Planning Limit (if target 
is close to structure, higher doses 
may be accepted) 
Spinal Cord 
Max dose ≤ 37.2 Gy 
same 
Spinal Cord + 5mm Max dose ≤ 39.2 Gy 
39.2-40.6Gy to <0.03cc 
Brachial Plexus 
No more than 5% >44.6 Gy 
No more than 5% >49.2 Gy 
 
Max dose ≤47.4 Gy 
Max dose ≤50Gy 
GTV 
97% of GTV receives the 
prescription dose 
95% of GTV receives the prescription 
dose 
 
maximum dose no more than 110% 
of the prescription dose 
maximum dose no more than 115% 
of the prescription dose 
 
100% of GTV receives 95% of 
prescription dose 
99% of GTV receives 93% of 
prescription dose 
Parotid gland 
ipsilateral to primary 
tumor sitea 
Mean dose <26 Gy 
Mean dose <30 Gy 
Parotid gland 
contralateral to 
primary tumor sitea 
Mean dose <25.3 Gy 
Mean dose <31.8 Gy 
Constrictorsa 
Mean dose <37.2 Gy; V39.6 < 33%; 
V44.5 <15% 
Mean dose <44.5 Gy; V46.9 <50%; 
Larynxa 
Mean dose <28.2 Gy 
Mean dose <37 Gy 
Esophagusa 
Mean dose <28.1Gy; no hot spots in 
the esophagus 
Mean dose <31.2 Gy; no hot spots in 
the esophagus 
Lipsa 
Mean dose <20 Gy 
Mean dose <25 Gy 
Oral Cavitya 
Mean dose <28.1 Gy; avoid hot 
spots >44.5 Gy 
Mean dose <34.2 Gy; avoid hot spots 
>44.5 Gy 
Mandiblea 
V44.5 <20%; Max 47.4 Gy to 
mandible 
V44.5 <20%; Max 47.4Gy; minimize 
hot spots in the mandible 
Submandibular 
gland(s) a 
Mean <33.6 Gy 
None 
a GTV involving a non-critical OAR will be excluded from OAR contour – if applicable, OARx 
structure contour will represent X-GTV. 
 
 
4.3.5 Radiotherapy Delivery:  
- 
External beam radiotherapy (photon or electron) will be delivered using 3D-conformal or 
intensity-modulated radiotherapy according to the treating radiation oncologist.  
- 
Image guidance will be performed at the discretion of the treating physician.  
- 
One cycle of quad-shot radiotherapy will be comprised of 14.8 Gy in 4 fractions (3.7 Gy 
per fraction) delivered twice daily (at least 6 hours apart) over two consecutive days. 
 
4.3.6 Radiotherapy Timing:  

 
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Wake Forest Baptist Comprehensive Cancer Center 
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- Radiation Therapy will be given as outlined in the Study Schema and according to the 
Study Calendar in Section 6.1: 
o Quad-shot Cycle #1: prior to cycle 4 (between pembrolizumab cycle 2-3 or 3-4) 
for all patients 
o Quad-shot Cycle #2 (if delivered): prior to cycle 8 (between pembrolizumab 
cycles 6-7 or 7-8) 
o Quad-shot Cycle #3 (if delivered): prior to cycle 13 (between pembrolizumab 
cycles 11-12 or 12-13).  
- 
Radiotherapy is NOT to be given on the same day as immunotherapy/ICI infusion.  
- 
Outside of this restriction, the timing of the delivery of 4 radiotherapy fractions that make 
up each cycle is not required.  
- 
Though specific days are not mandated, it is strongly recommended that at least 1 day 
of the two consecutive days (including 2 of the 4 planned RT fractions per cycle) falls 
within 7 days prior to the delivery of an immunotherapy infusion. 
 
4.4 
Immunotherapy 
 
Systemic immunotherapy will be delivered according to the standard of care for patients with 
recurrent/metastatic head and neck cancer.  
 
4.4.1 Pembrolizumab Formulation/packaging/storage 
 
Pembrolizumab will be obtained, stored, and administered in accordance with 
institutional guidelines. 
 
4.4.2 Pembrolizumab Doses and treatment regimens 
 
Pembrolizumab 200 mg will be given every 3 weeks to tumor progression or treatment 
tolerance. 
4.4.3 Preparation of Pembrolizumab doses for administration with an IV bag 
 
4.4.3.1 The dose of pembrolizumab for administration must be prepared by the 
Investigator’s or site’s designated IP manager using aseptic technique.  Total 
time from needle puncture of the pembrolizumab vial to the end of administration 
should not exceed: 24 hours at 2°C to 8°C (36°F to 46°F) or 8 hours at room 
temperature (up to 25°C (77°F)). If in-use storage time exceeds these limits, a 
new dose must be prepared from new vials. Infusion solutions must be allowed to 
equilibrate to room temperature prior to commencement of administration.  
4.4.3.2 Pembrolizumab will be administered at room temperature (approximately 25°C) 
by controlled infusion via an infusion pump into a peripheral or central vein. 
Following preparation of pembrolizumab, the entire contents of the IV bag should 
be administered as an IV infusion over approximately 30 minutes (±5 minutes), 
using a 0.2, or 0.22-μm in-line filter. Less than 25 minutes is considered a 
deviation. 
4.4.3.3 The IV line will be flushed with a volume of IV solution (0.9% [w/v] saline) equal 
to the priming volume of the infusion set used after the contents of the IV bag are 

 
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Wake Forest Baptist Comprehensive Cancer Center 
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fully administered, or complete the infusion according to institutional policy to 
ensure the full dose is administered and document if the line was not flushed. 
4.4.3.4 Standard infusion time is 30 minutes.  However, if there are interruptions during 
infusion, the total allowed time should not exceed 8 hours at room temperature.   
 
4.4.4 Monitoring of dose administration 
 
4.4.4.1 Subjects will be monitored before, during and after the infusion with assessment 
of vital signs at the times specified in the Schedule of Assessment. Subjects are 
monitored (pulse rate, blood pressure) every 30 minutes during the infusion 
period (including times where infusion rate is slowed or temporarily stopped). 
4.4.4.2 In the event of a ≤Grade 2 infusion-related reaction, the infusion rate of study 
drug may be decreased by 50% or interrupted until resolution of the event (up to 
4 hours) and re-initiated at 50% of the initial rate until completion of the 
infusion.  For subjects with a ≤Grade 2 infusion-related reaction, subsequent 
infusions may be administered at 50% of the initial rate.  Acetaminophen and/or 
an antihistamine (e.g., diphenhydramine) or equivalent medications per 
institutional standard may be administered at the discretion of the investigator.  If 
the infusion-related reaction is Grade 3 or higher in severity, study drug will be 
discontinued. The standard infusion time is thirty minutes, however if there are 
interruptions during infusion, the total allowed time from infusion start to 
completion of infusion should not exceed 8 hours at room temperature, with 
maximum total time at room temperature not exceeding 8 hours (otherwise 
requires new infusion preparation).   
4.4.4.3 As with any antibody, allergic reactions to dose administration are 
possible.  Appropriate drugs and medical equipment to treat acute anaphylactic 
reactions must be immediately available, and study personnel must be trained to 
recognize and treat anaphylaxis.  The study site must have immediate access to 
emergency resuscitation teams and equipment in addition to the ability to admit 
subjects to an intensive care unit if necessary. 
 
4.4.5 Accountability and dispensation 
Drug accountability logs will be maintained for the investigative agent used under this 
protocol. These logs shall record quantities of study drug received and quantities 
dispensed to patients, including lot number, date dispensed, patient identifier number, 
patient initials, protocol number, dose, quantity returned, balance remaining, and the 
initials of the person dispensing the medication. 
 
4.4.6 Dose Modification and Toxicity Management 
 
4.4.6.1 For adverse events (AEs) that are considered at least partly due to 
administration of pembrolizumab, the following dose adjustment guidance may 
be applied: 
 
4.4.6.1.1 
Treat each of the toxicities with maximum supportive care 
(including holding the agent suspected of causing the toxicity 
where required). Isolated increase in amylase has been noted 
after radiotherapy for the head and neck cancer, being released 

 
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Wake Forest Baptist Comprehensive Cancer Center 
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from the salivary glands included in the radiation field. In addition, 
asymptomatic increase in the lipase has been reported. If the 
patient does not have symptoms of pancreatitis, treatment with 
pembrolizumab does not need to be stopped when increase in 
amylase and/or lipase are identified. Follow up of the lab values 
until normalization is recommended.   
 
4.4.6.1.2 
If the symptoms promptly resolve with supportive care, 
consideration should be given to continuing the same dose of 
pembrolizumab along with appropriate continuing supportive care.  
 
4.4.6.1.3 
Otherwise, pembrolizumab should be permanently discontinued. 
Dose reductions are not permitted.  
 
4.4.6.2 Based on the mechanism of action of pembrolizumab leading to T-cell 
activation and proliferation, there is the possibility of observing immune related 
Adverse Events (irAEs) during the conduct of this study.  Potential irAEs include 
immune-mediated enterocolitis, dermatitis, hepatitis, and endocrinopathies. 
Subjects should be monitored for signs and symptoms of irAEs.  In the absence 
of an alternate etiology (e.g., infection or PD) signs or symptoms of enterocolitis, 
dermatitis, hepatitis, and endocrinopathy should be considered to be immune-
related.   
 
4.4.6.3 All toxicities will be graded according to NCI CTCAE v 5.0. 
 
4.4.7 Restrictions during the study 
 
4.4.7.1 Contraception 
 
Females of childbearing potential who are sexually active with a nonsterilised male partner must 
use 2 methods of effective contraception from screening, and must agree to continue using 
such precautions for 180 days after the final dose of investigational product.  Periodic 
abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth 
control. 
• 
Females of childbearing potential are defined as those who are not surgically sterile (i.e., 
bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or 
postmenopausal (defined as 12 months with no menses without an alternative medical 
cause). 
• 
Subjects must use 2 acceptable methods of effective contraception as described in the 
table below. 
• 
Nonsterilised males who are sexually active with a female partner of childbearing 
potential must use 2 acceptable methods of effective contraception (see Table 1) from 
Day 1 and for 90 days after receipt of the final dose of investigational product. 
 

 
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Wake Forest Baptist Comprehensive Cancer Center 
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Effective methods of contraception (two methods must be used) 
Barrier Methods 
Intrauterine Device Methods 
Hormonal 
Methods 
Male condom plus spermicide 
Copper T 
Implants 
Cap plus spermicide 
Progesterone Ta 
Hormone shot or 
injection 
Diaphragm plus spermicide 
Levonorgestrel-releasing 
intrauterine system (e.g., Mirena®)a 
Combined pill 
Minipill 
Patch 
a 
This is also considered a hormonal method. 
 
4.4.7.2 Blood donation:  
 
Subjects should not donate blood while participating in this study and for at least 90 days 
following the last infusion of pembrolizumab.   
 
4.4.7.3 Concomitant treatments 
 
Permitted concomitant medications 
Investigators may prescribe concomitant medications or treatments (e.g., acetaminophen, 
diphenhydramine) deemed necessary to provide adequate prophylactic or supportive care 
except for those medications identified as “excluded” as listed below. 
 
Excluded Concomitant Medications 
The following medications are considered exclusionary during the study.  
1. Any investigational anticancer therapy 
2. Any concurrent chemotherapy, radiotherapy (except palliative radiotherapy), 
immunotherapy, biologic or hormonal therapy for cancer treatment. Concurrent use of 
hormones for noncancer-related conditions (e.g., insulin for diabetes and hormone 
replacement therapy) is acceptable. 
3. Immunosuppressive medications including, but not limited to systemic corticosteroids at 
doses exceeding 10 mg/day of prednisone or equivalent, methotrexate, azathioprine, 
and TNF-α blockers. Use of immunosuppressive medications for the management of 
investigational product-related AEs or in subjects with contrast allergies is acceptable. In 
addition, use of inhaled and intranasal corticosteroids is permitted. A temporary period of 
steroids will be allowed for different indications, at the discretion of the principal 
investigator (e.g., chronic obstructive pulmonary disease, nausea, a short course of 
prednisone that is prescribed for acute allergic situations or for prevention of an allergy 
to contrast substance utilized for imaging studies, etc). 
4. Live attenuated vaccines within 30 days of pembrolizumab dosing (ie, 30 days prior to 
the first dose, during treatment with pembrolizumab and for 30 days post discontinuation 
of pembrolizumab.  Inactivated vaccines, such as the injectable influenza vaccine, are 
permitted. 

 
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Wake Forest Baptist Comprehensive Cancer Center 
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Prohibited and Rescue Medications 
Rescue/supportive medication/class of 
drug: 
Usage: 
Concomitant medications or treatments 
(eg, acetaminophen or diphenhydramine) 
deemed necessary by the Investigator to 
provide 
adequate 
prophylactic 
or 
supportive 
care, 
except 
for 
those 
medications identified as “prohibited” as 
listed above 
To be administered as prescribed by the 
Investigator 
Best supportive care (including antibiotics, 
nutritional support, correction of metabolic 
disorders, optimal symptom control, and 
pain management. 
Should be used when necessary for all patients 
 
4.5 
Other Non-study Treatments 
 
Other local treatments (including but not limited to radiation therapy, surgery, 
interventional procedures) to sites outside the QuadShot target region are 
allowed for local symptom palliation or in the case of limited oligometastatic or 
oligoprogressive disease.  
5.0 
Study Outcomes and Study Measures 
 
5.1 
Primary Outcome 
 
5.1.1 The overall response rate will be measured according to RECIST 1.1  
(Section 7.1.3).  
5.2 
Secondary Outcomes 
 
5.2.1 The response rate in the target lesion measured according to RECIST 1.1 
(Section 7.1.3).  
 
5.2.2 The response rate in the non-target lesions (if applicable) will be 
measured according to RECIST 1.1 (Section 7.1.3). 
 
5.2.3 The duration of response at the target lesion will be defined as the 
duration from the time measurement criteria are met for CR or PR 
(whichever is first recorded) until the first date of recurrent or progressive 
disease as defined in Section 7.1.4. 

 
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5.2.4 Progression-free survival (PFS) will be defined as in Section 7.1.5. 
 
5.2.5 Overall survival (OS) will be defined as in Section 7.1.5. 
 
5.2.6 Tolerability will be measured using the Patient-Reported Outcomes 
version of the Common Terminology Criteria for Adverse Events (PRO-
CTCAE). 
 
5.3 
Exploratory Objectives 
 
 Blood will be utilized to measure the effect of immunotherapy alone as well as in 
combination with quad-shot therapy on increase of the circulating immune microRNA.  
 
In addition, blood and saliva specimens will be utilized for mechanistic investigations of 
the effects of quad-shot on the response to immune checkpoint inhibitors. Detailed and 
comprehensive single cell RNA sequencing and multi-omics analysis of both plasma and 
exosomes fractions will be performed. 
 
Saliva will be utilized for metabolomics and miRNA and RNAseq analysis of oral 
microbiome 
 

 
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6.0 
Treatment Plan 
6.1 
Study Calendar  
 
 
 
 
Screening/ 
Pre-
Registrationi 
Cycle 1-3 ICI QuadShot #1 
Cycles 4-6 ICI 
QuadShot #2 
Cycles 7-11 ICI 
Quadshot #3 
Maintenance 
ICI Every 3 
Weeks  
Initial Screening for 
Eligibility 
X 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
Medical and 
Surgical History 
X 
 
 
 
 
 
 
 
Medication List 
X 
 
 
 
 
 
 
 
Comorbidities  
X 
 
 
 
 
 
 
 
Tobacco Use 
History 
X 
 
 
 
 
 
 
 
Pre-Toxicity Form 
X 
 
 
 
 
 
 
 
Hepatitis A 
antibody Hepatitis 
B surface Ag, 
Hepatitis C 
antibody and HIV 
X 
 
 
 
 
 
 
 
Urine hCG or 
serum βhCGa 
X 
As clinically indicated 
Pembrolizumab 
Administration 
 
X 
 
X 
 
X 
 
X 
Quad-shot 
Radiotherapyh 
 
 
X 
 
X 
 
X 
 
Physical 
Examinationb 
X 
X 
 
X 
 
X 
 
X 
Vital Signs 
X 
Xc 
 
X 
 
X 
 
X 

 
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Electrocardiogramd 
X 
X 
As clinically indicated 
Concomitant 
Medications 
X 
X 
 
X 
 
X 
 
X 
Adverse 
event/serious 
adverse event 
assessment 
 
 
 
X 
 
X 
 
X 
ECOG 
Performance 
Status 
X 
X 
Xm 
X 
Xm 
 
Xm 
 
Liver enzyme panel 
X 
Xj 
 
X 
 
X 
 
X 
Serum Chemistry 
X 
Xj 
 
X 
 
X 
 
X 
Magnesium 
X 
As clinically indicated 
Uric Acid 
X 
As clinically indicated 
LDH 
X 
Xj 
                                                      As clinically indicated 
Amylase, Lipase 
X 
Xj 
 
X 
 
X 
 
X 
Thyroid function 
tests (TSH and fT3 
and fT4)e 
X 
Xj 
 
X 
 
X 
 
X 
Hematology 
X 
Xj 
 
X 
 
X 
 
X 
Urinalysis 
X 
                                                                             As clinically indicated 
Coagulation 
parameters 
X 
As clinically indicated 
Tumor Assessment 
with CT scan or 
MRIf 
X 
 
 
X 
 
X 
 
X 
Tumor assessment 
with PET scang 
X 
 
 
X 
 
X 
 
X 
Blood Collection for 
Correlatives 
 
X 
X 
Xk 
Xk 
Xk 
Xk 
Xk 
Saliva Collection 
for Correlatives 
 
X 
X 
Xk 
Xk 
Xk 
Xk 
Xk 
PRO-CTCAE QOL 
Questionnairel 
 
X 
 
X 
 
X 
 
X 

 
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a. Female subjects of childbearing potential only 
b. Full physical examination at baseline; targeted physical examination at other timepoints 
c. With first administration of pembrolizumab only and then as clinically indicated.  Subjects will have their blood pressure and pulse measured before, during and 
after the infusion at the following times (based on a 60-minute infusion): 
• 
At the beginning of the infusion (at 0 minutes) 
• 
At 30 minutes during the infusion (±5 minutes) 
• 
At the end of the infusion (at 60 minutes ±5 minutes) 
• 
In the 1 hour observation period post-infusion: 30 and 60 minutes after the infusion (ie, 90 and 120 minutes from the start of the infusion) (±5 minutes) – 
for the first infusion only and then for subsequent infusions as clinically indicated 
• 
If the infusion takes longer than 60 minutes then blood pressure and pulse measurements should be collected every 30 minutes (±5 minutes) and as 
described above or more frequently if clinically indicated. 
d. ECG during screening and at Day1 –baseline. Thereafter as clinically indicated. Baseline and abnormal ECG at any time in triplicate others single. Triplicate 
EKG is only needed at screening, and not on Cycle 1 Day 1 unless something clinically significant was seen at screening. 
e. Free T3 and free T4 will only be measured if TSH is abnormal. They should also be measured if there is clinical suspicion of an adverse event related to the 
endocrine system. 
f. CT (preferred) or MRI scans, preferably with IV contrast, are collected during screening (for baseline) and as close to and prior to initiation of study treatment but 
not more than 14 days +/- 5 days prior to first treatment. Will then be performed every 5 cycles (+/- 1 cycle) for tumor response measurement  
g. PET scan will be performed in all cases if reimbursed by Medical Insurance or funded. It will be performed as close to the initiation of treatment but not more 
than 28 days prior to treatment. Will then be performed in follow up as clinically indicated and if approved by medical insurance.  
h. Prior to cycle 4 (between pembrolizumab cycle 2-3 or 3-4) for all patients. Subsequent quad-shot cycles, if applicable, will be given as follows: quad-shot cycle 
#2: prior to cycle 8 (between pembrolizumab cycles 6-7 or 7-8); quad-shot cycle #3: prior to cycle 13 (between pembrolizumab cycles 11-12 or 12-13). 
Radiotherapy shall not be given on the same day as immunotherapy administration. Though specific days are not mandated, it is recommended that at least 1 day 
of each quad-shot cycle is given within 7 days of the upcoming ICI administration. Only one quad-shot cycle is mandated by the protocol; the 2nd and 3rd cycles 
may be completed at the discretion of the treating radiation oncologist as per Section 4.3. 
i. Pre-study requirements listed in table must be completed within 30 days prior to registration. 
j. If screening laboratory assessments are performed within 3 days prior to Day 1 they do not need to be repeated at Day 1. Results for safety bloods must be 
available and reviewed before commencing an infusion. Creatinine clearance, gamma glutamyltransferase, magnesium, and uric acid testing are to be performed 
at screening, on Day 1 (unless screening laboratory assessments are performed within 3 days prior to Day 1), and if clinically indicated.    
k. Blood and Saliva for correlatives will be collected before each of the first five cycles of immunotherapy and before the first quad-shot treatment. Saliva and blood 
samples will only need to be collected on the first day of Quadshot treatment. For patients treated with subsequent radiotherapy cycles (between ICI cycles 6-7 or 
7-8  +/- cycles 11-12 or 12-13) to be collected before the quad-shot treatment and before each ICI cycle administered before and after the quad-shot treatment (ICI 
cycles 6 and 7 or cycles 7 and 8  +/- before cycles 11 and 12 or 12 and 13)  
l. The PRO-CTCAE  
m. ECOG performance status needs to be collected only on one of the two days of quadshot treatment – either day 1 or day 2. 
 
 
 

 
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6.2 
Schedule of study procedures: follow-up for subjects who have completed treatment or have 
discontinued treatment due to toxicity 
Evaluationa 
Month 1 
Month 
2 
Physical examination 
X 
X 
Vital signs (temperature, respiratory rate, blood pressure, pulse) 
X 
X 
Weight 
X 
X 
Urine hCG or serum βhCG 
X 
X 
AE/SAE assessment 
X 
X 
Concomitant medications 
X 
X 
ECOG performance status 
X 
X 
Subsequent anti-cancer therapy 
 
X 
Hematology 
X 
X 
Serum chemistry  
X 
X 
Thyroid function tests (TSH, and fT3 and fT4)b  
X 
X 
a  
A follow up visit for evaluation is preferred and will be scheduled monthly for 2 mo after the last administration of pembrolizumab whenever possible. 
Alternatively, available data will be collected from medical records and phone evaluation will be attempted as well.  
b 
Free T3 and free T4 will only be measured if TSH is abnormal. They should also be measured if there is clinical suspicion of an adverse event related to 
the endocrine system. 

 
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6.3 
Treatment Administration 
 
Systemic therapy (ICI) and radiotherapy will be administered according to the standard of care, 
according to the treating medical oncologist and radiation oncologist, respectively. Adverse events will 
be reported according to Section 8 and logged in the AE log.  
 
Medications considered necessary for the patient's well-being may be given at the discretion of the 
treating physician, i.e., chronic treatments for concomitant medical conditions, as well as agents 
required for life-threatening medical problems, etc.  
 
6.4 
Duration of Therapy 
 
In the absence of treatment delays due to adverse events, treatment may continue one of the following 
criteria applies:  
 
• 
Disease progression (not amendable to local therapy), 
• 
Intercurrent illness that prevents further administration of treatment, 
• 
Unacceptable adverse event(s), 
• 
Patient decides to withdraw from the study, or 
• 
General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator. 
 
6.5 
Duration of Follow Up 
 
Patients will be followed for a minimum of 2 times every 30 days after the last study drug is 
administered for adverse events monitoring. Follow-up for serious adverse events and mortality after 
the last study dose is administered will take place during the routine clinic visits that the patient will 
have during the 60-day follow-up window (Also referenced in Appendix D).  If no visit occurs during this 
window, a phone call confirmation should be made to the patient to determine vital status and whether 
any adverse events and in particular, Grade 4 unexpected adverse events occurred during that window 
of time and recorded on Appendix F.  
 
Patients will be followed according to the treating physician after removal from study or until death, 
whichever occurs first. Patients removed from study for unacceptable adverse events will be followed 
until resolution or stabilization of the adverse event.  
 
Patients will be followed until death for monitoring survival study endpoints. Frequency of visits will be 
established by the treating physician and will be done in person or over the phone. Tumor imaging will 
be also performed at the discretion of the treating physician and results will be collected from the 
medical records. Alternatively, if the patient stops visiting with our clinic, tumor status and survival 
information will be collected by phone from the patient and from any other oncology office.  
 
6.6 
Criteria for Removal from Study 
 
Patients will be removed from study when any of the following criteria apply:  

 
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• 
Patient withdrawal of consent or loss to follow-up.  
• 
Adverse event that, in the opinion of the investigator or the sponsor, contraindicates further dosing. 
• 
Subject is determined to have met one or more of the exclusion criteria for study participation at 
study entry and continuing investigational therapy might constitute a safety risk. 
• 
Pregnancy or intent to become pregnant 
• 
Grade ≥ 3 infusion reaction. 
• 
Subject noncompliance that, in the opinion of the investigator or sponsor, warrants withdrawal; eg, 
refusal to adhere to scheduled visits. 
• 
Initiation of alternative anticancer therapy including another investigational agent. 
• 
Confirmation of PD and investigator determination that the subject is no longer benefiting from 
protocol treatment.  
• 
Death.  
 
Subjects who are permanently discontinued from further receipt of investigational product, regardless of 
the reason (withdrawal of consent, due to an AE, other), will be identified as having permanently 
discontinued treatment.  
 
Subjects who are removed from study prior to completing at least 2 cycles of ICI followed by at least 1 
cycle of quad-shot radiotherapy followed by at least 2 cycles of ICI will be discontinued from the study 
and replaced. 
 
Subjects who are permanently discontinued from receiving investigational product will be followed for 
safety until follow-up criteria are met in Section 6.4. Subjects who decline to return to the site for 
evaluations will be offered follow-up by phone for at least 60 days as an alternative. 
 
Withdrawal of Consent 
Patients are free to withdraw from the study at any time without prejudice to further treatment. 
 
Patients who withdraw consent for further participation in the study will not receive any further study 
drug or radiotherapy or further study observation. Patient will be asked for permission to use collected 
specimens if deemed useful by the investigator.  
 
A patient who withdraws consent will always be asked about the reason(s) for withdrawal and the 
presence of any AE. The Investigator will follow up AEs outside of the clinical study. 
7.0 
Measurement of Effect 
 
7.1 
Antitumor Effect – Solid Tumors 
 
In accordance with the standard of care, after a baseline scans obtained prior to study 
registration, patients will be reevaluated for response after 5 cycles of immunotherapy. Patients 
who continue to receive ICI at the discretion of the medical oncologist will be evaluated again 
after 10 cycles of ICI.  
 
Response and progression will be evaluated in this study using the Response Evaluation 
Criteria in Solid Tumors (RECIST) criteria 1.1.(40) Changes in the largest diameter 

 
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(unidimensional measurement) of the tumor lesions and the shortest diameter in the case of 
malignant lymph nodes are used in the RECIST criteria. 
7.1.1 Definitions  
 
 
• 
Evaluable for toxicity:  
Only those patients who have received at least 1 fraction of radiotherapy and at least 1 cycle 
of ICI will be evaluable for toxicity from the time of their first fraction of radiotherapy.  
 
• 
Evaluable for objective response: 
Only those patients who received at least one cycle of quad-shot radiotherapy (given after at 
least 2 cycles of ICI), and have had their target disease re-evaluated will be evaluable. 
These patients will have their response classified according to the definitions stated below.   
 
Note: Per Section 6.6, subjects who are removed from study prior to completing at least 2 
cycles of ICI followed by at least 1 cycle of quad-shot radiotherapy followed by at least 2 
cycles of ICI will be discontinued from the study and replaced. 
 
• 
Evaluable Non-Target Disease Response.   
Patients who have lesions present at baseline that are evaluable but do not meet the 
definitions of target disease, have received at least one cycle of quad-shot radiotherapy, and 
have had their disease re-evaluated will be considered evaluable for non-target disease.  
The response assessment is based on the presence, absence, or unequivocal progression 
of the lesions. 
 
• 
Measurable disease / measurable lesions 
Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 mm with CT 
scan, or >10 mm with calipers by clinical exam.  All tumor measurements must be recorded 
in millimeters (or decimal fractions of centimeters). 
 
• 
Malignant lymph nodes.   
To be considered pathologically enlarged and measurable, a lymph node must be >15 mm 
in short axis when assessed by CT scan (CT scan slice thickness recommended to be no 
greater than 5 mm).  At baseline and in follow-up, only the short axis will be measured and 
followed. 
 
• 
Non-measurable disease / non-measurable lesions: 
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered non-measurable 
disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pneumonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
 

 
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‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-cystic 
lesions are present in the same patient, these are preferred for selection as target lesions. 
 
• 
Target lesions 
The lesions (up to a maximum of 2) identified by the treating radiation oncologist as target 
for quad-shot radiotherapy should be identified as target lesions and recorded and 
measured at baseline.  A sum of the diameters (longest for non-nodal lesions, short axis for 
nodal lesions) for all target lesions will be calculated and reported as the baseline sum 
diameters.   
 
If lymph nodes are to be included in the sum, then only the short axis is added into the sum.  
The baseline sum diameters will be used as reference to further characterize any objective 
tumor regression in the measurable dimension of the disease.  
 
If measurements are not able to be accurately made on target lesions either at baseline or in 
follow-up, that target lesion will be excluded from the sum diameters.  
 
• 
Non-target lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 4 lesions in total not 
treated with quad-shot radiotherapy (i.e. not identified as a target lesion) should be identified 
as non-target lesions and should also be recorded at baseline. The number of non-target 
lesions will not exceed 5.  Measurements of these lesions are not required, but the 
presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up. 
7.1.2 Methods for Evaluation of Measurable Disease 
 
 
 
• 
Method(s) for obtaining measurements: 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and not more than 30 days before registration. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination unless the 
lesion(s) being followed cannot be imaged but are assessable by clinical exam. 
Clinical lesions:  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as 
assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation 
by color photography, including a ruler to estimate the size of the lesion, is 
recommended. 
 
• 
Use of imaging techniques (e.g., x-ray, CT, MRI, PET) for measuring disease 
 
Imaging (CT, MRI, or PET/CT) will be obtained routinely as per clinical practice for 
patients being treated with immunotherapy. Either modality will be suitable for obtaining 

 
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measurements. When possible, efforts should be made to obtain the same imaging 
modality used for baseline imaging for all follow-up response assessments.  
 
7.1.3 Response Criteria 
 
• 
Definition of complete response (CR) for target and non-target lesions, as appropriate 
o Target Lesions:  
 
Disappearance (or decrease to the point at which measurement is not 
possible) of all target lesions. Any pathological lymph nodes (whether 
target or non-target) must have reduction in short axis to <10 
mm (the sum may not be “0” if there are target nodes) 
 
o Non-target lesions:  
 
Disappearance (or decrease to the point at which measurement is not 
possible) of all non-target lesions. All lymph nodes must be non-
pathological in size (< 10 mm short axis) 
 
• 
Definition of partial response (PR) for target and non-target lesions, as appropriate 
o Target lesions:  
 
At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum of diameters 
 
o Non-target lesions 
 
Non-CR/Non-PD: Persistence of 1 or more non-target lesion(s). 
 
 
• 
Definition of progressive disease (PD) for target and non-target lesions, as 
appropriate 
o Target Lesions:  
 
> 20% increase in the sum of the longest diameters (SLD) taking as 
reference the smallest SLD recorded since the treatment started 
(nadir) and minimum 5 mm increase over the nadir 
 
When sum becomes very small, increases within measurement error (2-3 
mm) can lead to 20% increase 
 
(Note:  the appearance of one or more new lesions is also considered 
progressions) 
 
o Non-target lesions: 
 
Unequivocal progression of existing non-target lesions. The appearance 
of one or more new lesions. 
 
Unequivocal progression should not normally trump target lesion status.  
It must be representative of overall disease status change, not a single 
lesion increase 
 
Although a clear progression of “non-target” lesions only is exceptional, 
the opinion of the treating physician should prevail in such circumstances, 
and the progression status should be confirmed at a later time by the 
review panel (or Principal Investigator). 

 
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• 
Definition of stable disease (SD) for target and non-target lesions, as appropriate 
o Target lesions:  
 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on 
study 
 
• 
Definition and evaluation of best overall response, if applicable 
The best overall response is the best response recorded from the start of the treatment 
across all time points. 
 
Criteria for Determination of Best Overall Response 
 
Target Lesion 
 
Non-Target Lesion  
 
New Lesions 
 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
NE 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
7.1.4 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented by clinical, radiographic, or 
pathologic findings (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
 
7.1.5 Survival Outcomes 
 
Progression-Free Survival is defined as the duration of time from registration to the time of 
progression, death, or date of last contact; those lost to follow-up will be censored. 
 
Overall Survival is defined as the duration of time from registration to date of death or date of 
last contact; those lost to follow-up will be censored. 
7.1.6 Response Review 
 

 
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Response will be assessed by the principal investigator(s) during the course of the study.  
 
Following study completion, responses may be reviewed by independent expert 
neuroradiologist(s). Simultaneous review of the patients’ files and radiological images is the best 
approach.  
8.0 
Adverse Events List and Reporting Requirements 
 
The Principal Investigator is responsible for ensuring that all staff involved in the study is familiar with the 
content of this section. 
8.1 
Safety Parameters 
 
Definition of adverse events:  
The International Conference on Harmonization (ICH) Guideline for Good Clinical Practice (GCP) E6(R1) 
defines an AE as: 
 
Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical 
product and which does not necessarily have a causal relationship with this treatment. An AE can therefore be 
any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal product, whether or not considered related to the medicinal 
product. 
 
An AE includes but is not limited to any clinically significant worsening of a subject’s pre-existing condition. An 
abnormal laboratory finding (including ECG finding) that requires an action or intervention by the investigator, or 
a finding judged by the investigator to represent a change beyond the range of normal physiologic fluctuation, 
should be reported as an AE. 
 
Adverse events may be treatment emergent (ie, occurring after initial receipt of investigational product) or 
nontreatment emergent. A nontreatment-emergent AE is any new sign or symptom, disease, or other untoward 
medical event that begins after written informed consent has been obtained but before the subject has received 
investigational product.  
 
Elective treatment or surgery or preplanned treatment or surgery (that was scheduled prior to the subject being 
enrolled into the study) for a documented pre-existing condition, that did not worsen from baseline, is not 
considered an AE (serious or nonserious). An untoward medical event occurring during the prescheduled 
elective procedure or routinely scheduled treatment should be recorded as an AE or SAE. 
 
The term AE is used to include both serious and non-serious AEs. 
 
Definition of serious adverse events 
A serious adverse event is an AE occurring during any study phase (i.e., screening, run-in, treatment, wash-
out, follow-up), at any dose of the study drugs that fulfils one or more of the following criteria: 
• 
Results in death 
• 
Is immediately life-threatening 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization  
• 
Results in persistent or significant disability or incapacity 

 
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• 
Is a congenital abnormality or birth defect in offspring of the subject 
• 
Is an important medical event that may jeopardize the patient or may require medical intervention to 
prevent one of the outcomes listed above. 
• 
Medical or scientific judgment should be exercised in deciding whether expedited reporting is appropriate in 
this situation. Examples of medically important events are intensive treatment in an emergency room or at 
home for allergic bronchospasm, blood dyscrasias, or convulsions that do not result in fatality 
The causality of SAEs (their relationship to all study treatment/procedures) will be assessed by the 
investigator(s). 
 
Definition of adverse events of special interest (AESI) 
An adverse event of special interest (AESI) is one of scientific and medical interest specific to understanding of 
the Investigational Product and may require close monitoring. An AESI may be serious or non-serious.  
 
AESIs for pembrolizumab include but are not limited to events with a potential inflammatory or immune-mediated 
mechanism and which may require more frequent monitoring and/or interventions such as steroids, 
immunosuppressants and/or hormone replacement therapy. These AESIs are being closely monitored in clinical 
studies with pembrolizumab monotherapy and combination therapy. An immune-related adverse event (irAE) is 
defined as an adverse event that is associated with drug exposure and is consistent with an immune-mediated 
mechanism of action and where there is no clear alternate aetiology. Serologic, immunologic, and histologic 
(biopsy) data, as appropriate, should be used to support an irAE diagnosis. Appropriate efforts should be made 
to rule out neoplastic, infectious, metabolic, toxin, or other etiologic causes of the irAE.  
 
AESIs observed with pembrolizumab include: 
• 
Colitis 
• 
Pneumonitis 
• 
ALT/AST increases / hepatitis / hepatotoxicity  
• 
Neuropathy / neuromuscular toxicity (i.e. events of encephalitis, peripheral motor and sensory 
neuropathies, Guillain-Barré, and myasthenia gravis) 
• 
Endocrinopathy (i.e. events of hypophysitis, adrenal insufficiency, and hyper- and hypothyroidism) 
• 
Dermatitis 
• 
Nephritis 
• 
Pancreatitis  (or labs suggestive of pancreatitis - increased serum lipase , increased serum amylase)   
 
Patients should be thoroughly evaluated to rule out any alternative etiology (e.g., disease progression, infections 
etc.) 
 
Steroids should be considered in the absence of clear alternative etiology even for low grade events (Grade 2), 
in order to prevent potential progression to higher grade event. 
 
 

 
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Severe and Fatal Immune-Mediated Adverse Reactions 
Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue 
and usually occur during treatment; however, they can also occur after discontinuation. Early identification and 
management are essential to ensuring safe use of PD-1–blocking antibodies. Monitor for symptoms and signs 
of immune-mediated adverse reactions. Evaluate clinical chemistries, including liver tests and thyroid function 
tests, at baseline and periodically during treatment. Institute medical management promptly to include specialty 
consultation as appropriate. 
 
In general, withhold pembrolizumab for Grade 3 or 4 and certain Grade 2 immune-mediated adverse reactions. 
Permanently discontinue pembrolizumab for Grade 4 and certain Grade 3 immune-mediated adverse 
reactions. For Grade 3 or 4 and certain Grade 2 immune-mediated adverse reactions, administer 
corticosteroids (1 to 2 mg/kg/day prednisone or equivalent) or other appropriate therapy until improvement to 
Grade 1 or less followed by a corticosteroid taper over 1 month. Consider administration of other systemic 
immunosuppressants in patients whose immune-mediated adverse reaction is not controlled with 
corticosteroids. Institute hormone replacement therapy for endocrinopathies as warranted. 
 
Immune-mediated pneumonitis: Immune-mediated pneumonitis occurred in about 2.5% of the patients 
treated with immune checkpoint inhibitors and leads to permanent discontinuation of the drug in about half of 
the patients. Systemic corticosteroids are required in all patients with pneumonitis. Withhold pembrolizumab for 
Grade 2, and permanently discontinue for Grade 3 or 4. Resume in patients with complete or partial resolution 
(Grade 0 to 1) after corticosteroid taper. 
 
Immune-mediated colitis: Immune-mediated colitis occur in about 1% of patients receiving immune 
checkpoint inhibitors leading to permanent discontinuation pembrolizumab in a small percent of patients. 
Systemic corticosteroids are required in all patients with colitis. Withhold pembrolizumab for Grade 2 or 3, and 
permanently discontinue for Grade 4. Resume in patients with complete or partial resolution (Grade 0 to 1) 
after corticosteroid taper. 
 
Immune-mediated hepatitis: Immune-mediated hepatitis occurred in general in about 2% of patients 
receiving immune checkpoint inhibitors. Systemic corticosteroids are required in all patients with hepatitis. 
Withhold pembrolizumab if AST or ALT increases to more than 3 and up to 10 times the upper limit of normal 
(ULN) or if total bilirubin increases up to 3 times the ULN. Permanently discontinue pembrolizumab if AST or 
ALT increases to more than 10 times the ULN or total bilirubin increases to more than 3 times the ULN. 
Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. 
 
Immune-mediated endocrinopathies: Withhold pembrolizumab if clinically necessary for Grade 2, 3, or 4. 
• 
Adrenal insufficiency: Adrenal insufficiency occurs in less than 1% of patients receiving immune 
checkpoint inhibitors 
• 
Hypophysitis: Hypophysitis, which can result in hypopituitarism, occurs very rarely, around 0.2% of 
patients on immune checkpoint inhibitors 
• 
Hypothyroidism: Hypothyroidism occurred in about 6% of patients receiving immune checkpoint 
inhibitors it is not necessary for the patients to discontinue  hormone replacement therapy 
• 
Hyperthyroidism: Hyperthyroidism occur in about 1.5% of patients receiving immune checkpoint 
inhibitors. 
• 
Type 1 diabetes mellitus: Type 1 diabetes mellitus, which can present with diabetic ketoacidosis, 
occurred in less than 1% of patients undergoing immune checkpoint inhibitors and leads to permanent 
discontinuation of the drug in exceptional cases.  
 

 
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Immune-mediated nephritis with renal dysfunction: Immune-mediated nephritis occurs in about 0.5% of 
patients receiving immune checkpoint inhibitors and leads to permanent discontinuation of the drug in about 
half of the patients. Systemic corticosteroids are required in all patients with nephritis. Withhold pembrolizumab 
for Grade 3, and permanently discontinue for Grade 4. Resume in patients with complete or partial resolution 
(Grade 0 to 1) after corticosteroid taper. 
 
Immune-mediated dermatologic adverse reactions: Immune-mediated dermatologic reactions, including 
erythema multiforme and pemphigoid, occur in about 2% of patients receiving immune checkpoint inhibitors. In 
addition, SJS and TEN have been observed with immune checkpoint inhibitors. Systemic corticosteroids are 
required in all patients with dermatologic reactions. Withhold pembrolizumab for Grade 3, and permanently 
discontinue for Grade 4. Resume in patients with complete or partial resolution (Grade 0 to 1) after 
corticosteroid taper. 
 
Other immune-mediated adverse reactions: The following clinically significant immune-mediated adverse 
reactions occur at an incidence of <1% of patients who receive immune checkpoint inhibitors. Severe or fatal 
cases have been reported for some of these adverse reactions. Withhold pembrolizumab for Grade 3, and 
permanently discontinue for Grade 4. Resume in patients with complete or partial resolution (Grade 0 to 1) 
after corticosteroid taper. 
• 
Neurological: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia 
gravis, Guillain-Barré syndrome, nerve paresis, and autoimmune neuropathy  
• 
Cardiovascular: Myocarditis, pericarditis, and vasculitides 
• 
Ocular: Uveitis, iritis, and other ocular inflammatory toxicities. Some cases can be associated with 
retinal detachment. Various Grades of visual impairment to include blindness can occur. If uveitis 
occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-
Harada–like syndrome, as this may require treatment with systemic corticosteroids to reduce the risk of 
permanent vision loss 
• 
Gastrointestinal: Pancreatitis to include increases in serum amylase and lipase levels, gastritis, and 
duodenitis 
• 
Musculoskeletal and connective tissue: Myositis, rhabdomyolysis, and associated sequelae, 
including renal failure, arthritis, and polymyalgia rheumatica 
• 
Hematological and immunological: Hemolytic anemia, aplastic anemia, hemophagocytic 
lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis 
(Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, and solid organ transplant 
rejection 
 
Infusion-related reactions 
Severe infusion-related reactions (Grade 3) occur in about 0.2% of patients receiving checkpoint inhibitors. 
Monitor patients for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for 
Grade 1 or 2, and permanently discontinue for Grade 3 or 4. 
 
Embryo-fetal toxicity 
Pembrolizumab can cause fetal harm when administered to a pregnant woman due to an increased risk of 
immune-mediated rejection of the developing fetus resulting in fetal death. Advise women of the potential risk 
to a fetus. Advise females of reproductive potential to use effective contraception during treatment with 
pembrolizumab and for at least 4 months after the last dose. 
 
Adverse reactions 

 
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• 
Serious adverse reactions occurred in 28% of patients. Serious adverse reactions that occurred in ≥2% 
of patients were cellulitis, sepsis, pneumonia, pneumonitis, and urinary tract infection. The most 
common Grade 3-4 adverse reactions (≥2%) were cellulitis, sepsis, hypertension, pneumonia, 
musculoskeletal pain, skin infection, urinary tract infection, and fatigue 
• 
pembrolizumab was permanently discontinued due to adverse reactions in 5% of patients; adverse 
reactions resulting in permanent discontinuation were pneumonitis, autoimmune myocarditis, hepatitis, 
aseptic meningitis, complex regional pain syndrome, cough, and muscular weakness 
• 
The most common adverse reactions (incidence ≥20%) were fatigue, rash, and diarrhea 
 
Assessment of safety parameters 
Assessment of severity 
Assessment of severity is one of the responsibilities of the investigator in the evaluation of 
AEs and SAEs. Severity will be graded according to the NCI CTCAE v 5.0. 
The determination of severity for all other events not listed in the CTCAE should be made by 
the investigator based upon medical judgment and the severity categories of Grade 1 to 5 as 
defined below.  
Grade 1 (mild)  
An event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere with usual 
activities of daily living. 
 
Grade 2 (moderate)  An event that is usually alleviated with additional specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the subject. 
 
Grade 3 (severe)  
An event that requires intensive therapeutic intervention. The event interrupts usual 
activities of daily living, or significantly affects the clinical status of the subject. 
 
Grade 4 (life threatening) An event, and/or its immediate sequelae, that is associated with 
an imminent risk of death or with physical or mental disabilities that affect or limit the 
ability of the subject to perform activities of daily living (eating, ambulation, toileting, etc). 
 
Grade 5 (fatal)  
Death (loss of life) as a result of an event. 
 
 
It is important to distinguish between serious criteria and severity of an AE. Severity is a measure of intensity 
whereas seriousness is defined by the criteria in Section 10.1.2. A Grade 3 AE need not necessarily be 
considered an SAE. For example, a Grade 3 headache that persists for several hours may not meet the 
regulatory definition of an SAE and would be considered a nonserious event, whereas a Grade 2 seizure 
resulting in a hospital admission would be considered an SAE. 
 
Assessment of relationship 
The Investigator will assess the causal relationship between the IP and each AE and answer 
“yes” or “no” to the question “Do you consider that there is a reasonable possibility that the 
event may have been caused by the investigational product?” 
 
For SAEs, causal relationship will also be assessed for other medications and study 
procedures. Note that, for SAEs that could be associated with any study procedure, the causal 
relationship is implied as “yes.” 

 
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When making an assessment of causality, consider the following factors when deciding if there is a 
“reasonable possibility” that an AE may have been caused by the drug. 
• 
Time Course. Exposure to suspect drug. Has the patient actually received the 
suspect drug? Did the AE occur in a reasonable temporal relationship to the 
administration of the suspect drug? 
 
• 
Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties? 
 
• 
De-challenge experience. Did the AE resolve or improve on stopping or reducing 
the dose of the suspect drug? 
 
• 
No alternative cause. The AE cannot be reasonably explained by another etiology 
such as the underlying disease, other drugs, or other host or environmental factors. 
 
• 
Laboratory tests. A specific laboratory investigation (if performed) has confirmed 
the relationship in difficult cases, other factors could be considered such as: 
- 
Is this a recognized feature of overdose of the drug? 
- 
Is there a known mechanism? 
 
Causality of “related” is made if, following a review of the relevant data, there is evidence for a “reasonable 
possibility” of a causal relationship for the individual case. The expression “reasonable possibility” of a causal 
relationship is meant to convey, in general, that there are facts (evidence) or arguments to suggest a causal 
relationship. The causality assessment is performed based on the available data including enough information 
to make an informed judgment. With limited or insufficient information in the case, it is likely that the event(s) 
will be assessed as “not related.” Causal relationship in cases where the disease under study has deteriorated 
due to lack of effect should be classified as no reasonable possibility. 
 
8.2 
Adverse Event Characteristics 
 
• 
CTCAE term (AE description) and grade:  The descriptions and grading scales found in 
the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will 
be utilized for AE reporting. All appropriate treatment areas should have access to a copy of 
the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be downloaded from the 
CTEP web site (http://ctep.cancer.gov). 
 
• 
‘Expectedness’: AEs can be ‘Unexpected’ or ‘Expected’ (see Section 7.1 above) for 
expedited reporting purposes only.   
 
• 
Attribution of the AE: 
 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 

 
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8.3 
STRC SAE Reporting Requirements 
 
The Data Safety Monitoring Committee (DSMC) is responsible for reviewing SAEs for WFBCCC 
Institutional studies as outlined in Appendix B. All Adverse Events that occur during protocol 
intervention and are coded as either 1) unexpected grade 4, 2) unplanned inpatient hospitalization ≥ 24 
hours (regardless of grade), or grade 5 (death) must be reported to the DSMC using the using the SAE 
console in WISER.  
 
All WFBCCC Clinical Protocol and Data Management (CPDM) staff members assisting a Principal 
Investigator in investigating, documenting and reporting an SAE qualifying for DSMC reporting are 
responsible for informing a clinical member of the DSMC as well as the entire committee via the email 
notification procedure of the occurrence of an SAE.  
 
8.4 
WFUHS IRB AE Reporting Requirements 
 
Any unanticipated problems involving risks to subjects or others and adverse events shall be promptly 
reported to the IRB, according to institutional policy. Reporting to the IRB is required regardless of the 
funding source, study sponsor, or whether the event involves an investigational or marketed drug, 
biologic or device. Reportable events are not limited to physical injury, but include psychological, 
economic and social harm. Reportable events may arise as a result of drugs, biological agents, 
devices, procedures or other interventions, or as a result of questionnaires, surveys, observations or 
other interactions with research subjects. 
 
All members of the research team are responsible for the appropriate reporting to the IRB and other 
applicable parties of unanticipated problems involving risk to subjects or others. The Principal 
Investigator, however, is ultimately responsible for ensuring the prompt reporting of unanticipated 
problems involving risk to subjects or others to the IRB. The Principal Investigator is also responsible 
for ensuring that all reported unanticipated risks to subjects and others which they receive are reviewed 
to determine whether the report represents a change in the risks and/or benefits to study participants, 
and whether any changes in the informed consent, protocol or other study-related documents are 
required. 
 
Any unanticipated problems involving risks to subjects or others occurring at a site where the study has 
been approved by the WFUHS IRB (internal events) must be reported to the WFUHS IRB within 7 
calendar days of the investigator or other members of the study team becoming aware of the event. 
 
Any unanticipated problems involving risks to subjects or others occurring at another site conducting 
the same study that has been approved by the WFUHS IRB (external events) must be reported to the 
WFUHS IRB within 7 calendar days of the investigator or other members of the study team becoming 
aware of the event. 
 
Any event, incident, experience, or outcome that alters the risk versus potential benefit of the research 
and as a result warrants a substantive change in the research protocol or informed consent 
process/document in order to insure the safety, rights or welfare of research subjects. 

 
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9.0 
Correlative/Special Studies 
 
9.1 
Laboratory Correlative Studies 
 
Biological sampling procedures 
Immunogenicity sampling and evaluation methods 
 
• Saliva and blood for correlative studies will be collected as described in Section 4.2.  
• Blood specimens will be drawn into EDTA tubes. Samples will be labelled and transported at 
room temperature within one hour to Dr. Furdui laboratory in Nutrition Building 2nd floor  for 
isolation of plasma and exosomes, which will then be frozen in liq N2 for long-term storage until 
the completion of study. 
• A portion of plasma will be submitted to Dr. Triozzi’s lab for measurement of immune micro 
RNA. 
• A portion of the blood sample will be submitted to Dr. Wei Zhang’s lab for single cell RNA 
sequencing.  
 
Saliva collection procedures 
• We will target collection of 5 ml saliva from each patient.   
 
Saliva Collection Recommendations 
• Participants should not eat or brush their teeth within 4h prior to sample collection. 
• Dental work should not be performed within 24 hours prior to sample collection. 
• Saliva samples visibly contaminated with blood should be discarded and recollected. 
Contamination that is not visible is not of concern for this study.  
• For saliva sample collection we will use 50 ml Falcon tube kept on ice. 5 mL of saliva will be 
collected.  
 
Instructions for Collecting Saliva 
1. Remove cap from tube. We will use laboratory tubes with large diameter.  
2. Instruct participants to allow saliva to pool in the mouth. Some find it helpful to imagine eating 
their favorite food. 
3. With head tilted forward, participants should drool through the SCA to collect saliva in the tube. 
4. Replace cap onto tube. 
5. Place label immediately. 
6. Place tube in refrigerator and transport as soon as possible in an ice box.  
7. Samples will be transported within one hour to Dr. Furdui’s laboratory in Nutrition building.  
Saliva samples will be processed immediately after collection.  
 
Proteomics 
For global protein identification analysis, 10 µL of plasma will be purified by passing through a Pierce 
top-2 abundant protein depletion spin column before protein extraction. Protein will be reduced and 
alkylated by treatment with dithiothreitol (DTT) and iodoacetamide (IAM), and then will be precipitated 
by adding four times the sample volume of cold acetone with incubation at -20°C. 10 ug of protein 
extracted from the exosome fraction will be similarly processed. Protein pellet will be air-dried at room 
temperature and re-suspended in 50 mM ammonium bicarbonate. 5 – 25 µg of protein will be taken and 
digested with sequencing-grade modified trypsin. The peptide mixture will be acidified to quench 
enzyme activity and purified using a C18 desalting spin column. Peptides will be prepared in 5% (v/v) 

 
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ACN containing 1% (v/v) formic acid and analyzed on an Orbitrap Velos Pro Mass Spectrometer 
(Thermo Scientific, Waltham, MA) with a Dionex Ultimate-3000 nano-UPLC system (Thermo Scientific, 
Waltham, MA).  The LC-MS/MS system will be equipped with an Acclaim PepMap 100 (C18, 5 μm, 100 
Å, 100 μm x 2 cm) trap column and an Acclaim PepMap RSLC (C18, 2 μm, 100 Å, 75 μm x 50 cm) 
analytical column for peptide separation. MS spectra will be acquired by data dependent scans 
consisting of MS/MS scans of the ten most intense ions from the full MS scan with dynamic exclusion 
option. To identify proteins, spectra will be searched using Sequest HT algorithm within the Proteome 
Discoverer v2.2 (Thermo Scientific, Waltham, MA) in combination with the UniProt protein FASTA 
database. Search results will contain description of identified proteins or compounds with their peak 
areas which represent relative abundance. Data will be exported and finalized in Microsoft Excel 
spreadsheet format for further statistical analysis. 
 
Metabolomics 
For metabolomics analysis, 50 µL of plasma or exosome suspension spiked with an internal standard, 
2-morpholinoethanesulfonic acid (MES) will be mixed with four times the sample volume of cold 
methanol. Supernatant will be obtained from centrifugation, which will be dried down and re-constituted 
in water for LC-MS/MS analysis. Sample will be analyzed on a Q Exactive HF hybrid quadrupole-
Orbitrap mass spectrometer (Thermo Scientific, Waltham, MA) combined with a Vanquish UHPLC 
system (Thermo Scientific, Waltham, MA). Metabolites will be separated on an Ultra PFPP column (3 
µm, 2.1 mm x 150 mm, Restek, Bellefonte, PA) using a linear gradient with 100% water (mobile phase 
A) and 90% acetonitrile (mobile phase B) both of which equally contain 0.1% formic acid and 10mM 
ammonium formate. Compound Discoverer v2.1 (Thermo Scientific, Waltham, MA) will be used for 
metabolite annotation and relative quantification. Search results will contain description of identified 
compounds with their peak areas which represent relative abundance. Data will be exported and 
finalized in Microsoft Excel spreadsheet format for further statistical analysis. 
 
Untargeted proteomics and metabolomics data processing 
We will utilize an integrated mixomics data processing pipeline to align and interpret proteomic and 
metabolomics profiles to identify drivers of response to immunotherapy with prior quad-shot treatment. 
Expression of the top five candidate biomarkers identified, as determined by predictive value and fold-
expression, will be secondarily validated by Western blot or mass spectrometry-based targeted analysis 
using standard techniques.  
 
Immune microRNA (miRs) measurements 
Levels of immune-regulatory miRs will be quantified in plasma using PCR-based techniques. 
 
miRs are important regulators of immune response miRs negatively regulate gene expression by base 
pairing with the 3′ untranslated region of their target mRNAs. Most cellular processes, both 
physiological and pathological, are affected. These include differentiation, development, metabolism, 
proliferation, death, viral infection, and malignant transformation. Recent studies have shown that miRs 
play a critical role in regulating the development of immune cells and in modulating innate and adaptive 
immune responses. Several miRs, referred to as “immunomiRs,” have been identified. miR-125b, 155, 
181a, and miRs of the 17-92 complex play central roles in T-cell; miR 146a and 155, in NK cell; miR-
155 and 146a, in dendritic cell; miR 125b, 146a, 155, and miRs of the 17-92 complex, in T regulatory 
cell; and miR-223, in myeloid derived suppressor cell development and function. Because of their low 
complexity (when compared to proteins), their stability, and highly sensitive detection methods, miRs 
are attractive biomarkers. Because of incorporation in microparticles and exosomes, miRs are stable 
and can be measured in blood and several other body fluids, including saliva.  

 
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Total RNA will be isolated from plasma and saliva using the miRNeasy Mini Kit (Qiagen). Reverse 
transcription reactions are performed using a TaqMan MicroRNA Reverse Transcription Kit (Applied 
Biosystems) according to the manufacturer’s instructions. qRT-PCR will be performed using the reverse 
transcription reaction product, TaqMan MicroRNA Assay kits, and TaqMan Universal PCR Master Mix 
(Applied Biosystems. Data are normalized to a C. elegans synthetic miR sequence, cel miR-39 
(Qiagen), which is spiked in as a control during RNA isolation.  
 
Single cell RNA-sequencing in blood before and after treatment.  
We propose to examine our blood samples collected before and after treatment with Pembrolizumab by 
single cell sequencing experiments at the Cancer Genomics Shared Resource and data analyzed by 
the Bioinformatics Shared Resources to determine the complex response in the immune cell 
populations. PBMCs from selected patients are thawed, assessed for > 70% viability, and then 
processed for single cell gene expression using the Next GEM Single Cell 3’ GEM, Library & Gel Bead 
Kit v3.1 and 10X Genomics Chromium platform. Barcoded UMI-tagged libraries are sequenced on an 
Illumina NovaSeq 6000 targeting 4000 cells per sample at a median read depth of 50,000 reads per 
cell. Raw bcl and fastq data will be demultiplexed, normalized and post-processed using Cell Ranger 
mkfastq pipelines and QC algorithms (10X Genomics). The Cell Ranger mkfastq pipelines (10X 
Genomics) is used to process, QC and align sequencing reads and to optimize cell calling.  Graph-
based or K-means clustering algorithms implemented in Cell Ranger are applied to delineate 
populations of diverse immune cell lineages whose identities are frequently confirmed by the presence 
or absence of marker gene combinations informed by antibody-based cell sorting and identification 
methods, or published transcriptional signatures of FACS-sorted immune cells (42-44). 
scRNAseq data processing. Transcript read counts will be normalized and statistically compared for 
differential expression between patients using DESeq2 [2] that applies the negative binomial model with 
independent dispersions. Differentially expressed genes (DEGs; FDR-corrected, p<0.05) will be 
analyzed by Ingenuity Pathway Analysis (IPA, www.ingenuity.com) and Gene Set Enrichment Analysis 
(GSEA) [3] to identify gene enrichment for biological processes or signaling pathways that underlie 
response.  
 
Red Blood Cells (RBCs) that are left over after the isolation of plasma for metabolomics and miRNA 
measurement, and of PBMCs for the scRNA sequencing, instead of being discarded as per routine 
protocols, will be saved and utilized for testing the optimization of protocols designed to quench redox 
metabolism. Redox metabolism is tightly associated with all aspects of cancer pathophysiology, 
including response to immunotherapy and radiotherapy. However, redox metabolism remains 
inadequately studied and utilized in clinic due to the lack of appropriate biospecimen preservation 
technologies. RBC, a valuable source of redox components, will be washed and either used 
immediately for testing of redox preservation media or stored for future use.   
Currently, simple banking of whole blood or its components fails to capture an accurate redox status of 
blood or tissues because of artifacts introduced by handling and the absence of redox preservation 
mechanism.   
 
The research-dedicated blood samples are de-identified by the clinical study team such that a study 
research ID replaces any subject identifier (MRN, name). The clinical study team securely maintains 
the key for study IDs and patient information.   
 
Remaining samples will be retained for future research after the study report has been finalized if 
agreed by patients in the ICF. Otherwise, it will be disposed.  
 

 
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Oral microbiota profiling will be performed using 16S rRNA gene sequencing to characterize the 
bacterial diversity and composition in the saliva collected from these patients at indicated time points 
before and during treatment.  
 
PD-L1 Testing 
To ensure comparability of data across all studies of pembrolizumab and to gain real world experience 
on the performance of this assay, it is strongly encouraged that all studies that include PD-L1 testing 
utilize the Dako 22C3 assay.   
Estimate of volume of blood to be collected for research purposes 
 
The total volume of blood that will be drawn from each subject in this study is as follows: 
Volume of Blood to Be Drawn From Each Subject 
Assessment 
Sample volume 
(mL) 
No. of samples 
Total volume (mL) 
Immune Studies 
20                              7 
140 
Additional Research Samples 
(with patient’s consent per ICF) 
20 
7 
140 
Total: 280 ml 
 
 
 
Three additional samples of blood (120 ml) will be collected for each additional quad-shot treatment ( blood 
collection before starting radiotherapy and before each cycle of pembrolizumab administered before and after 
the quad-shot treatment) 
 
Withdrawal of informed consent for donated biological samples 
If a subject withdraws consent to the use of donated samples, the samples will be disposed 
of/destroyed, and the action documented.   
 
The Principal Investigator: 
• 
Ensures that biological samples from that subject, if stored at the study site, are immediately 
identified, disposed of /destroyed, and the action documented. 
• 
Ensures the laboratory(ies) holding the samples is/are informed about the withdrawn consent 
immediately and that samples are disposed/destroyed. 
• 
Ensures that the subject is informed about the sample disposal. 
10.0 Pharmaceutical Information 
 
A list of the adverse events and potential risks associated with the investigational or 
commercial agents administered in this study can be found in Section 10.1.3. 
 
Pharmaceutical Accountability 
 
Drug accountability logs will be maintained for all [investigative (if appropriate)] agents 
used under this protocol. These logs shall record quantities of study drug received and 
quantities dispensed to patients, including lot number, date dispensed, patient identifier 
number, patient initials, protocol number, dose, quantity returned, balance remaining, 
and the initials of the person dispensing the medication. 

 
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11.0 Statistical Considerations 
11.1 Analysis of Primary Objective 
 
 
11.1.1 For this pilot study, the primary analytic objective is to measure the overall response rate 
measured according to RECIST criteria and determine the percent of patients with either 
a partial or complete response (PR or CR) and the corresponding 95% Clopper Pearson 
exact confidence interval.  This estimate will provide useful information concerning the 
potential efficacy of this treatment for planning future studies. 
11.2 Analysis of Secondary Objective 
 
There are 6 secondary outcomes of interest for this pilot study.  These are 1) response rate for 
the target lesion; 2) response rate for non-target lesions 3) duration of response for the target 
lesion 4) progression free survival (PFS) 5) overall survival (OS) and tolerability assessed using 
PRO-CTCAE.  We now describe our analytic approach for each measure.  
 
For the response rate measures we will estimate the percent of responders (PR or CR) and the 
corresponding 95% Clopper Pearson exact confidence intervals. For the duration of response, 
among responders we will estimate both the mean and median duration and the corresponding 
95% confidence intervals for the mean and inter-quartile range for the median.  For time to 
event measures (PFS and OS) we will estimate Kaplan Meier survival curves and estimate the 
median time to event times as well as the percent PFS and OS at 6 months and 1 year post 
treatment.  For tolerability, we will estimate the percent of patients with different AEs assessed 
using the PRO-CTCAE and corresponding 95% Clopper Pearson exact confidence intervals. 
  
11.3 Power and Sample Size 
 
Since this is a pilot study there will be no formal hypothesis tests performed.  With a sample size 
of 15 evaluable patients (patients must be evaluable for objective response as described in 
Section 7.1.1), the maximum width of a 95% Clopper Pearson exact confidence interval is 0.52 
(since the interval may not be symmetric this corresponds to approximately +/- 0.26 (if the 
response rate is as high as 7/15).  If the response rate is lower than this then the width of the 
confidence interval will be less.  With this sample size we will be able to determine whether the 
response rate in this treatment is high enough to warrant future examination. Based on 
preliminary data presented in Table 1 the response rates from previous studies is between 13 
and 36% thus we would anticipate that the response rate in this study will need to be at least 
this high to warrant future studies.  
 
11.4 Estimated Accrual Rate 
 
According to the TriNetX tool (live.trinetx.com), using the query as defined below, the Wake 
Forest Baptist Medical Center has seen an average of 2.6 historic arrivals per month over the 
past 3 years. Using the predicted arrivals tool, 3.5 arrivals per month are expected over the next 
1 year. Considering ineligibility and patient declination, we expect to accrue 15 evaluable 
patients over the course of 2 years. This would correspond to approximately 0.7 patients per 
month being accrued (meaning 20% of the arrivals per month participating).  
 

 
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11.5 Estimated Study Length 
 
We anticipate that accrual will be accomplished within 21 months and then follow-up for 
response can be finished within approximately 3 months, thus this study should be completed 
within approximately 24 months once accrual commences.  
12.0 Ethical and regulatory requirements 
 
12.1 Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, and applicable regulatory 
requirements Subject data protection. 
12.2 Ethics and regulatory review 
Institutional Review Board (IRB) will approve the final study protocol, including the final version of the 
ICF and any other written information and/or materials to be provided to the patients. The 
Investigator will ensure the distribution of these documents to the IRB and to the study site staff. 
The opinion of IRB should be given in writing.  
The protocol should be re-approved by the IRB annually. Before enrollment of any patient into the 
study, the final study protocol, including the final version of the ICF, should be approved by the 

 
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national regulatory authority or a notification to the national regulatory authority should be approved, 
according to local regulations.  
Principal Investigator is responsible for providing the IRB with reports of any serious and unexpected 
adverse drug reactions from any other study conducted with the IP.  
12.3 Informed consent 
 
The Principal Investigator will: 
 
• Ensure that each patient is given full and adequate oral and written information about the 
nature, purpose, possible risk, and benefit of the study 
• Ensure that each patient is notified that he or she is free to discontinue from the study at any 
time 
• Ensure that each patient is given the opportunity to ask questions and allowed time to consider 
the information provided 
• Ensure that each patient provides a signed and dated informed consent before conducting any 
procedure specifically for the study 
• Ensure that the original, signed ICF(s) is/are stored in the Investigator’s Study File 
• Ensure that a copy of the signed ICF is given to the patient 
• Ensure that any incentives for patients who participate in the study as well as any provisions 
for patients harmed as a consequence of study participation are described in the ICF that is 
approved by an EC/IRB. 
 
Changes to the protocol and informed consent form 
If there are any substantial changes to the study protocol, then these changes will be documented in 
a study protocol amendment and, where required, in a new version of the study protocol (revised 
clinical study protocol). The amendment is to be approved by the relevant IRB and, if applicable, the 
national regulatory authority, before implementation. Local requirements will be followed for revised 
protocols. 
 
12.4 Audits and inspections 
 
The CCCWFU, a  regulatory authority, or IRB may perform audits or inspections at the center, 
including source data verification. The purpose of an audit or inspection is to systematically and 
independently examine all study-related activities and documents, to determine whether these 

 
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activities were conducted, and to determine if data were recorded, analyzed, and accurately reported 
according to the protocol, GCPs, ICH 
guidelines, and any applicable regulatory requirements. The Investigator will contact AstraZeneca 
immediately if contacted by a regulatory agency about an inspection at the center. 
13.0 Study Management 
13.1 Training of study site personnel 
 
The Principal Investigator will ensure that appropriate training relevant to the study is given to all of 
these staff and that any new information relevant to the performance of this study is forwarded to the 
staff involved. 
 
13.2 Data Management 
 
Informed consent document 
EPIC 
Protocol registration form 
WISER/OnCore 
Off Study, Off Treament,Survival 
WISER/OnCore 
Pre-toxicity 
WISER/OnCore 
Cycle Tracking 
Redcap 
Adverse Events Log 
WISER/OnCore 
Treatment Response Evaluation 
Redcap 
Evaluation of Best Overall Response 
WISER/OnCore 
Tumor Measurement 
Redcap 
PRO-CTCAE 
Redcap 
Comorbidites 
Redcap 
Specimen Tracking 
Redcap 
Tobacco Use 
Redcap 
Withdrawal of Consent for the 
Intervention 
WISER/OnCore 
Follow up post washout 
WISER/OnCore 
Demographics 
Redcap 
Medications 
Redcap 
ECOG Status 
WISER/OnCore 
 
13.3 Confidentiality and Privacy 
 
Confidentiality will be protected by collecting only information needed to assess study outcomes, 
minimizing to the fullest extent possible the collection of any information that could directly identify 
subjects, and maintaining all study information in a secure manner. To help ensure subject privacy 
and confidentiality, only a unique study identifier will appear on the data collection form. Any collected 
patient identifying information corresponding to the unique study identifier will be maintained on a 
linkage file, store separately from the data. The linkage file will be kept secure, with access limited to 

 
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designated study personnel. Following data collection subject identifying information will be destroyed 
(state the anticipated time the data will be destroyed, e.g. three years after closure of the study, and 
the method of destruction), consistent with data validation and study design, producing an 
anonymous analytical data set. Data access will be limited to study staff. Data and records will be 
kept locked and secured, with any computer data password protected. No reference to any individual 
participant will appear in reports, presentations, or publications that may arise from the study. 
 
13.4 Data Safety and Monitoring  
 
The principal investigator will be responsible for the overall monitoring of the data and safety of study 
participants. The principal investigator will be assisted by other members of the study staff. 
 
13.5 Reporting of Unanticipated Problems, Adverse Events or Deviations 
 
Any unanticipated problems, serious and unexpected adverse events, deviations or protocol changes will be 
promptly reported by the principal investigator or designated member of the research team to the IRB and 
sponsor or appropriate government agency if appropriate.

 
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squamous cell carcinoma. The Journal of Laryngology & Otology. 2002;116(4):269-71. 
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Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, et al. Platinum-based 
chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 2008;359(11):1116-27. 
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Ferris RL, Blumenschein G, Jr., Fayette J, Guigay J, Colevas AD, Licitra L, et al. Nivolumab for 
Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med. 2016;375(19):1856-67. 
11. 
Seiwert TY, Burtness B, Mehra R, Weiss J, Berger R, Eder JP, et al. Safety and clinical activity of 
pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck 
(KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol. 2016;17(7):956-65. 
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Chow LQM, Haddad R, Gupta S, Mahipal A, Mehra R, Tahara M, et al. Antitumor Activity of 
Pembrolizumab in Biomarker-Unselected Patients With Recurrent and/or Metastatic Head and Neck 
Squamous Cell Carcinoma: Results From the Phase Ib KEYNOTE-012 Expansion Cohort. J Clin Oncol. 
2016;34(32):3838-45. 
13. 
Cohen EEW, Soulieres D, Le Tourneau C, Dinis J, Licitra L, Ahn MJ, et al. Pembrolizumab versus 
methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma 
(KEYNOTE-040): a randomised, open-label, phase 3 study. Lancet. 2019;393(10167):156-67. 
14. 
Burtness B, Harrington KJ, Greil R, Soulieres D, Tahara M, de Castro G, Jr., et al. Pembrolizumab 
alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell 
carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet. 
2019;394(10212):1915-28. 
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Shahid Iqbal M, Kelly C, Kovarik J, Goranov B, Shaikh G, Morgan D, et al. Palliative radiotherapy for 
locally advanced non-metastatic head and neck cancer: A systematic review. Radiother Oncol. 
2018;126(3):558-67. 
16. 
Spanos W, Jr., Guse C, Perez C, Grigsby P, Doggett RL, Poulter C. Phase II study of multiple daily 
fractionations in the palliation of advanced pelvic malignancies: preliminary report of RTOG 8502. Int J Radiat 
Oncol Biol Phys. 1989;17(3):659-61. 
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Paris KJ, Spanos WJ, Lindberg RD, Jose B, Albrink F. Phase I–II study of multiple daily fractions for 
palliation of advanced head and neck malignancies. International Journal of Radiation 
Oncology*Biology*Physics. 1993;25(4):657-60. 

 
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18. 
Lok BH, Jiang G, Gutiontov S, Lanning RM, Sridhara S, Sherman EJ, et al. Palliative head and neck 
radiotherapy with the RTOG 8502 regimen for incurable primary or metastatic cancers. Oral Oncol. 
2015;51(10):957-62. 
19. 
Corry J, Peters LJ, D'Costa I, Milner AD, Fawns H, Rischin D, et al. The ‘QUAD SHOT’—a phase II 
study of palliative radiotherapy for incurable head and neck cancer. Radiother Oncol. 2005;77(2):137-42. 
20. 
Finnegan TS, Bhatt NH, Shaughnessy JN, Perez C, Redman R, Silverman C, et al. Cyclical 
hypofractionated radiotherapy technique for palliative treatment of locally advanced head and neck cancer: 
institutional experience and review of palliative regimens. J Community Support Oncol. 2016;14(1):29-36. 
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Carrascosa LA, Yashar CM, Paris KJ, Larocca RV, Faught SR, Spanos WJ. Palliation of Pelvic and 
Head and Neck Cancer with Paclitaxel and a Novel Radiotherapy Regimen. Journal of Palliative Medicine. 
2007;10(4):877-81. 
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Chen AM, Vaughan A, Narayan S, Vijayakumar S. Palliative radiation therapy for head and neck 
cancer: toward an optimal fractionation scheme. Head Neck. 2008;30(12):1586-91. 
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Gamez ME, Agarwal M, Hu KS, Lukens JN, Harrison LB. Hypofractionated Palliative Radiotherapy with 
Concurrent Radiosensitizing Chemotherapy for Advanced Head and Neck Cancer Using the "QUAD-SHOT 
Regimen". Anticancer Res. 2017;37(2):685-91. 
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Arnold KM, Flynn NJ, Raben A, Romak L, Yu Y, Dicker AP, et al. The Impact of Radiation on the Tumor 
Microenvironment: Effect of Dose and Fractionation Schedules. Cancer Growth Metastasis. 
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Manukian G, Bar-Ad V, Lu B, Argiris A, Johnson JM. Combining Radiation and Immune Checkpoint 
Blockade in the Treatment of Head and Neck Squamous Cell Carcinoma. Front Oncol. 2019;9:122-. 
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Demaria S, Kawashima N, Yang AM, Devitt ML, Babb JS, Allison JP, et al. Immune-Mediated Inhibition 
of Metastases after Treatment with Local Radiation and CTLA-4 Blockade in a Mouse Model of Breast Cancer. 
Clinical Cancer Research. 2005;11(2):728. 
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Dovedi SJ, Adlard AL, Lipowska-Bhalla G, McKenna C, Jones S, Cheadle EJ, et al. Acquired 
Resistance to Fractionated Radiotherapy Can Be Overcome by Concurrent PD-L1 Blockade. Cancer 
Research. 2014;74(19):5458. 
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Demaria S, Formenti SC. Radiation as an immunological adjuvant: current evidence on dose and 
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Signaling in Tumors Mediates Resistance to Anti-PD-1 Treatment That Can Be Overcome by Radiotherapy. 
Cancer Res. 2017;77(4):839-50. 
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Friedman D, Baird JR, Young KH, Cottam B, Crittenden MR, Friedman S, et al. Programmed cell 
death-1 blockade enhances response to stereotactic radiation in an orthotopic murine model of hepatocellular 
carcinoma. Hepatology Research. 2017;47(7):702-14. 
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Crittenden MR, Zebertavage L, Kramer G, Bambina S, Friedman D, Troesch V, et al. Tumor cure by 
radiation therapy and checkpoint inhibitors depends on pre-existing immunity. Scientific Reports. 
2018;8(1):7012. 
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Dewan MZ, Galloway AE, Kawashima N, Dewyngaert JK, Babb JS, Formenti SC, et al. Fractionated 
but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-
CTLA-4 antibody. Clinical cancer research : an official journal of the American Association for Cancer 
Research. 2009;15(17):5379-88. 
33. 
Young KH, Baird JR, Savage T, Cottam B, Friedman D, Bambina S, et al. Optimizing Timing of 
Immunotherapy Improves Control of Tumors by Hypofractionated Radiation Therapy. PLOS ONE. 
2016;11(6):e0157164. 
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Centanni M, Moes DJAR, Trocóniz IF, Ciccolini J, van Hasselt JGC. Clinical Pharmacokinetics and 
Pharmacodynamics of Immune Checkpoint Inhibitors. Clinical Pharmacokinetics. 2019;58(7):835-57. 

 
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35. 
Shinde A, Novak J, Freeman ML, Glaser S, Amini A. Induction of the Abscopal Effect with 
Immunotherapy and Palliative Radiation in Metastatic Head and Neck Squamous Cell Carcinoma: A Case 
Report and Review of the Literature. Cureus. 2019;11(3):e4201. 
36. 
Ferris RL, Gillison ML, Harris J, Colevas AD, Mell LK, Kong C, et al. Safety evaluation of nivolumab 
(Nivo) concomitant with cetuximab-radiotherapy for intermediate (IR) and high-risk (HR) local-regionally 
advanced head and neck squamous cell carcinoma (HNSCC): RTOG 3504. Journal of Clinical Oncology. 
2018;36(15_suppl):6010-. 
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Gillison ML, Ferris RL, Harris J, Colevas AD, Mell LK, Kong C, et al. Safety and disease control 
achieved with the addition of nivolumab (Nivo) to chemoradiotherapy (CRT) for intermediate (IR) and high-risk 
(HR) local-regionally advanced head and neck squamous cell carcinoma (HNSCC): RTOG Foundation 3504. 
Journal of Clinical Oncology. 2019;37(15_suppl):6073-. 
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Welsh JW, Heymach JV, Chen D, Verma V, Cushman TR, Hess KR, et al. Phase I Trial of 
Pembrolizumab and Radiation Therapy after Induction Chemotherapy for Extensive-Stage Small Cell Lung 
Cancer. Journal of Thoracic Oncology. 2020;15(2):266-73. 
39. 
Wong S, Torres-Saavedra P, Le QT, Chung C, Jang S, Huq MS, et al. Safety of reRT with SBRT plus 
concurrent and adjuvant pembrolizumab in patients with recurrent or new second primary head and neck 
squamous cell cancer in a previously irradiated field: RTOG 3507 Foundation (KEYSTROKE). International 
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Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-47. 
 

 
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The following Appendices are required for all WFBCCC cancer treatment protocols. 
 
Add additional appendices as needed. 
 
ALL data collection forms must be included as protocol appendices at the time the protocol is submitted to the 
WFBCCC Protocol Review Committee (PRC) for review. 
 

 
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Appendix A – Eligibility Checklist 
 
 
IRB Protocol No.  
WFBCCC Protocol No. 
Study Title: Quad-Shot Radiotherapy in Combination with Immune Checkpoint Inhibition for 
Advanced/Recurrent Head and Neck Cancer 
Principal Investigator:  Dr. Mercedes Porosnicu 
 
Inclusion Criteria 
(as outlined in study protocol) 
Criteria 
is met 
Criteria 
is NOT 
met 
Source Used to Confirm * 
(Please document dates and 
lab results) 
Advanced, recurrent or metastatic head and neck squamous cell carcinoma, as defined by clinical or 
pathological diagnosis of any of the following: 
 
 
Locally advanced head and neck squamous cell 
carcinoma not suitable for curative local treatment. 
 
□ 
□ 
 
Locally recurrent head and neck squamous cell 
carcinoma not suitable for curative local treatment within 
or outside a previously irradiated tissue. 
 
□ 
□ 
 
Metastatic head and neck squamous cell carcinoma. 
 
□ 
□ 
 
Target site in the head and neck region amenable to 
quad-shot palliative radiotherapy, as determined by the 
treating radiation oncologist. 
 
□ 
□ 
 
Age 18 years or greater at time of registration 
 
□ 
□ 
 
 
ECOG Performance Status of 0-2. 
 
□ 
□ 
 
Women of child-bearing potential and men must agree to 
use adequate contraception (hormonal or barrier method 
of birth control; abstinence) prior to study entry and for 
the duration of study participation. Should a woman 
become pregnant or suspect she is pregnant while 
participating in this study, she should inform her treating 
physician immediately. 
 
□ 
□ 
 
Ability to understand and the willingness to sign an IRB-
approved informed consent document (either directly or 
via a legally authorized representative). 
 
□ 
□ 
 
Willingness to provide blood and saliva samples for 
exploratory research purposes 
□ 
□ 
 

 
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Organ and Marrow Function as defined below:  
 
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 
 
□ 
□ 
 
Platelet count ≥ 100 x 109/L 
 
□ 
□ 
 
Hemoglobin ≥ 9.0 g/dL 
 
□ 
□ 
 
Serum bilirubin ≤ 1.5 x ULN (institutional upper limit of 
normal) 
 
□ 
□ 
 
AST and ALT ≤ 2.5 x ULN (institutional upper limit of 
normal) 
 
□ 
□ 
 
Serum creatinine CL>40 mL/min by the Cockcroft-Gault 
formula (Cockcroft and Gault 1976) or by 24-hour urine 
collection for determination of creatinine clearance: 
Males: 
 
 
Creatinine 
CL (mL/min) 
= Weight (kg) x (140 – Age)       . 
72 x serum creatinine (mg/dL) 
Females 
 
 
Creatinine 
CL (mL/min) 
= Weight (kg) x (140 – Age)       x 0.85 
72 x serum creatinine (mg/dL) 
□ 
□ 
 
Exclusion Criteria 
(as outlined in study protocol) 
Criteria 
NOT 
present 
Criteria 
is 
present 
Source Used to Confirm * 
(Please document dates and 
lab results) 
Radiation therapy to the head and neck region within 30 
days of registration. 
 
□ 
□ 
 
Prior radiotherapy to the head and neck that precludes 
safe delivery of study radiotherapy, as determined by the 
treating radiation oncologist. 
 
□ 
□ 
 
Active medical conditions that are contraindications to 
study radiotherapy (i.e. scleroderma), as determined by 
the treating radiation oncologist.  
 
□ 
□ 
 
Pregnant or lactating women are excluded from this 
study because radiotherapy is contraindicated in 
pregnancy and because there is an unknown but 
potential risk for adverse events in nursing infants 
secondary to treatment of the mother with 
immunotherapy. 
 
□ 
□ 
 
Participation in another clinical study with an 
investigational product during the last 3 months. 
□ 
□ 
 

 
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Any previous treatment with a PD1 or PD-L1 inhibitor 
□ 
□ 
 
Any anti-cancer therapy (chemotherapy, immunotherapy, 
endocrine therapy, targeted therapy, biologic therapy, 
tumor embolization, monoclonal antibodies, other 
investigational agent) within the last 30 days.  
 
□ 
□ 
 
Mean QT interval corrected for heart rate (QTc) ≥470 
ms. except for patients with pacemaker who have a 
paced ventricular rhythm 
 
□ 
□ 
 
Current or prior use of immunosuppressive medication 
within 30 days, with exceptions of intranasal and inhaled 
corticosteroids or systemic corticosteroids at 
physiological doses, which are not to exceed 10 mg/day 
of prednisone, or an equivalent corticosteroid.and with 
the exception of a short course of prednisone that is 
prescribed for acute allergic situations or for prevention 
of an allergy to contrast substance utilized for imaging 
studies. 
 
□ 
□ 
 
Any unresolved toxicity (>CTCAE grade > 2) from 
previous anti-cancer therapy. Subjects with irreversible 
toxicity that is not reasonably expected to be 
exacerbated by the investigational product may be 
included (e.g., hearing loss, peripherally neuropathy).  
 
□ 
□ 
 
Any prior Grade ≥3 immune-related adverse event (irAE) 
while receiving any previous immunotherapy agent, or 
any unresolved irAE >Grade 1. 
 
□ 
□ 
 
Active or prior documented autoimmune disease within 
the past 2 years 
NOTE: Subjects with vitiligo, Grave’s disease, or 
psoriasis not requiring systemic treatment (within the 
past 2 years) are not excluded. 
 
□ 
□ 
 
Active or prior documented inflammatory bowel disease 
(e.g., Crohn’s disease, ulcerative colitis). 
□ 
□ 
 
History of primary immunodeficiency. 
 
□ 
□ 
 
History of primary immunodeficiency. 
 
□ 
□ 
 
History of hypersensitivity to any excipient in 
pembrolizumab. 
 
□ 
□ 
 
History of pneumonitis or interstitial lung disease. 
 
□ 
□ 
 
Subjects with uncontrolled seizures. 
 
□ 
□ 
 

 
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Uncontrolled intercurrent illness including, but not limited 
to, ongoing or active infection, symptomatic congestive 
heart failure, uncontrolled hypertension, unstable angina 
pectoris, uncontrolled cardiac arrhythmia, active peptic 
ulcer disease or gastritis, active bleeding diatheses, 
evidence of acute or chronic hepatitis B, hepatitis C or 
human immunodeficiency virus (HIV), or psychiatric 
illness/social situations that would limit compliance with 
study requirements or compromise the ability of the 
subject to give written informed consent. 
 
□ 
□ 
 
Known history of active tuberculosis. 
 
□ 
□ 
 
Receipt of live attenuated vaccination within 30 days 
prior to study entry or within 30 days of receiving 
pembrolizumab. 
 
□ 
□ 
 
Any condition that, in the opinion of the investigator, 
would interfere with evaluation of study treatment or 
interpretation of patient safety or study results. 
 
 
□ 
□ 
 
 
This subject is      
 eligible /  ineligible     for participation in this study. 
 
OnCore Assigned PID: ___ ___ ___ ___ ___ ___ ___ ___  
 
 
 
 
 
 
 
 
Signature of research professional confirming eligibility: _______________________  
 
Date: ___ ___ / ___ ___ / ___ ___ 
 
Signature of Treating Physician:  _____________________________________  
 
Date:  ___ ___ / ___ ___ / ___ ___ 
 
Signature of Principal Investigator**:  _____________________________________  
 
Date:  ___ ___ / ___ ___ / ___ ___ 
 
* Examples of source documents include clinic note, pathology report, laboratory results, etc. When listing the source, 
specifically state which document in the medical record was used to assess eligibility. Also include the date on the 
document. Example: “Pathology report, 01/01/14” or “Clinic note, 01/01/14” 
 
**Principal Investigator signature can be obtained following registration if needed 
 

 
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Appendix B – Protocol Registration Form 
 
DEMOGRAPHICS 
Patient: Last Name: _____________________ First Name: ___________________________ 
MRN:          ___ ___ ___ ___ ___ ___ ___ ___ DOB (mm/dd/yy): ___ ___ / ___ ___ / ___ ___ 
ZIPCODE:  ___ ___ ___ ___ ___ 
 
 
SEX:   
  Male      Female 
Ethnicity (choose one):   Hispanic 
Non-Hispanic 
Race (choose all that 
apply): 
 WHITE           BLACK            ASIAN 
 PACIFIC ISLANDER                 NATIVE AMERICAN 
Height:   ___ ___.___ inches 
Weight: ___ ___ ___.___lbs.(actual) 
Surface Area: ___ ___.___m2   
 
Primary Diagnosis: ____________________________________________________________ 
Date of Diagnosis: ___ ___ /___ ___/___ ___ 
 
Performance Status: ___  ECOG   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol Registrar can be contact by calling 
 between 8:30 AM and 4:00 PM, Monday – Friday. 
 
Compete the eligibility checklist in WISER and then give the completed Eligibility Checklist and Protocol Registration Form 
must be hand delivered, faxed or e-mailed to the registrar at 
 respectively. 
 
 
PROTOCOL INFORMATION 
Date of Registration: 
___ ___ / ___ ___ / ___ ___ 
MD Name (last) : 
______________________       
Date protocol treatment started: 
___ ___ / ___ ___ / ___ ___ 
Informed written consent: 
(consent must be signed prior to registration) 
 YES   NO 
 
Date Consent Signed: 
___ ___ / ___ ___ / ___ ___ 
 
PID # (to be assigned by OnCore): 
___ ___ ___ ___ ___ ___ ___ ___ 
 

 
 
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Appendix C - Race & Ethnicity Verification Form 
 
Thank you so much for helping us to verify your race and ethnicity to ensure the quality of our 
information. As a brief reminder, the information you provide today will be kept confidential. 
 
1. Are you: 
Hispanic or Latino/a 
Not Hispanic or Latino/a 
 
2. What is your race? One or more categories may be selected. 
White or Caucasian 
Black or African American 
American Indian or Alaskan Native 
Asian 
Native Hawaiian or Other Pacific Islander 
Other, Please Specify: ___________________________ 
 
 
Internal use only: 
 
 
 Name: ____________________ MRN#: ____________________  
 
Was the self-reported race and ethnicity of the participant verified at the time of consent? 
Yes        No 
 
Was a discrepancy found?       Yes         No 
         If yes, please provide what is currently indicated in the EMR:  
 
 
Ethnicity: ____________________  
Race: ____________________ 
Additional comments: __________________________________________________________________ 
_____________________________________________________________________________________ 
___________________________________________________________________________________

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0BAppendix D  
 
Data and Safety Monitoring 
Committee (DSMC) Serious Adverse 
Event (SAE) Notification SOP 
Date: 02/11/2021 
 
Mandatory DSMC SAE Reporting Requirements in WISER 
This document describes reporting requirements of adverse events from WFBCCC Investigator 
Initiated interventional trials to the Data and Safety Monitoring Committee (DSMC). A trial is 
considered a WFBCCC Investigator Initiated interventional trial if the following criteria are met: 
 
1) The Principal Investigator (PI) of the trial is a member of a department at the Wake Forest 
University Baptist Medical Center. 
2) WFBCCC is considered as the primary contributor to the design, implementation and/or 
monitoring of the trial. 
3) The trial is designated as “Interventional” using the Clinical Research Categories 
definitions provided by the NCI in the Data Table 4 documentation. 
(https://cancercenters.cancer.gov/GrantsFunding/DataGuide#dt4) 
 
There are two distinct types of WFBCCC Investigator Initiated interventional trials based on where 
patient enrollment occurs.  These include: 
 
1) Local WFBCCC Investigator Initiated interventional trials defined as trials where all patients are 
enrolled from one of the WFBCCC sites. These include the main outpatient Cancer Center 
clinics (located in Winston-Salem) as well as WFBCCC affiliate sites located in Bermuda Run 
(Davie Medical Center), Clemmons, Lexington, High Point, or Wilkesboro. 
2) Multi-Center WFBCCC Investigator Initiated interventional trials defined as trials where 
patients are enrolled from other sites in addition to WFBCCC sites.   
There are three types of trials that are included in this category: 
a. Trials sponsored by the NCI Community Oncology Research Program (NCORP) that are 
conducted at multiple sites where the PI is a member of a department at the Wake 
Forest University Baptist Medical Center. 
b. Trials sponsored by Industry that are conducted at multiple sites and the PI is a 
member of a department at the Wake Forest University Baptist Medical Center. 
c. Trials sponsored by WFBCCC that are conducted at multiple sites and the PI is a 
member of a department at the Wake Forest University Baptist Medical Center. 
 
All Adverse Events (AEs) and Serious Adverse Events (SAEs) that occur on any patients enrolled on 
WFBCCC Investigator Initiated Interventional trials must be entered into the WISER system. The only 
exception to this requirement is for patients enrolled on NCORP trials at non- WFBCCC sites. AEs and 
SAEs for NCORP patients enrolled at WFBCCC sites must be entered into the WISER system. Once these 
AEs and SAEs are entered in WISER, certain actions must be taken regarding the reporting of specific 

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Adverse Events to the DSMC. 
All Adverse Events that occur during protocol intervention (defined below) and are coded as either 1) 
unexpected grade 4, 2) unplanned inpatient hospitalization > 24 hours (regardless of grade), or grade 
5 (death) must be reported to the DSMC using the using the SAE console in WISER. 
 
A research nurse or clinical research coordinator when made aware that an adverse event meets one 
of the above criteria has occurred on a WFBCCC Investigator Initiated interventional trial, is responsible 
for informing a clinical member of the DSMC by phone (or in-person) about the adverse event. The 
nurse/coordinator should contact the treating physician prior to calling the DSMC clinical member to 
obtain all details of the SAE, as well as all associated toxicities to be recorded along with the SAE. In 
addition, this nurse or coordinator is responsible for entering the adverse event information into the 
SAE console in WISER.  Once the adverse event has been entered into the SAE console an email 
informing the entire DSMC will be generated. 
 
THESE REPORTING REQUIREMENTS APPLY TO any staff member on the study team for a WFBCCC Institutional 
Interventional trial. Ultimately, the protocol PI has the primary responsibility for AE identification, 
documentation, grading and assignment of attribution to the investigational agent/intervention. However, 
when an AE event as described above is observed, it is the responsibility of the person who observed the event 
to be sure that it is reported to the DSMC. 
 
What is considered during protocol intervention? 
During protocol intervention is considered to be the time period while a patient is on study treatment or 
during the time period within 30 days of last study treatment (even if patient begins a new (non-study) 
treatment during the 30 days). This window of 30 days should be the standard window to be used in all 
protocols unless a specific scientific rationale is presented to suggest that a shorter window can be used 
to identify events. If it is a trial sponsored by Industry and the sponsor requires a longer window for 
monitoring of SAEs, then the longer window of time specified by the sponsor should be followed. 
 
What is considered as an Unexpected Grade 4 event? 
Any grade 4 event that was not specifically listed as an expected adverse event in the protocol should be 
considered as unexpected. A grade 4 adverse event can be considered to be unexpected if it is an event 
that would not be expected based on the treatment being received or if it is unexpected based on the 
health of the patient. In either case, if there is any uncertainty about whether a grade 4 adverse event is 
expected or unexpected it should be reported to DSMC. 
 
DSMC notification responsibilities of the person (e.g., nurse) handling the reporting/documenting of the SAE in 
WISER: 
1. Make a phone call (or speak in person) to the appropriate clinical member of the DSMC 
according to the schedule as listed below (page if necessary). 
2. Enter a new SAE into the SAE module that is located in the Subject>> CRA Console in WISER 
WITHIN 24 HOURS of first knowledge of the event. Information can be entered and saved, but 
the DSMC members will not be notified until a date is entered into the  DSMC Notification Date 

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Field. This will ensure that all persons that need to be made aware of the event (i.e., PI, study 
team members and DSMC members) will be notified; remember to file a copy of the 
confirmation. 
3. Document that the appropriate person(s) on the DSMC has been contacted. Indicate the name of 
the DSMC clinician that was contacted and the date and time contacted in the Event Narrative 
field in the SAE console of the particular subject. 
4. Document whether or not the protocol should be suspended based on the discussion with the 
DSMC clinician. This is the major function of the email notification. Enter whether the protocol 
should be suspended in the Event Narrative Field. 
5. Follow up/update the clinical member(s) of DSMC regarding any new developments or 
information obtained during the course of the SAE investigation and reporting process. 
 
Elements needed to complete the SAE form in the Subject Console in WISER (see Screen Shot 3): 
1. Event Date 
2. Reported Date 
3. Reported by 
4. If Grade 5, enter Death Date 
5. If Grade 5, enter Death occurred: within 30 days 
6. Event Narrative: Brief description (include brief clinical history relevant to this event, including 
therapies believed related to event). Begin narrative with the DSMC clinician who was notified and 
Date/Time notified. In addition, state attribution by DSMC clinician as either “Unrelated”, 
“Unlikely”, “Possibly”, “Probably”, or “Definitely”.  Always include the following here: 
i. DSMC clinician name, date/time contacted and comments 
ii. Date of last dose before the event 
iii. Is suspension of the protocol needed? Y/N 
7. Treating Physician comments 
8. PI comments, if available 
9. Protocol Attribution after discussion with DSMC clinician 
10. Outcome (Fatal/Died, Intervention for AE Continues, Migrated AE, Not Recovered/Not Resolved, 
Recovered/Resolved with Sequelae, Recovered/Resolved without Sequelae, Recovering and 
Resolving) 
11. Consent form Change Required? Y/N 
12. SAE Classification *This is required in order for the email notification to be sent* 
13. Adverse Event Details – Enter all details for each AE associated with the SAE. 
a. Course start date 
b. Category 
c. AE Detail 
d. Comments 
e. Grade/Severity 
f. Unexpected Y/N 
g. DLT Y/N 
h. Attributions 

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i. Action 
j. Therapy 
k. Click ADD to attach the AE Detail to the SAE. 
14. Enter Date Notified DSMC -- *This is required for the email notification to be sent* 
15. Click Submit. The auto-generated notification email will disseminate within 5 minutes. If you do 
not receive an email within 5 minutes, check that you have entered the “Date Notified DSMC” and 
the “SAE Classification”. If these have been entered and the email still has not been received, take 
a screen shot of the SAE in WISER and immediately email it out to all of the DSMC members listed 
in this SOP. In the subject line, indicate that this is a manual transmission of the SAE in lieu of the 
auto-generated email. It is required that a notification goes to the DSMC members immediately so 
that their assessment can be obtained within the 24 hour period requirement. Contact the Cancer 
Center Programmer/Analyst to alert that there is an issue with the auto-generated email. 
 
The Clinical Members of DSMC to Notify by Phone or Page: 
 
Monday 
Tuesday 
Wednesday Thursday 
Friday 
Saturday Sunday 
Lesser 
Hughes 
Goodman 
Reed 
Porosnicu Seegars 
Lesser 
Hughes 
Goodman 
Reed 
Porosnicu 
Seegars 
Lesser 
Hughes 
Goodman 
Reed 
Porosnicu 
Seegars 
Lesser 
Hughes Goodman 
Reed 
Porosnicu 
Seegars 
Lesser 
Hughes Goodman 
Reed 
Porosnicu 
Seegars 
Lesser 
Hughes 
Goodman 
Reed Porosnicu 
Seegars 
Lesser 
Hughes 
Goodman 
Reed 
Porosnicu Seegars 
 
  
 
 
 
 
 
 
 
Definition of Unavailable: 
As a general guideline if the first clinician that is contacted does not respond to the phone call or page 
within 30 minutes, then initiate contact with the next DSMC clinician listed in the table above on the 
particular day the SAE is being reported. Allow up to 30 minutes for the new DSMC clinician to respond to 
a phone call or page before contacting the next member in the table. These times (30 minutes) are a 
general guideline. Best judgment as a clinical research professional should be used giving considerations 
of the time of day, severity of the SAE, and other circumstances as to when it is appropriate to contact 
backup clinicians. If the event occurs near the end of day, then leave messages (voice or email) as 
appropriate and proceed with submitting the DSMC notification form. It is important to take reasonable 
steps and to document that some type of contact has been initiated to one or more of the clinical 
members of DSMC. 
 
 
 

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DSMC CLINICAN RESPONSIBILITY: 
It is the responsibility of the DSMC clinician to review all reported events, evaluate the events as they are 
reported; and communicate a response to the Investigator, event reporter and the members of DSMC. 
The review will include but not be limited to the information reported; there may be times when 
additional information is needed in order for an assessment to be made and further communication 
directly with the investigator may be warranted. DSMC reserves the right to disagree with the 
Investigator's assessment. If DSMC does not agree with the Investigator, DSMC reserves the right to 
suspend the trial pending further investigation. If there is any immediate danger or harm that could be 
present for a future patient based on the information provided in the DSMC report then an immediate 
suspension of enrollment should be considered. 
 
AMENDMENTS TO PREVIOUS REPORTS 
If all pertinent information is unavailable with the initial submission, once the additional information is 
available do not submit a new report. Rather, go to the original email that was sent to the DSMC and 
using that email “reply to all”. Entitle this new email “Amendment for (list date of event and patient ID)” 
this will avoid duplications of the same event. List the additional information being reported. This 
information needs to be entered into WISER as well. To do this, go to the Subject console and click SAEs 
on the left column. Click on the appropriate SAE number that needs updating. Then click Update. This 
will allow additional  information to be added. 
 
Acronyms 
AE – Adverse Event 
DSMC-Data and Safety Monitoring Committee 
SAE-Serious Adverse Event 
WFBCCC – Wake Forest Baptist Comprehensive Cancer Center 
NCI-National Cancer Institute 
WISER –Wake Integrated Solution for Enterprise Research 
 
Screen Shots: 
 
The following screen shots come from the SAE Console within the Subject Console in WISER. 
Screen Shot 1: 

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Screen Shot 2:
 

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Screen Shot 3: 
 
 
 
Screen Shot 4: