Clinical trial NCT02289209
Conditions: Recurrent Head and Neck Cancer Carcinoma, Squamous Cell of Head and Neck
Keywords: head and neck cancer reirradiation MK-3475 Anti-PD-1 monoclonal antibody Squamous cell carcinoma Keytruda pembrolizumab
Sponsor: Dan Zandberg
Start date: 2016-03-09; Completion date: 2024-08-31
Enrollment: 48 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Eligible participants with locoregional inoperable recurrence or second primary squamous cell carcinoma of the head and neck will be treated with reirradiation combined with anti-PD-1 mAb MK-3475 (generic name: pembrolizumab, trade name Keytruda®).

Detailed description:
Each participant will undergo screening and then be treated with reirradiation with 1.2 Gy BID, 5 days a week (weeks 1-5). MK-3475 (generic name: pembrolizumab, trade name Keytruda®) will be given at 200mg intravenous every 3 weeks starting day one of reirradiation and will be continued in all participants until 3 months post completion of reirradiation, at which time a PET/CT will be done to evaluate response. Participants with progressive disease (PD) will be taken off MK-3475 and followed for survival. Participants that have a complete response (CR) will be followed clinically and radiographically, and if disease recurs may be eligible to be retreated with MK-3475 for up to one year. Participants with partial response (PR) or stable disease (SD) will continue treatment with MK-3475 for up to two years unless one of the following occurs:

* documented disease progression
* unacceptable adverse event(s)
* intercurrent illness that prevents further administration of treatment
* investigator decision to withdraw the subject
* withdrawal of consent
* pregnancy
* noncompliance
* administrative reasons (i.e. trial is closed prematurely).

Participants who have not progressed at completion of 24 months of therapy will be observed, but may be eligible for 1 year of retreatment with MK-3475 if they develop recurrence/progression and qualify for retreatment as detailed in the protocol,and if the trial is still ongoing.

Arms: arm 1: Reirradiation 1.2 Gy BID for 5 days a week for 5 weeks with MK-3475 (Keytruda, pembrolizumab) 200mg intravenous every 3 weeks until 3 months post completion of reirradiation.
Interventions: intervention 1: Reirradiation intervention 2: MK-3475
Intervention descriptions: intervention 1: Reirradiation 1.2 GY BID 5 days a week for 5 weeks. intervention 2: MK-3475 will be given at 200mg intravenous every 3 weeks starting day one of reirradiation and will be continued once every 3 weeks until 3 months post completion of reirradiation. Further continuation of MK-3475 will be determined by response evaluation at 3 months post completion of reirradiation

Protocol documents:
Prot_SAP_000.pdf: 
Amendment 8, 07/26/2018 
 
Page 1 
 
 
COORDINATING CENTER: UPMC Hillman Cancer Center 
 
TITLE: A Phase II trial of reirradiation combined with open label Pembrolizumab in 
patients with locoregional inoperable recurrence or second primary squamous cell 
carcinoma of the head and neck (SCCHN) 
 
STUDY NUMBER: HCC #18-009 
 
IND NUMBER: EXEMPT 
 
Sponsor/Lead Investigator 
Dan P Zandberg, MD 
UPMC Hillman Cancer Center 
5150 Centre Avenue, 5th Floor 
Pittsburgh, PA 15232 
Telephone: 412-864-7955 
Fax: 412-648-6579 
Email: zandbergdp@upmc.edu 
 
Participating Sites 
University of Maryland Greenebaum Comprehensive Cancer Center  
22 South Greene Street 
Baltimore, MD 21201 
 
Fox Chase Cancer Center 
333 Cottman Ave. 
Philadelphia, PA 19111 
 
Johns Hopkins University 
401 North Broadway 
Baltimore, MD 21231 
 
Research Laboratories 
Ferris Lab 
UPMC Hillman Cancer Center 
Research Pavilion Lab 2.19 
5117 Centre Avenue 
Pittsburgh, PA 15213 
 
QualTek Molecular Laboratories 300 
Pheasant Run 
Newtown, PA 18940 


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Statistician 
Dan P Normolle, PhD 
 
Monitor 
Dr. Dan Zandberg 
 
Trial Financial Support 
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 


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Table of Contents 
1.0 Trial Summary 
4 
2.0 Trial Design 
5 
3.0 Objectives and Hypothesis 
7 
4.0 Background and Rationale 
8 
5.0 Methodology 
18 
6.0 Trial Flow Charts 
38 
7.0 Trial Procedures 
46 
8.0 Statistical Analysis Plan 
65 
9.0 Labeling, Packaging, Storage and Return of Clinical Supplies 
69 
10.0 Administrative and Regulatory Details 
70 
11.0 List of References 
73 
12.0 Appendices 
78 


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1.0  TRIAL SUMMARY 
 
Abbreviated Title 
Reirradiation combined with pembrolizumab (trade  name:  Keytruda®) 
in recurrent SCCHN 
Trial Phase 
Phase II 
Clinical Indication 
Locoregional recurrence or second primary SCCHN which is 
unresectable or the patient is unwilling to undergo resection who are able 
to undergo reirradiation 
Trial Type 
Interventional 
Type of Control 
NA-historical 
Route of Administration 
Intravenous 
Trial Blinding 
Unblinded 
Treatment Groups 
Single arm trial 
Number of Trial Subjects 
48 evaluable subjects 
Estimated Duration of Trial 
The estimated time from opening the trial to data analysis is 
approximately 36 months. This allows for accrual over 24 months and a 
minimum 12 month maturation period for all patients enrolled. 
Duration of Participation 
Each subject will participate in the trial from the time the subject signs 
the Informed Consent Form (ICF) through the final protocol-specified 
evaluation. Each patient will undergo screening and then be treated with 
reirradiation with 1.2 Gy BID, 5 days a week (weeks 1-5). 
Pembrolizumab will be given at 200mg intravenous every 3 weeks 
starting day one or day two of reirradiation and will be continued in all 
patients until 3 months post completion of reirradiation, at which time a 
PET/CT will be done to evaluate response. Patients with progressive 
disease (PD) will be taken off the study. Patients that have a complete 
response (CR) will be followed clinically and radiographically, and if 
disease recurs may be eligible to be retreated with pembrolizumab for up 
to one year. Patients with partial response (PR) or stable disease (SD) will 
continue treatment with pembrolizumab for up to two years unless one of 
the following occurs: 
--documented confirmed disease progression 
--unacceptable adverse event(s) 
--intercurrent illness that prevents further administration of treatment 
--investigator decision to withdraw the subject 
--subject withdraw of consent 
--subject pregnancy 
--subject noncompliance 
--administrative reasons (i.e. trial is closed prematurely). 
Patients who have not progressed at completion of 24 months of therapy 
will be observed, but may be eligible for 1 year of retreatment with 
pembrolizumab if they develop recurrence/progression if they qualify as 
detailed in the protocol and if the trial is still ongoing. 


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2.0 TRIAL DESIGN 
 
2.1 Trial Design 
 
This is a single arm phase II clinical trial investigating the combination of open label anti- PD-
1 mAb pembrolizumab (trade name: Keytruda®) and reirradiation (RT) in patients with 
locoregional inoperable recurrence or second primary SCCHN. The accrual goal is 48 patients. 
The primary endpoint is progression free survival (PFS). Secondary endpoints are toxicity, best 
overall response rate (RR), clinical benefit rate (CBR), time to in field progression, overall 
survival (OS), and patient reported quality of life as measured by the EORTC QLQ-C30 and 
EORTC QLQ-H&N35 questionnaires. 
 
Patients that meet the eligibility criteria will undergo PET/CT for baseline imaging and will 
require tumor tissue for evaluation for PD-L1 expression. Fresh tissue or archival tissue will be 
obtained and used for PD-L1 analysis. PD-L1 expression will not be required for entry onto the 
study, given it is unknown if PD-L1 is predictive when pembrolizumab is combined with 
radiation, and given preclinical data suggesting that radiation leads to an increase in IFN-γ and 
subsequent PD-L1 expression in the tumor.1 As highlighted in the study schema, patients will 
be treated with radiation (1.2Gy BID for total 60Gy) concurrent with pembrolizumab at 200mg 
intravenous every 3 weeks. The first dosage of pembrolizumab will be given on the first or 
second day of radiation. After completion of radiation treatment, patients will continue to 
receive pembrolizumab as a single agent for 3 months. At 3 months after completion of 
radiation, all patients will undergo a PET/CT to evaluate for response. Patients with a complete 
response (CR) at 3 months will discontinue pembrolizumab therapy and be observed with 
clinical exam and repeat CT neck at least every 3 months in the first year and every 6 months in 
year 2. These patients will then have continued annual follow-up with physical exam and CT 
neck (as clinically indicated) until the end of the study. Patients with a partial response or stable 
disease will continue treatment with pembrolizumab up to a total of 24 months (104 weeks) 
from the first cycle of treatment as long as they do not develop progressive disease, an 
intolerable toxicity, or other criteria for study withdrawal. These patients will be monitored 
with CT neck/chest after every 3rd cycle of pembrolizumab or more frequently if clinically 
indicated. Patients with progressive disease at 3 months post reirradiation will be taken off 
pembrolizumab and followed for survival. A patient who achieves a CR at 3 months post 
reirradiation and subsequently progresses may be eligible for retreatment with pembrolizumab 
as a single agent for up to one year. However, only the time to initial progression will be 
included in the PFS analysis, the primary endpoint of the study. Determination of response will 
be as per RECIST 1.l. However, given the experience with immune co-signaling blockade and 
the possibility of an inflammatory reaction leading to an increase in size of target lesions as 
well as the development of new lesions initially (before subsequent regression), progressive 
disease in the absence of clinical deterioration will be verified with repeat CT imaging not less 
than 4 weeks from prior imaging. 2, 3 
While this will be the first time in humans that an anti-PD-1 mAb is combined with radiation, 
safety data with pembrolizumab as a single agent reveals no difference in toxicity at different 
dosages. It is, however, necessary to establish the safety of combining pembrolizumab with 


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radiation. Therefore, instead of a phase I component with dose escalation or de-escalation, this 
trial will be done as a phase II trial with a stop rule if the pre-specified acute non- hematologic 
toxicity boundary is crossed as detailed in the statistical consideration section 
8.0. The first 20 patients enrolled on the study will be included in the pre-specified acute non-
hematologic toxicity threshold evaluation. Toxicity will be evaluated using CTCAE v4.0, and 
pembrolizumab will be held for grade > 4 acute radiation toxicity, or for all other grade > 3 
toxicities. If the first 20 patients complete reirradiation in combination with pembrolizumab 
(plus 2 weeks) without crossing the toxicity boundary, all subsequent patients to the goal of 48 
total evaluable patients will be enrolled without a formal stop rule for toxicity.  All patients will 
be evaluated for efficacy endpoints. 
 
2.2 Trial Diagram 
 
 
1. Tumor tissue for PD-L1 analysis from archival or fresh biopsy. 
2. 
Cycles 1 and 2 of pembrolizumab given concurrent with reirradiation 1.2Gy BID Monday through Friday X 
25 treatment days (weeks 1-5). 
3. 
Continue treatment with pembrolizumab alone (cycles 3-6) (weeks 6-16). 
4. 
Patients will be followed with imaging and clinical exams as per section 6.0, and if cancer recurs, they may 
be eligible for retreatment with pembrolizumab for 12 months. 
5. 
Patients can continue treatment with pembrolizumab for up to 24 months (from initiation of treatment) as 
long as continue to respond or have stable disease. 
Locoregional recurrence or second primary SCCHN 
Obtain Tissue for PD-L1 Analysis1 
Treatment with Pembrolizumab + Reirradiation2 
Continue Pembrolizumab treatment alone3 
PET/CT Restaging 3 months post completion of Reirradiation 
Complete response 
Partial response 
or stable disease 
Progressive disease 
Surveillance and if 
recur may be eligible 
for retreatment with 
pembrolizumab4 
Continue pembrolizumab 
as long as continued 
response or stable 
disease5 
Stop pembrolizumab 
and enter survival 
follow-up 


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3.0 OBJECTIVE(S) & HYPOTHESIS(ES) 
 
3.1 Primary Objective(s) & Hypothesis(es) 
 
1) Objective: The primary objective is to evaluate the progression free survival (PFS) in 
patients with locoregional inoperable recurrence or second primary squamous cell carcinoma of 
the head and neck (SCCHN) treated with reirradiation in combination with pembrolizumab. 
 
Hypothesis: The combination of pembrolizumab and reirradiation will lead to improved 
progression free survival in patients with locoregional inoperable recurrence or second primary 
SCCHN compared to historical outcomes with concurrent chemotherapy and reirradiation. 
 
3.2 Secondary Objective(s) & Hypothesis(es) 
 
1. Objective: To evaluate the safety and toxicity profile of the combination of 
reirradiation and pembrolizumab in patients with locoregional inoperable recurrence or 
second primary SCCHN. 
 
 Hypothesis: The combination of pembrolizumab and reirradiation will be safe and show 
acceptable toxicity in the range of what is currently seen with concurrent chemotherapy 
with reirradiation. We hypothesize that pembrolizumab will not sensitize the tissue to 
reirradiation, as would be expected with traditional cytotoxic chemotherapy, but rather 
reirradiation will stimulate the immune system making pembrolizumab more efficacious. 
Therefore, we hypothesize that acute radiation toxicity should not be increased compared to 
that observed with concurrent chemotherapy and reirradiation. 
 
2. Objective: To evaluate the best overall response rate (ORR) by RECIST 1.1 in patients 
with locoregional inoperable recurrence or second primary SCCHN treated with 
reirradiation combined with pembrolizumab. 
 
3. Objective: To evaluate the clinical benefit rate (CBR) by RECIST 1.1 in patients with 
locoregional inoperable recurrence or second primary SCCHN treated with reirradiation 
combined with pembrolizumab. 
 
4. Objective: To evaluate the time to in field progression in patients with locoregional 
inoperable recurrence or second primary SCCHN treated with reirradiation combined 
with pembrolizumab. 
 
5. Objective: To evaluate the Overall Survival (OS) in patients with locoregional 
inoperable recurrence or second primary SCCHN treated with reirradiation combined 
with pembrolizumab. 
6. Objective: To evaluate patient reported quality of life as measured by questionnaires 
EORTC QLQ-C30 and EORTC QLQ-H&N35 in patients with locoregional inoperable 
recurrence or second primary SCCHN treated with reirradiation combined with 
pembrolizumab. 
 
 


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3.3 Exploratory Objectives 
 
The following exploratory post-hoc analyses will be carried out to evaluate: 
 
1. Whether there is any correlation between PD-L1 expression on initial biopsy and the 
efficacy of pembrolizumab combined with reirradiation. 
 
2. Whether there is any correlation between p16 expression in tumor biopsies and the 
efficacy of pembrolizumab combined with reirradiation. 
 
3. Whether there is any correlation between percentages of Cytotoxic T cells (CTL), 
Regulatory T cells (Treg), or Myeloid Derived Suppressor cells (MDSC) in the 
peripheral blood at initiation of therapy, and efficacy of pembrolizumab combined with 
reirradiation. 
 
4. Whether there is any correlation between changes in percentages of Cytotoxic T cells, 
Regulatory T cells, or Myeloid Derived Suppressor cells over time, and efficacy 
pembrolizumab combined with reirradiation. 
 
5. Whether there is any correlation between irradiated volume of vascular structures (as 
evaluated by dose-volume histogram) and efficacy of pembrolizumab combined with 
reirradiation. 
 
4.0 BACKGROUND & RATIONALE 
 
4.1 Background 
 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on pembrolizumab. 
 
4.1.1 
Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades4. Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies5-9. In particular, the presence of CD8+ T-cells and the ratio of CD8+ 
effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and 
long-term survival in many solid tumors. 
 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated T- 
cells under healthy conditions, is to down-modulate unwanted or excessive immune responses, 
including autoimmune reactions.   PD-1 (encoded by the gene Pdcd1) is an Ig superfamily 
member related to CD28 and CTLA-4 which has been shown to negatively regulate antigen 
receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2)  10,11. The structure of 
murine PD-1 has been resolved12. PD-1 and family members are type I transmembrane 
glycoproteins containing an Ig Variable-type (V-type) domain responsible for ligand binding 


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and a cytoplasmic tail which is responsible for the binding of signaling molecules. The 
cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine- based switch motif 
(ITSM). Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and 
SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of 
effector molecules such as CD3ζ, PKCθ and ZAP70 which are  involved in the CD3 T-cell 
signaling cascade10, 13-15. The mechanism by which PD-1 down modulates T-cell responses is 
similar to, but distinct from that of CTLA-4 as both molecules regulate an overlapping set of 
signaling proteins16, 17. PD-1 was shown to be expressed on activated lymphocytes including 
peripheral CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer cells18, 19. Expression has 
also been shown during thymic development on CD4-CD8- (double negative) T-cells as well as 
subsets of macrophages and dendritic cells20. The ligands for PD-1 (PD-L1 and PD-L2) are 
constitutively expressed or can be induced in a variety of cell types, including non-
hematopoietic tissues as well as in various tumors16, 21-23. Both ligands are type I 
transmembrane receptors containing both IgV- and IgC-like domains in the extracellular region 
and contain short cytoplasmic regions with no known signaling motifs. Binding of either PD-1 
ligand to PD-1 inhibits T-cell activation triggered through the T-cell receptor. PD-L1 is 
expressed at low levels on various non-hematopoietic tissues, most notably on vascular 
endothelium, whereas PD-L2 protein is only detectably expressed on antigen-presenting cells 
found in lymphoid tissue or chronic inflammatory environments. PD-L2 is thought to control 
immune T-cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted 
T-cell function in peripheral tissues16. Although healthy organs express little (if any) PD-L1, a 
variety of cancers were demonstrated to express abundant levels of this T-cell inhibitor. PD-1 
has been suggested to regulate tumor-specific T-cell expansion in subjects with melanoma 
(MEL)24. This suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune 
evasion and should be considered as an attractive target for therapeutic intervention. 
 
Pembrolizumab (previously known as SCH 900475) is a potent and highly selective humanized 
monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the 
interaction between PD-1 and its ligands, PD-L1 and PD-L2. 
 
4.1.2 
Preclinical and Clinical Trial Data with Pembrolizumab (summarized from 
Investigator’s Brochure) 
Preclinical data with pembrolizumab in melanoma, squamous cell carcinoma, pancreatic 
cancer, and colorectal cancer has shown that blockade of PD-1 interaction with PD-L1 and PD-
L2 leads to activation and infiltration by cytotoxic CD8 T cells and subsequent regression of 
tumor. This has led to ongoing and completed clinical trials with pembrolizumab in melanoma, 
NSCLC, and numerous other advanced solid tumors including triple negative breast, urothelial 
cell cancer, head and neck cancer, and gastric cancer. 
In PN001, the first in human study of pembrolizumab at three different dose levels in solid 
tumors, no DLT (dose limiting toxicity) or serious infusion reactions have been observed. 
Further details of the experience with pembrolizumab at different dose levels and rationale for 
ongoing dosing schedule are provided in section 4.2.2.1. In ongoing trials pembrolizumab has 
been generally well tolerated. The most common adverse events are fatigue, nausea, cough, 
pruritus, diarrhea and rash. The most commonly reported immune- related adverse events 
across the dose-schedules are rash, pruritus, vitiligo, hypothyroidism, arthralgia, diarrhea, and 


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pneumonitis. Further information about toxicity, including in SCCHN can be found in the 
pembrolizumab Investigator Brochure and Keytruda® package insert. 
 
In melanoma, overall response rates with pembrolizumab monotherapy in ipilimumab 
exposed and ipilimumab naïve advanced melanoma were 25% and 39% respectively by 
central independent review by RECIST 1.1. Importantly responses were durable with a 1 year 
survival of 71% for all melanoma patients. Pembrolizumab was approved for use in advanced 
melanoma by the FDA in September 2014. Pembrolizumab has also gained FDA approval 
based on efficacy in advanced urothelial carcinoma, NSCLC, Hodgkin lymphoma, and 
SCCHN.  Data for SCCHN is reported in section 4.2.1 below 
 
4.2 Rationale 
 
4.2.1    Rationale for the Trial and Selected Subject Population 
Squamous cell carcinoma of the head and neck (SCCHN) is the 6th most common malignancy 
worldwide.25 For patients with locally advanced SCCHN, radiation is part of either initial 
definitive therapy or adjuvant therapy after surgical resection. Despite aggressive initial 
definitive therapy, patients with SCCHN are at high risk for the development of second primary 
tumors and a significant proportion of patients will recur, commonly within the first 2 years.26, 
27 The majority of these recurrences are locoregional  and are associated with significant pain, 
disfigurement, and functional decline.28 Unfortunately, a significant proportion of these patients 
will not have a salvage surgical option.  Even with salvage surgery, local failure rates are 
upwards of 59%.29 
 
Patients with locoregional recurrence or second primary without a surgical option are currently 
treated with reirradiation with concurrent chemotherapy. Reported outcomes from the largest 
trials that evaluated reirradiation with concurrent chemotherapy include a median PFS of 7-8 
months and median OS of 10-12 months,30-33 with even worse survival in patients who recurred 
within a year compared to patients recurring more than one year after primary radiation 
(median OS 5.8 vs. 9.8 months respectively, p = .036). 3 Improved outcomes are desperately 
needed for this patient population. 
 
While concurrent chemotherapy is given with reirradiation, there is no data evaluating whether 
concurrent therapy improves outcome compared to reirradiation alone. Additionally, various 
chemotherapy regimens including Cisplatin/Paclitaxel, 5FU/hydrea, Docetaxel, 
Cisplatin/Docetaxel have been used concurrently without direct comparison of effectiveness 
and there is not one chemotherapy regimen that can be regarded as standard of care. 30-35 
Traditional chemotherapy sensitizes the tissue to radiation allowing for increased efficacy 
when given concurrent with radiation. However, this sensitization comes at the cost of 
increased hematologic and non-hematologic toxicity. In trials with reirradiation concurrent 
with chemotherapy for recurrent SCCHN, grade 4 and 5 acute toxicity rates are 16-23% and 
upwards of 5% respectively in the largest trials.30-32, 34 
 
The PD-L1:PD-1 Pathway in SCCHN 
Robust data supporting the significant role of the PD-L1:PD-1 pathway in SCCHN has led 
to ongoing clinical trials with single agent anti-PD-L1 and anti-PD-1 mAbs including 
pembrolizumab. In SCCHN, PD-L1 expression has been observed in 43-100% of patients, 


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across multiple primary sites.35-36 (Table 1) Given the recognized importance of HPV in the 
etiology of oropharyngeal SCCHN, several investigators have now sought to correlate 
expression of PD-L1 with HPV status. Three independent studies have revealed higher 
expression of PD-L1 in HPV positive compared to negative patients: 70% vs. 29%,37 49.2% 
vs. 34.1%,38 and 62.5% vs. 40%. 39 Importantly, PD-L1 expression has  been observed in  
43% and 70% of  recurrent and metastatic patients, respectively.37  PD-1 has been shown to  
be expressed on effector T cells in the tumor microenvironment in both HPV positive and 
negative SCCHN.37,39 
 
Table 1. PD-L1 Expression in SCCHN 40 
 
Study 
Primary Site 
Sample Size 
Percent of 
tumors with 
PD-L1 
expression 
Percent of 
tumors with 
PD-L1 
expression in 
HPV positive 
cases 
Percent of 
tumors with 
PD-L1 
expression in 
HPV negative 
cases 
Strome et al. 
OC, HP, L, PNS 
24 
66 
NA 
NA 
Ukpo et al. 
OP 
181 
46.4 
49.2 
34.1 
Lyford-pike et al. 
OP 
27 
59 
70 
29 
Badoual et al. 
OC, OP, HP 
64 
51.5 
62.5 
40 
Cho et al. 
OC 
45 
87 
NA 
NA 
Zhang et al. 
NP 
59 
67.8 
NA 
NA 
Hsu et al. 
NP 
25 
100 
NA 
NA 
OC-Oral Cavity; OP-Oropharynx; NP-Nasopharynx; HP-Hypopharynx; PNS-Paranasal 
Sinus; L- Larynx. NA–Non-Applicable 
 
Multiple preclinical studies have shown the efficacy of blockade of the PD-1:PD-L1 
pathway in a SCCHN model.35, 36 Strome et al, transfected plasmid-encoding mouse PD-L1 
into  mouse SCC cell line SCCVII, creating a mouse model of SCCHN with tumor 
expression of PD-L1. Next they examined the efficacy of 10B5, a hamster mAB against 
mouse PD-L1 after adoptive T-cell therapy. Activated T-cells were prepared from mice 
that were preimmunized with SCCVII-pulsed dendritic cells and expanded in vitro by anti-
CD3 and IL-2. All of the mice treated with these activated T cells and control IgG rapidly 
developed tumors and died within 40 days of inoculation with tumor. Therefore, T cell 
therapy alone was not effective. However the majority of mice treated with T cells and 
10B5 remained alive more than 80 days. The survival of mice treated with T cells and anti-
PD-L1 mAb was significantly improved compared to animals treated with T cells and 
control IgG.35 
Preclinical data led to clinical trials with anti-PD-L1 mAb and anti-PD-1 mAbs including 
pembrolizumab. Reported clinical trial data with pembrolizumab in SCCHN led to the FDA 
granting accelerated approval for pembrolizumab in the treatment of recurrent or metastatic 
SCCHN with disease progression on or after platinum-containing chemotherapy. This was 
based on efficacy data in 174 patients with R/M SCCHN with an ORR of 16%. The median 


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duration of response has not been reached and the range of duration of response was 2.4 
months to 27.7 months. Among the responding patients 82% had responses for 6 months or 
longer. 41 
The Immunogenic Effects of Radiation. 
Inherent to the efficacy of PD-1 mAb blockade is the need for the immune system to be 
activated. The literature consistently shows that radiation can initiate and promote both innate 
and adaptive immunity against tumors by mechanisms including: 1. Enhanced expression of 
damage associated molecular patterns (DAMP), leading to stimulation of dendritic cells and 
subsequent increase in antigen presentation. 2. Enhanced expression of MHC class I molecules, 
adhesion molecules and stress-induced ligands, and death receptors on tumor cells leading to 
increased recognition and killing by T cells. 3. Induction of chemokines CXCL9, CXCL10 and 
CXCL16 promoting recruitment of effector CD 8 T cells. 
4. Release of pro-inflammatory cytokines such as interleukin 1β, TNFα, IFNγ driving anti- 
tumor immunity.42-44 
 
Radiation in combination with anti-PD-1 mAb and anti-PD-L1 mAb has shown synergy,  with 
resultant increased efficacy compared to mAb or RT alone in glioblastoma multiforme (GBM) 
as well as colon and mammary cancer mouse models.1, 45 For example Deng et al demonstrated 
that radiation plus anti-PD-L1 mAb lead to an increase in antigen specific CD8 T cells and a 
decrease in MDSCs, leading to significantly increased anti-tumor effect compared to RT alone 
or anti-PD-L1 mAb alone in a mammary cancer mouse model. Importantly, radiation led 
specifically to increased PD-L1 expression in tumor cells, additionally enhancing the effect of 
anti-PD-L1 mAb.1  Zeng et al did a similar experiment in a GBM mouse model and found that 
the combination of anti-PD-1 mAb plus radiation led to significantly increased cytotoxic CD8 
T cells and decreased Tregs in the brains of the mice  as well as prolonged survival compared 
to radiation or anti-PD-1 mAb alone.45 Additionally, they injected tumor cells in mice that were 
cured of tumor by the anti-PD-1 mAb and radiation, and found that at 60 days there was no 
growth of tumor in these mice, suggesting that effective immunologic memory had developed. 
59 While the best schedule of radiation (single dose or fractionated) to promote immunogenic 
cell death has not been defined, there is preclinical data to suggest that a fractionated schedule 
is more immunogenic.46, 47 
Specifically in SCCHN, studies have been done investigating the immunologic effects of 
radiation. Moyer et el, using a SCCHN mouse model, found that there was  increased  efficacy 
to the combination of intratumoral DC injections combined with chemoradiation compared to 
chemoradiation alone which was dependent on the presence of CD4, CD8, and NK (natural 
killer) cells. Importantly, they observed a decrease in intratumoral Tregs after treatment with 
chemoradiation.48 Other studies have observed a decrease in T regs after radiation.49, 50 These 
observations are important as Tregs promote immune tolerance. Tabachnyk et al evaluated the 
tumor microenvironment in 58 patients with SCC of the oral cavity who were treated with 
neoadjuvant chemoradiation using standard fractionated RT to 50.4 Gy with concurrent 
Cisplatin/5Fluorouracil chemotherapy, followed by surgical resection. They compared various 
tumor infiltrating lymphocytes in  pretreatment  biopsy with post resection tissue samples. 
They found that in the peritumoral stroma the most pronounced reduction was in Tregs with an 
increase in favorable CD8/Treg ratio in post resection peritumoral stroma after chemoradiation. 
Decrease in T regs, increase in dendritic cells, and increase in CD8/Treg ratio post 


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chemoradiation were each associated with improved survival. 49 Also in SCCHN treatment with 
radiation was associated with increased CD8 tumor infiltrating lymphocyte proliferative 
activity. 51 
While the combination of radiation and anti-PD-1 mAb or anti-PD-L1 mAb has not been 
combined in humans, there is data with anti-CTLA4 mAb Ipilimumab in combination with 
radiation. A phase I/II dose escalation trial was done in metastatic castrate resistant prostate 
cancer patients with Ipilimumab as a single agent, as well as following a onetime dosage of 8 
Gy of radiation to 1-3 bone lesions. Importantly, no DLT was observed with  the  combination 
of radiation and ipilimumab, and the full dosage of 10mg/kg was expanded.52 This lead to a 
phase III trial comparing radiation plus ipilimumab to radiation plus placebo in metastatic 
castrate resistant prostate cancer. The radiation and ipilimumab group showed a significant 
increase in PFS and PSA (prostate specific antigen) response. Importantly, the incidence and 
severity of immune-related adverse events were similar to those reported as single agent 
ipilimumab in melanoma.53 Similarly, in a retrospective study of patients with melanoma 
treated with ipilimumab that had also received palliative radiation during their course, the 
combination was not associated with increased toxicity compared to historical controls of 
single agent ipilimumab therapy.54 Thus, Ipilimumab, which is associated with higher toxicity 
than reported with anti-PD-1 or anti-PD-L1 mAb blockade,55 did not show increased toxicity 
when combined with radiation. 
 
Rationale for the Combination of Pembrolizumab and Reirradiation in SCCHN. 
In summary, preclinical data strongly supports that radiation will lead to the stimulation of 
innate and adaptive immunity with subsequent blockade of PD-1 by mAb, having a synergistic 
effect leading to increased immune mediated destruction of tumor cells. Preclinical data 
provides strong support for the therapeutic potential of anti-PD-1 mAb blockade in SCCHN. 
Experience with pembrolizumab as a single agent in recurrent/metastatic SCCHN has shown 
promising activity. We hypothesize that the combination of reirradiation and pembrolizumab 
will have a synergistic effect and lead to improvement in progression free survival compared to 
historical controls in SCCHN patients who have developed inoperable locoregional recurrence 
or second primary squamous cell carcinoma in the head and neck region. 
4.2.2 
Rationale for Dose Selection/Regimen/Modification 
 
4.2.2.1 Rationale for Dose Selection/Regimen/Modification of Pembrolizumab 
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and clinical 
activity of single agent pembrolizumab. The dose escalation portion of this trial evaluated three 
dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects 
with advanced solid tumors. All three dose levels were well tolerated, and no dose-limiting 
toxicities were observed. This first in human study of pembrolizumab showed evidence of 
target engagement and objective evidence of tumor size reduction at all dose levels (1 mg/kg, 3 
mg/kg and 10 mg/kg Q2W).  No MTD has been identified to date. 
 
PK data analysis of pembrolizumab administered Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half-life (refer to Investigator 
Brochure). Pharmacodynamic data (IL-2 release assay) suggested that peripheral target 
engagement is durable (>21 days). This early PK and pharmacodynamic data provided 


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scientific rationale for testing a Q2W and Q3W dosing schedule. 
 
In Protocol 001, two randomized cohort evaluations of melanoma subjects receiving 
pembrolizumab at a dose of 2 mg/kg versus 10 mg/kg Q3W have been completed, while one 
randomized cohort evaluation of 10 mg/kg Q3W versus 10 mg/kg Q2W is ongoing. The 
clinical efficacy and safety data demonstrate a lack of clinically important differences in 
efficacy response or safety profile at these doses. For example, in Cohort B2, advanced 
melanoma subjects who had received prior ipilimumab therapy were randomized to receive 
pembrolizumab at 2 mg/kg versus 10 mg/kg Q3W. The ORR was 26% (21/81) in the 2 mg/kg 
group and 26% (25/79) in the 10 mg/kg group. The proportion of subjects with drug related 
AE, grade 3-5 drug-related AE, serious drug-related AE, death or discontinuation due to an AE 
was comparable between groups or lower in the 10 mg/kg group. PK data analysis of 
pembrolizumab administered Q2W and Q3W showed slow systemic clearance, limited volume 
of distribution, and a long half-life (refer to IB). Pharmacodynamic data (IL- 
2 release assay) suggested that peripheral target engagement is durable (>21 days). This early 
PK and pharmacodynamic data provides scientific rationale for testing a Q3W dosing 
schedule. Because Q3W dosing is more convenient for subjects, Q3W dosing will be further 
studied. 
 
A population pharmacokinetic analysis has been performed using serum concentration time 
data from 476 patients. Within the resulting population PK model, clearance and volume 
parameters of pembrolizumab were found to be dependent on body weight. The relationship 
between clearance and body weight, with an allometric exponent of 0.59, is within the range 
observed for other antibodies and would support both body weight normalized dosing or a 
fixed dose across all body weights. Pembrolizumab has been found to have a wide therapeutic 
range based on the melanoma indication. The differences in exposure for a 200 mg fixed dose 
regimen relative to a 2 mg/kg Q3W body weight-based regimen are anticipated to remain well 
within the established exposure margins of 0.5 – 5.0 for pembrolizumab in the melanoma 
indication. The exposure margins are based on the notion of similar efficacy and safety in 
melanoma at 10 mg/kg Q3W vs. the proposed dose regimen of 2 mg/kg Q3W (i.e. 5-fold 
higher dose and exposure). The population PK evaluation revealed that there was no 
significant impact of tumor burden on exposure. In addition, exposure was similar between 
the NSCLC and melanoma indications. Therefore, there are no anticipated changes in 
exposure between different indication settings and a dosage of 200mg fixed dose intravenous 
every 3 weeks will be tested in all future trials. 
 
4.2.2.2 Rationale for Dose Selection/Regimen/Modification of Radiation. 
The prescribed radiotherapy dose will be a total dose of 60 Gy given as twice daily fractions of 
1.2 Gy per fraction. This dose and schedule is a validated reirradiation regimen.26, 30, 56 The 
rational and specifics of the radiation plan are detailed in section 5.2.1. Radiation techniques 
that can be used in this trial include 3DCT, IMRT (Intensity-modulated radiation therapy), or 
IMPT (Intensity-modulated proton therapy). IMRT or IMPT is preferred over 3DCT. 
 
Proton Therapy (IMPT) as an option for Reirradiation. 
Reirradiation of recurrent or second primary HNSCC is emphasized as an indication for proton 
therapy. While the ability to use proton therapy in the treatment of patients with HNSCC is 


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more recent than IMRT, the use of protons as a treatment modality dates back to 194657 IMRT 
utilizes radiation portals in which the intensity of photon (X-ray) radiation varies throughout 
the field. To achieve high dose conformality for tumor targets and avoid critical normal 
structures, lower dose to non-target structures has to be increased. Therefore, normal non-target 
tissues receive a “low dose bath” of radiation with IMRT. 
 
While X-rays deliver dose to tumor they also expose “exit dose” to normal tissues distal to the 
tumor; protons, however are able to “stop” precisely within tumors and therefore have no exit 
dose. Protons lose all their energy in the last few millimeters of their penetration in tissue 
resulting in a sharply localized peak of dose known as the Bragg Peak. Hence the desired dose 
can be placed precisely at any given depth within the patient, according to the energy given to 
each proton. Because protons are absorbed in the Bragg peak within the tumor, this ‘‘dose 
bath’’ to normal non target tissue seen in IMRT, can be reduced with proton radiation 
therapy.58 
 
As the intensity of conventional photon radiation can be modulated to produce IMRT, the 
intensity of the proton radiation can also be modulated to produce intensity-modulated proton 
therapy (IMPT). This is achieved by a pencil beam scanning technique in which a small 
circular beam is scanned across the defined treatment field with the energy and intensity 
varying so that the dose in each voxel can be optimized. IMRT achieves two-dimensional 
optimization with modulation of the fluence occurring in the plane orthogonal to the beam 
direction. IMPT, in contrast, allows modulation of the fluence and the position of the Bragg 
peak. IMPT is therefore a three-dimensional optimization technique. IMPT has been shown to 
have a better ability  to spare normal tissues than IMRT for the treatment of head and neck 
cancers. Sparing of normal tissue is especially important in reirradiation, however it should be 
noted that the dose to the target volume is the same with photons or protons. In addition protons 
are a low LET (linear energy transfer) radiation similar to photons and have a comparable 
biologic effect in tissue relative to photons.59 Therefore, the most important difference with 
protons is their finite range in tissue, with subsequent decrease in dose bath to normal non 
target tissue.60, 61 Additionally, proton radiation is not experimental in head and neck cancer as 
it has been used outside of protocols as part of standard of care in the primary treatment of 
HNSCC and in the reirradiation setting.62-64 
 
4.2.3 
Rationale for Endpoints 
 
4.2.3.1 
Efficacy Endpoints 
 
4.2.3.1.1 
Primary 
The primary endpoint will be progression free survival (PFS), defined as the time from the date 
of initiation of treatment to the date of progression or death (whichever occurs first). This is a 
clinically relevant and appropriate endpoint for a phase II trial and one in which there are 
established historical comparisons based on previous reirradiation with concurrent 
chemotherapy trials. This endpoint encompasses prolonged stable disease which is important, 
given the propensity for pembrolizumab to lead to durable stable disease. 
 
4.2.3.1.2 
Secondary 


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Secondary endpoints include toxicity, overall survival, best overall response rate, clinical 
benefit rate, and time to in field progression. These are important and commonly used 
secondary endpoints in phase II trials. As detailed in Section 2.0 and 8.0, toxicity will be 
evaluated closely as this is an important end point for this trial. A stop rule is in place if the 
acute toxicity boundary is crossed, as detailed in Section 8.0. 
 
Patient reported outcomes, as measured by questionnaires EORTC QLQ-C30 and EORTC 
QLQ-H&N35, will be evaluated as patient experienced morbidity and quality of life are 
important measures in the treatment of SCCHN patients. The EORTC QLQ-C30 is one of the 
most widely used cancer specific health related quality of life tools. It contains 30 items.  It 
measures 5 functional dimensions (physical, role, cognitive, social, emotional), 6 single items 
(appetite loss, constipation, dyspnea, financial impact, sleep disturbance, diarrhea), 3 symptom 
items (fatigue, pain, nausea/vomiting) and a global health and quality of  life scale.65 
The EORTC QLQ-H&N35 is one of the most widely used tools for measuring quality of life in 
patients with SCCHN.66 It consists of 7 multi-item scales, measuring problems with 
swallowing, pain in the mouth, speech, senses, social eating and social contact, and 11 single-
item scales assessing problems with mouth opening, teeth, sticky saliva, dry mouth, coughing, 
feeling ill, use of nutritional supplements, use of feeding tube, weight gain and weight loss, and 
use of analgesics.67 The EORTC QLQ-C30 and EORTC QLQ-H&N35 are validated tools for 
assessing quality of life in SCCHN and have been used in both recurrent/metastatic trials as 
well as radiation trials.68, 69  They will be used at different times during this trial (as detailed in 
Section 6.0) to evaluate QOL of patients undergoing  treatment. 
 
4.2.3.2 
Biomarker/Exploratory Research 
The following exploratory post-hoc analyses will be done. 
4.2.3.2.1 
Tumor PD-L1 expression 
Tumor PD-L1 expression will be measured in biopsy specimens obtained before entry and 
analyzed retrospectively. While PD-L1 expression will not be required for entry onto the  trial, 
an increased response rate observed with anti-PD-1 and anti-PD-L1 mAb treatment in patients 
with baseline PD-L1 expression in NSCLC and melanoma has been observed.70-72 Therefore, 
we will retrospectively evaluate whether baseline PD-L1 expression correlates with efficacy 
endpoints. 
 
4.2.3.2.2 
Peripheral blood levels of cytotoxic T cells (CTL), regulatory T cells (Treg), and 
myeloid derived suppressor cells (MDSC) 
It will be important to study the effects of radiation in combination with pembrolizumab on the 
levels of cells of the immune system, including cytotoxic T cells, Tregs and MDSC, which 
have an important role in the immune response to malignancy. We will analyze percentages of 
CTLs, Tregs, and MDSCs in the peripheral blood over time. Serum will be drawn at initiation 
of therapy, completion of reirradiation, 3 months post completion of reirradiation, and at time 
of progression as detailed in Section 6.0. Percentages of these cells will be analyzed 
retrospectively by flow cytometry to see if there is any correlation with efficacy endpoints. 
 
4.2.3.2.3 
Human papilloma virus 
HPV associated oropharyngeal cancer, as measured by p16 expression in tumor biopsy 


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specimens from oropharyngeal cancer patients by immunohistochemistry, has been associated 
with improved outcomes, including in the recurrent/metastatic setting. 73-76 Additionally, HPV 
associated tumors have been observed to have higher PD-L1 expression and increased density 
of tumor infiltrating lymphocytes as detailed in the background section. Therefore, we will 
evaluate p16 status in pretreatment tumor biopsies from oropharyngeal cancer patients to 
evaluate retrospectively, if p16 expression correlates with efficacy endpoints. 
 
4.2.3.2.4 
Irradiated volume of vascular structures 
Different lymphocytes have varying degrees of sensitivity to radiation. Changes in radiation 
target volume size may alter the radiation dosage to circulating lymphocytes in the blood. 
Therefore, we will retrospectively analyze whether there was any correlation between 
irradiated volume of vascular structures during reirradiation and the efficacy of pembrolizumab 
combined with reirradiation. 
 
4.2.3.3 Future biomedical research 
With patient consent, the UPMC Hillman Cancer Center will conduct future biomedical 
research on blood and tumor tissue specimens collected during this clinical trial. This research 
may include but is not limited to genetic analyses (DNA), gene expression profiling (RNA), 
proteomics, metabolomics (serum, plasma) and/or the measurement of other analytes. Such 
research is for biomarker testing to address emergent questions not described elsewhere in the 
protocol (as part of the main trial). The objective of collecting specimens for future biomedical 
research is to explore and identify biomarkers that inform the scientific understanding of 
diseases and/or their therapeutic treatments. 
 
5.0 METHODOLOGY 
 
5.1 Entry Criteria 
 
5.1.1 
Diagnosis/Condition for Entry into the Trial 
Patients with biopsy proven locoregional recurrence or second primary SCCHN in a previously 
radiated field which is unresectable or the patient is unwilling to undergo resection. 
Determination of unresectability will be based on multidisciplinary review of each case. 
 
5.1.2 
Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
 
1. Patients with biopsy proven locoregional recurrence or second primary SCCHN which 
is unresectable or the patient is unwilling to undergo resection. 
 
2. Have received only one prior radiation treatment course. Prior radiation course must 
have been with curative intent. 
 
3. At least a 6-month interval since completion of prior radiation. 
 
4. Based on prior radiation records, have had most of the tumor volume (>50%) 
previously radiated at doses > 45 Gy without exceeding spinal cord tolerance 
(combining previous and future radiation dose to 1cc of the spinal cord of < 60 Gy). 


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5. Be willing and able to provide written informed consent/assent for the trial. 
 
6. Be willing to return to the center for all study-related follow up procedures, including 
blood collections and completion of imaging studies as required by the protocol. 
 
7. Be willing to undergo percutaneous endoscopic gastrostomy (PEG) placement, if 
necessary. 
 
8. Be ≥ 18 years of age on day of signing informed consent. 
9. Have at least one measurable area of disease based on RECIST 1.1 within the 
previously radiated field. 
10. Provide adequate tissue (core or incisional/excisional biopsy) prior to starting study 
treatment. This tissue will be used for PD-L1 analysis. Fresh tissue or archival tissue 
sample can be used. If adequate tissue cannot be safely obtained than the patient may 
still be enrolled on the trial after discussion with the study principal investigator as long 
as FNA was done to confirm recurrent/second primary HNSCC. 
 
11. Have a performance status of 0-1 on the ECOG Performance Scale. 
 
12. Life expectancy of at least 12 weeks based on investigator estimate. 
 
13. Demonstrate adequate organ function as determined by the labs in Table 2, performed 
within 21 days of treatment initiation. 
 
Table 2.  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
Absolute Neutrophil Count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L 
Renal 
Serum creatinine OR 
Measured or calculateda 
creatinine clearance 
(GFR can also be used in place 
of creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
≥60 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN 
Hepatic 
Serum total bilirubin 
≤ 1.5 X ULN OR 
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 
1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN OR 
≤ 5 X ULN for subjects with liver metastases 
Coagulation 
International Normalized Ratio (INR) 
or Prothrombin Time (PT) 
Activated Partial Thromboplastin 
Time (aPTT) 
≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as 
PT or PTT is within therapeutic range of intended use of anticoagulants 
≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as 
PT or PTT is within therapeutic range of intended use of anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 


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14. Female subjects of childbearing potential should have a negative urine or serum 
pregnancy within 72 hours prior to receiving the first dose of study medication. If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be 
required. 
 
15. Female subjects of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study medication (Reference Section 
5.8.2). Women of childbearing potential are those who have not been surgically 
sterilized or have not been free from menses for > 1 year. 
 
16. Male subjects should agree to use an adequate method of contraception starting with the 
first dose of study therapy through 120 days after the last dose of study therapy. 
 
17. Because informed consent and study materials will be in English, proficiency in English 
language is required. 
 
5.1.3 
Subject Exclusion Criteria 
 
The subject must be excluded from participating in the trial if the subject has any of the 
following: 
 
1. Presence of distant metastatic disease. 
 
2. Is currently participating in or has participated in a study of an investigational agent  or 
used an investigational device within 4 weeks of the first dose of treatment. 
 
3. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of trial 
treatment. 
 
4. Has had a prior monoclonal antibody, chemotherapy, or targeted small molecule 
therapy within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 
or at baseline) from adverse events due to agents administered more than 4 weeks 
earlier (alopecia is an exception). 
 
a. Note: Subjects with ≤ Grade 2 neuropathy or ototoxicity are an exception to this 
criterion and may qualify for the study. 
b. Note: If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy. 
 
5. History of other malignancy within 5 years with the exception of prior SCCHN, 
adequately treated basal cell or squamous cell skin cancer, or carcinoma of the cervix. 
 
6. Has an active autoimmune disease requiring systemic treatment within the past 3 


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months or a documented history of clinically severe autoimmune disease, or a 
syndrome that requires systemic steroids or immunosuppressive agents.  Subjects  with 
vitiligo, Grave’s disease, or psoriasis not requiring systemic therapy or resolved 
childhood asthma/atopy would be an exception to this rule. Subjects that require 
intermittent use of bronchodilators or local steroid injections would not be excluded 
from the study. Subjects with hypothyroidism stable on hormone replacement or 
Sjorgen’s syndrome will not be excluded from the study. 
 
7. Has a history of non-infectious pneumonitis that required steroids, evidence of 
interstitial lung disease, or currently active non-infectious pneumonitis. 
8. Has an active infection requiring systemic therapy. 
 
9. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation for 
the full duration of the trial, or is not in the best interest of the subject to participate, in 
the opinion of the treating investigator. 
 
10. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
 
11. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the screening visit through 120 days after 
the last dose of trial treatment. 
 
12. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or 
anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including 
ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or 
checkpoint pathways). 
 
13. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
 
14. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g. Hep C Ab 
positive with positive hepatitis C virus RNA PCR) 
 
15. Has received a live vaccine within 30 days prior to the first dose of trial treatment. 
 
5.2 Trial Treatments 
 
5.2.1 
Radiation Treatment 
 
5.2.1.1 Dose Fractionation 
The prescribed radiotherapy dose will be a total dose of 60 Gy given as twice daily fractions of 
1.2 Gy per fraction (total of 50 fractions and 25 intended treatments days), delivered at a 
minimum of 6 hours apart, five days a week for 5 consecutive weeks. This dose and schedule is 
a validated reirradiation regimen.26, 30, 56 This reirradiation regimen is considered a standard of 
care regimen for treatment of locoregional recurrence or second primary SCCHN. 
 


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Radiation treatment can begin Monday through Wednesday. Dose-limiting normal tissue 
constraints are listed in Section 5.2.1.5, including a limit of 60 Gy total (prior plus current) to 
1cc of the spinal cord. Missed treatments (for any reason) should be made up to reach the 
prescribed total radiation dose as detailed in Section 5.2.1.7. 
 
5.2.1.2 Technical Factors 
Patients will be treated with either photons alone or a combination of photons and electrons or 
with protons alone. Charged particle therapy will not be used. Those patients treated with 
photons will be treated using either the IMRT (intensity-modulated radiation therapy) 
preferentially or 3-D conformal techniques. Patients treated with protons will be treated with 
IMPT. Those patients whose recurrent tumor is in close vicinity of dental fillings would best be 
treated using IMRT rather than protons because of the stopping power of protons by the dental 
amalgam fillings. Otherwise, the choice of radiation modality will be determined by the 
treating radiation oncologist. Linear accelerators with appropriate photon and electron energies 
of 4 - 18 MV and/or 6-25 MeV must be used. Verification and quality assurance of isocenter 
placement, field placement, and dose distribution will be performed as per established 
departmental standards. 
 
Proton therapy being a low-LET (linear energy transfer) radiation is similar in biological 
behavior to photons. There will be no difference in the prescribed dose to the target which will 
receive the same conformal dose with protons as with photons. The active scanning pencil 
beam technique using either the SFO (single-field optimization) or MFO (multiple- field 
optimization) technique will be used to best cover the target and provide maximal sparing of 
critical adjacent tissues. Whether proton or photon radiation is used, the same localization, 
simulation, immobilization requirements, target volume, and treatment planning will be used as 
described below. 
 
5.2.1.3 Localization, Simulation, and Immobilization Requirements 
Patients will be treated in supine or other proper positions with their arms down to facilitate the 
positioning of the shoulders as low as possible, without compromising patient comfort. 
Dentures should be removed and metal crowns should be covered with a shielding agent 
(beeswax) to prevent mucosal irritation. Pre-therapy extraction of extensively diseased teeth 
and gingiva should be carried out with conservation of restorable teeth where possible. At least 
10 days should be allowed prior to the start of radiation for healing of gingivae post- extraction. 
Patients must be reproducibly immobilized in a thermoplastic (Aquaplast) mask including neck 
and shoulder immobilization whenever possible. When mask immobilization techniques are not 
possible due to patient discomfort, alternative techniques are allowed, but require stringent 
daily localization and imaging as described in Section 5.2.1.6 below. Radio- opaque markers 
should be used whenever possible to delineate the extent of nodal disease, skin involvement, 
and any gross disease. 
 
CT Simulation is mandatory. CT scan thickness should be at most 0.3 cm through the region 
that contains the primary target volumes. Intravenous contrast is recommended to better 
delineate tumor volume. Tumor volume must be identifiable on the CT images. CT/MRI or 
CT-PET fusion techniques may be used for better tumor delineation. 
 
5.2.1.4 Target Volumes 


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Gross tumor volume (GTV) is defined as the visible tumor and grossly enlarged lymph nodes 
on CT, MRI, PET-CT, or physical exam. No elective lymph node radiation will be performed. 
Clinical target volume, CTV = GTV + an isotropic expansion of 1.0 cm. In specific situations 
where a smaller expansion is deemed clinically necessary, a smaller expansion is acceptable in 
order to respect anatomic boundaries, or normal tissue dose constraints. Expansion of the GTV 
to CTV in the areas of natural boundaries such as bone should be per the physician’s 
judgment. The minimum boundary of any CTV should be 2-3 mm deep to the skin unless 
clinically involved. Planning target volume, PTV = CTV + 0.3 cm isotropic margin. Total 
margins less than 1.0 cm around the GTV will be deemed an acceptable deviation only in 
instances of spinal cord or carotid artery encroachment. Partial miss of the GTV or gross tumor 
cut through is an unacceptable deviation. 
 
5.2.1.5 Treatment Planning 
Records of prior radiotherapy treatments will be obtained. Records will be reviewed to 
determine and record the dose received. Representative cross-sectional images of patient 
anatomy and plan data will be reviewed to determine the regions treated and doses received. 
Whenever possible, dose-volume histograms will be reviewed. Doses to critical organs at risk, 
to at least include the spinal cord, brainstem, and optic apparatus when in or adjacent to a 
treatment field, will be recorded. Dose to overlapping regions of the spinal cord must be 
limited to 60 Gy total (prior plus current) to 1cc. If the spinal cord constraints cannot be met or 
previous treatment data are not available, patients will not be offered treatment on study. 
 
Radiation dose should be prescribed to an isodose line that encompasses the PTV. The 
inhomogeneity within the target volume should not exceed ±10% of the target dose. The 
following are treatment planning goals are listed in priority order (violation of goals 2-5 will 
not constitute study ineligibility; only goal 1 will be required for all patients): 
 
1. The spinal cord max dose to 1 cc will be <60 Gy total (prior plus current). 
 
2. 100% of the prescription dose should minimally cover 100% of the GTV. 
 
3. 95% of the prescription dose should minimally cover 95% of the PTV. 
 
4. No points should receive >105% of the prescription dose outside of the PTV. 
 
5. If possible, avoid the development of hotspots over the carotid arteries. 
 
Documentation (typically in the form of treatment plan report pdf) of both prior and current 
radiation treatment records must be submitted to the coordinating center within 1 week of 
starting treatment for quality assurance. 
 
Dose-Volume Analysis: 
Please note that coverage of the target volumes according to the criteria listed above should not 
be sacrificed in order to meet the dose constraint of any organ at risk, with the exception of the 
spinal cord.  The following are general guidelines for organ at risk (OAR) constraints: 
 
Organ at Risk 
Dose Constraint 


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Retina 
Max dose ≤45Gy 
 
Optic nerves 
Max dose ≤55Gy 
 
Optic chiasm 
Max dose ≤55Gy 
 
Lacrimal glands 
Max dose ≤30Gy 
 
Brainstem 
Max dose ≤54Gy 
 
Cochleas 
Max dose ≤35Gy 
 
Spinal cord 
V48 < 0.3cc 
 
Parotid glands (each) 
Mean <26Gy 
D50% <30Gy 
At least 20 cc <20Gy (combined) 
 
Mandible 
Max dose ≤ 60Gy 
 
Oral cavity 
Mean dose < 50 Gy 
 
Brachial plexus 
Max dose ≤60Gy 
 
The following additional contours will be added for data collection, but will not be used for 
plan optimization or evaluation: 
 
• Right carotid: common and internal carotid superiorly to base of skull, inferiorly to 2cm 
below PTV 
• Left carotid: common and internal carotid superiorly to base of skull, inferiorly to 2cm 
below PTV 
• Right lymphatics: neck LN levels II - IV, inferiorly to 2cm below PTV 
• Left lymphatics: neck LN levels II - IV, inferiorly to 2cm below PTV 
Right vascular structures (when intravenous contrast used): to include the internal carotid to the 
skull base, external carotid and named branches within 1 cm to the level of the maxillary artery, 
and internal jugular to the base of skull. Inferior extent 2cm below PTV. 
 
Left vascular structures (when intravenous contrast used): to include the internal carotid to the 
skull base, external carotid and named branches within 1 cm to the level of the maxillary artery, 
and internal jugular to the base of skull. Inferior extent 2cm below PTV. 
Organ-at-risk, target coverage, and secondary dosimetric endpoint data [found in Corollary 
Dosimetric Data form] should be documented in the form of DVH, clinical goals, and 
completed corollary data form and included in the treatment plan report sent to the coordinating 


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center. 
 
5.2.1.6 Treatment Delivery and Verification 
When 3-D conformal technique is used, a combination of lateral opposing fields, single fields, 
anterior and lateral wedge pair fields, and oblique fields may be used for the site of 
recurrent tumor. When IMRT is used, static or dynamic techniques may be utilized as per 
institutional preference. Beam/Isocenter localization films (portal films) or electronic portal 
images (EPIs) should be obtained for all photon and electron fields before and at least once a 
week during the whole course of radiation therapy. Similarly, in the case of proton treatments, 
orthogonal fields will be taken prior to each treatment delivery to verify and confirm the 
treatment localization. 
 
Daily imaging is necessary to keep the PTV margin at 3mm. 
 
For photon patients, on the first day of treatment, kV images should be obtained and the 
patient’s position corrected by bony alignment, then a cone-beam CT (CBCT) should be 
obtained if available to ensure appropriate alignment of the treated volumes with the soft tissue 
anatomy. CBCT should be repeated on days #2 and #3 in order to establish a correlation 
between kV and CBCT. This may require a member of the primary team to help with 
alignments. Thereafter, daily kV and weekly CBCT should be performed. Alternatively, daily 
CBCT localization may be employed for patients unable to tolerate thermoplastic (Aquaplast) 
mask immobilization. 
 
For proton patients, daily kV images should be obtained and the patient’s position corrected by 
bony alignment. Since CBCT is not routinely available for proton therapy, patients receiving 
proton therapy should receive at least weekly re-simulation CT scans if CBCT is not available 
to assess for changes in tumor and/or patient anatomy as detailed below. If CBCT is available 
to proton patients, then at least weekly CBCT should be performed; re- simulation CT scans 
would then only be necessary if re-planning may be considered due to significant changes on 
CBCT. 
 
Re-simulation for proton or photon patients should occur if the PTV no longer covers the entire 
GTV as seen on CBCT, if the patient’s immobilization devices no longer fit properly due to 
weight loss or soft tissue swelling, or if there is ≥ 2.0 cm change in SSD. Re- simulation may 
also be considered if there is profound tumor regression that would affect immobilization or 
plan accuracy. Re-planning should be performed at the discretion of the treating physician and 
guided by the ability to maintain adequate target volume coverage and acceptable normal organ 
dose. Because even slight changes in tumor and normal tissue anatomy much more 
significantly affect target volume and normal tissue dose delivery from proton therapy versus 
photon therapy, re-simulation should especially be considered for patients receiving proton 
therapy. It is strongly recommended to re-simulate proton patients on a weekly basis, especially 
if CBCT is not available, or even more frequently based on the physician’s clinical assessment 
of the patient. 
 
5.2.1.7 Missed treatments 
Treatment breaks must be clearly indicated in the treatment record. Protocol management of 
treatment breaks resulting from acute toxicity are described in section 5.3.2. Missed treatments 


Amendment 8, 07/26/2018 
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for any reason should be made up to reach the prescribed total radiation dose. Whenever 
possible, a sixth treatment day (i.e. Saturday or Sunday) may be added per week to complete all 
fractions within the originally planned treatment duration.  Should a single fraction be missed 
(i.e. only one fraction delivered in a given day), treatment should be resumed as soon as 
feasible with the next planned fraction without any attempt to offset the schedule to complete 
treatment with two fractions in the final day. At no point should there be an interval less than 6 
hours between fractions. 
 
5.2.1.8 
Documentation Requirements 
At the completion of treatment, the following should be kept in patient’s file: 
 
1. The administration times of the RT 
2. Daily treatment record 
3. All isodose distributions 
4. Simulation and portal films 
5. Radiotherapy summary 
6. CT/MRI documentation 
7. Treatment (beam-on) duration. 
 
5.2.2 Treatment with Pembrolizumab 
 
The dosing of pembrolizumab is outlined below in Table 3. 
Table 3.  Trial Treatment 
 
Drug 
Dose/ 
Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/ Treatment 
Period 
Use 
Pembrolizumab 
200mg 
Q3W 
IV infusion 
Day 1 of each 
cycle 
Experimental 
The pembrolizumab dosing interval may be increased due to toxicity as described in Section 5.4.2 
 
Treatment with pembrolizumab should begin on Day 1 or Day 2 of radiation. Doses of 
pembrolizumab during radiation treatment can be given before or after the first radiation 
treatment of the day. 
 
5.3  Dose Selection/Modification of Radiation Therapy 
 
5.3.1 
Dose Selection 
The rationale for selection of radiation dosing and schedule of treatment to be used in this trial 
is provided in Section 5.2.1. 
 
5.3.2 
Radiation Therapy Toxicity Evaluation and Dose Modification 
All acute radiation toxicities (defined as toxicities occurring within 90 days from therapy start) 
will be graded according CTCAE v.4.0. During treatment with reirradiation plus concurrent 
chemotherapy, Grade 3, therapy-induced, acute non-hematologic toxicities have been observed 
in upwards of 30-50% patients.56 30-32, 34 Common acute radiation adverse events in this patient 


Amendment 8, 07/26/2018 
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population include mucositis, pain, esophagitis, dysphagia, fatigue, weight loss, regional 
alopecia, xerostomia, hoarseness, transient ear discomfort, dysgeusia, and skin erythema and 
desquamation within the treatment fields. Nutritional evaluation prior to the initiation of 
therapy is highly recommended. Placement of a prophylactic gastrostomy tube or PEG tube 
during therapy will be at the discretion of the treating physician. In the case of severe weight 
loss, the use of tube feedings is encouraged as it is anticipated to minimize further treatment 
interruptions. 
 
Late toxicities (defined as toxicities occurring after 90 days of therapy initiation) will be graded 
according to CTCAE v4.0. Late toxicities can include permanent xerostomia and occasionally 
persistent dysphagia. Less common long-term treatment adverse events include: 
hypothyroidism, loss of hearing, chronic swallowing dysfunction requiring permanent feeding 
tube, and cervical fibrosis. Rarer late radiation adverse events include: mandibular 
osteoradionecrosis and cervical myelopathy. Special attention should be directed in follow-up 
exams to any numbness or paresthesia, particularly in the first 6-12 months of follow-up. There 
is a relatively small, but real risk of carotid rupture in patients whose tumors overlap the carotid 
artery. Most of these events have occurred in association with active tumor in this region and 
may not necessarily be due to adverse effects of treatment. 
 
Every effort should be made to continue radiation therapy without interruption.  Grade 3 acute 
radiation toxicity is expected in a significant proportion of cases and should, in general, not 
lead to interruption of radiation therapy. However, interruptions in radiotherapy may be 
necessitated by > grade 4 skin or mucosal toxicity or uncontrollable pain. Should severe 
radiation associated toxicity such as confluent mucositis, moist desquamation unresponsive to 
topical dressings, or severe stomatitis resulting in weight loss greater than 15% occur, treatment 
may be interrupted in order to relieve morbidity at the sole discretion of the treating radiation 
oncologist. If a treatment delay for acute toxicity is required, the total RT dose and dose per 
fraction will not be modified. Note, that any grade 4-5 acute radiation toxicity that occurs 
within 7 weeks of initiation of therapy counts toward the early stopping rule which is detailed 
in Section 8.0. 
 
Acute local toxicity attributable to radiation effects (≤ grade 3) and not pembrolizumab should 
be managed accordingly with optimal supportive care measures. If toxicity ≥ grade 4 persists, 
then a radiation break is allowable as defined above. Every effort should be made to avoid 
breaks in radiation treatment. If pembrolizumab is held due to other toxicity attributed solely to 
the pembrolizumab, as discussed in section 5.4.2, the radiation therapy should be continued. 
 
Patients will be seen by a radiation oncologist each week during Weeks 1-7 for directed 
physical exam and toxicity evaluation. After the seventh week they will be seen at least once a 
month until 3 months after completion of radiation.  This is detailed in table 6.1. 
 
 


Amendment 8, 07/26/2018 
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5.4  Dose Selection/Modification for Pembrolizumab 
 
5.4.1 
Dose Selection for Pembrolizumab 
The rationale for selection of doses to be used in this trial is provided in Section 4.0 – 
Background and Rationale. 
 
Pembrolizumab will be given at a dosage of 200mg intravenously every 3 weeks for all 
patients. 
 
5.4.2 
Pembrolizumab Toxicity Evaluation and Dose Modification 
Toxicity from pembrolizumab will be graded by CTCAE v4.0. Pembrolizumab will be 
withheld for drug-related grade 4 hematologic toxicities. As discussed above, due to the 
expectation of significant grade < 3 acute radiation toxicity with reirradiation, treatment with 
pembrolizumab will only be held for acute radiation toxicity that is grade 4, and resumed 
when this toxicity is < grade 3. Acute radiation toxicity includes pain, local skin toxicity, 
mucositis/esophagitis, dysphagia, odynophagia, weight loss, hoarseness, regional alopecia, 
xerostomia, transient ear discomfort, or other toxicity that in the investigators opinion is from 
acute radiation toxicity. Pembrolizumab will be held for grade > 3 non-hematologic toxicity 
attributed to pembrolizumab rather than radiation. If the patient requires a treatment break 
from radiation and the patient is due for the next dosage of pembrolizumab during the time of 
a treatment break, then that dosage of pembrolizumab will be held. The next dosage of 
pembrolizumab will be given on the first Monday after resumption of radiation treatment and 
continued every 3 weeks as per protocol. 
 
 
 


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Table 4.  Pembrolizumab dose modification guidelines for drug-related adverse events 
 
Toxicity 
Grade 
Hold 
Treatment 
(Y/N) 
Timing for 
Restarting 
Treatment 
Dose/Schedule for 
Restarting Treatment 
Discontinue 
Subject (after 
consultation 
with Sponsor) 
Hematological 
Toxicity 
1, 2 
No 
N/A 
N/A 
N/A 
3* 
 
Yes 
Toxicity 
resolves to 
Grade 0-1 or 
baseline 
May increase the dosing 
interval by 1 week** 
Toxicity does not 
resolve within 12 
weeks of last 
infusion 
Permanent 
discontinuation 
should be 
considered for 
any severe or 
life-threatening 
event 
4 
Yes 
Toxicity 
resolves to 
Grade 0-1 or 
baseline 
May increase the dosing 
interval by 1 week** 
Non-
hematological 
toxicity 
 
Note: Exception 
to be treated 
similar to grade 
1 toxicity: 
• Grade 2 
alopecia 
• Grade 2 
fatigue 
 
For additional 
information 
regarding 
Adverse 
Events with a 
potential 
Immune- 
Etiology 
reference 
Section 5.7.2. 
1 
No 
N/A 
N/A 
N/A 
2 
Consider 
withholding 
for 
persistent 
symptoms 
Toxicity 
resolves to 
Grade 0-1 or 
baseline 
Clinical AE resolves within 4 
weeks: Same dose and 
schedule 
(reference Section 5.7.3 for 
recommendations regarding 
pneumonitis) 
Clinical AE does not 
resolve within 4 weeks: 
May increase the dosing 
interval by 1 week for each 
occurrence** 
Toxicity does not 
resolve within 12 
weeks of last 
infusion 
3***, 4 
Yes 
Toxicity 
resolves to 
Grade 0-1 or 
baseline 
May increase the dosing 
interval by 1 week for each 
occurrence** 
Toxicity does not 
resolve within 12 
weeks of last 
infusion 
Permanent 
discontinuation 
should be 
considered for 
any severe or 
life-threatening 
event 
*Excluding Grade 3 neutropenia, anemia, and thrombocytopenia ; 
** The dosing interval can be increased to every 4 weeks. If toxicity resolves to grade 0-1 or baseline the dosing 
interval can be decreased to every 3 weeks again at the discretion of the investigator;  
*** Pembrolizumab will be held for a grade 3 or 4 toxicity that is considered related to pembrolizumab. However a 
grade 3 toxicity that is considered an acute radiation toxicity will not require holding of pembrolizumab unless 
radiation therapy is on hold. Pembrolizumab will be held for a grade 4 acute radiation toxicity. Pembrolizumab can 
be restarted when acute radiation toxicity improves to grade <3. 
 
In case a drug related toxicity that is not a toxicity associated with radiation does not resolve 
to grade 0-1 within 12 weeks after last infusion, trial treatment should be discontinued after 
consultation with the Sponsor. With investigator and Sponsor agreement, subjects with a 
laboratory adverse event still at grade 2 after 12 weeks may continue treatment in the trial 


Amendment 8, 07/26/2018 
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only if the adverse event is asymptomatic and controlled. For information on medications to 
manage adverse events, see Section 5.7. 
 
Subjects who experience a recurrence of the same severe or life-threatening event at the same 
grade or greater with re-challenge of pembrolizumab should be discontinued from trial 
treatment. 
 
5.4.3 
Timing of Dose Administration 
Trial treatment should be administered after all procedures/assessments have been completed 
as detailed in Section 6.0. The first dosage of pembrolizumab should be given on the first or 
second day of radiation. Every effort should be made to give the second pembrolizumab dose 
on a Monday as well. Doses of pembrolizumab during radiation treatment can be given before 
or after the first radiation treatment of the day. Subsequent pembrolizumab treatment may be 
administered up to 3 days before or after the scheduled Day 1 of each cycle due to 
administrative reasons. 
 
Pembrolizumab will be administered as a 30 minute IV infusion (treatment cycle intervals may 
be increased due to toxicity as described in Section 5.4.2). Every effort should be made to 
target infusion timing to be as close to 30 minutes as possible. However, given the variability 
of infusion pumps, a window of -5 minutes and +10 minutes is permitted (i.e., infusion time is 
30 minutes: -5 min/+10 min). 
 
5.5 Trial Registration 
 
This is an open-label, single arm trial. All patients will undergo the study treatment. The 
investigator and subject will know the treatments and dosages administered. 
 
5.6 Concomitant Medications/Vaccinations (allowed & prohibited) 
 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial. If there is a clinical indication for one of these or other medications or 
vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination schedule may be required. The investigator should discuss any questions regarding 
this with the Sponsor. The final decision on any supportive therapy or vaccination rests with 
the investigator and/or the subject's primary physician. However, the decision to continue the 
subject on trial therapy or vaccination schedule requires the mutual agreement of the 
Investigator and the subject. 
 
5.6.1 
Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplement, and IV medications.  If 
changes occur during the trial period, documentation of drug dosage, frequency, route, and date 
may also be included on the CRF. 
 
All concomitant medications received within 30 days before the first dose of trial treatment and 


Amendment 8, 07/26/2018 
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30 days after the last dose of trial treatment should be recorded. Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs and 
ECIs (events of clinical interest) as defined in Section 7.2. 
 
5.6.2 
Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
 
• Anti-cancer systemic chemotherapy or biological therapy 
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab 
• Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chicken pox, yellow fever, rabies, tuberculosis 
(bacille Calmette-Guerin—BCG), and typhoid (oral) vaccine. Seasonal influenza 
vaccines for injection are generally killed virus vaccines and are allowed; however 
intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated vaccines and are not 
allowed. 
• Glucocorticoids for any purpose other than the treatment or prophylaxis of any adverse 
event (intermittent use of bronchodilators or local steroid injections is allowed). 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial. Subjects 
may receive other medications that the investigator deems to be medically necessary. 
 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.7  Rescue Medications & Supportive Care 
 
5.7.1 
Supportive Care Guidelines for Pembrolizumab 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator, including, but not limited to the items outlined below.  Additional details 
are provided in the event of clinical interest and immune-related adverse event guidance 
document Section 12. 
 
• Diarrhea: Subjects should be carefully monitored for signs and symptoms of 
enterocolitis (such as diarrhea, abdominal pain, blood or mucus in stool, with or without 
fever) and of bowel perforation (such as peritoneal signs and ileus). In symptomatic 
subjects, infectious etiologies should be ruled out. If symptoms are persistent and/or 
severe, endoscopic evaluation should be considered. 
o In subjects with severe enterocolitis (grade 3), pembrolizumab will be 
permanently discontinued and treatment with systemic corticosteroids should be 
initiated at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When 
symptoms improve to grade 1 or less, corticosteroid taper should be started and 


Amendment 8, 07/26/2018 
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continued over at least 1 month. 
o In subjects with moderate enterocolitis (grade 2), pembrolizumab should be 
withheld and anti-diarrheal treatment should be started. If symptoms are 
persistent for more than one week, systemic corticosteroids should be initiated 
(e.g., 0.5 mg/kg/day of prednisone or equivalent).  When symptoms improve to 
grade 1 or less, corticosteroid taper should be started and continued over at least 
1 month. For guidelines for continuing treatment with pembrolizumab, see 
Section 5.4.2. 
o All subjects who experience diarrhea should be advised to drink liberal 
quantities of clear fluids. If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion. 
• Nausea/vomiting: Nausea and vomiting should be treated aggressively, and 
consideration should be given to the administration of prophylactic antiemetic therapy 
according to standard institutional practice. Subjects should be strongly encouraged to 
maintain liberal oral fluid intake. 
• Anti-infectives: Subjects with a documented infectious complication should receive 
oral or IV antibiotics or other anti-infective agents as considered appropriate by the 
treating investigator for a given infectious condition, according to standard 
institutional practice. 
• Immune-related adverse events: Please see Section 5.7.2 below and the separate 
guidance document in appendix Section 12 regarding diagnosis and management of 
adverse experiences of a potential immunologic etiology. 
• Management of infusion reactions: Acute infusion reactions (which can include 
cytokine release syndrome, angioedema, or anaphylaxis) are different from 
allergic/hypersensitive reactions, although some of the manifestations are common to 
both types of AEs. Signs and symptoms usually develop during or shortly after drug 
infusion and generally resolve completely within 24 hours of completion of infusion. 
Signs/symptoms may include: allergic reaction/hypersensitivity (including drug 
fever); arthralgia (joint pain); bronchospasm; cough; dizziness; dyspnea (shortness of 
breath); fatigue (asthenia, lethargy, malaise); headache; hypertension; hypotension; 
myalgia (muscle pain); nausea; pruritus/itching; rash/desquamation; rigors/chills; 
sweating (diaphoresis); tachycardia; tumor pain (onset or exacerbation of tumor pain 
due to treatment); urticaria (hives, welts, wheals); vomiting. 
 
Table 5 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab. 
 
 
 


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Table 5.  Infusion Reaction Treatment Guidelines 
 
NCI CTCAE Grade 
Treatment 
Premedication at 
Subsequent Dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
None 
Grade 2 
Requires infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤ 24 hrs 
Stop infusion and monitor symptoms. 
Additional appropriate medical therapy 
may include but is not limited to: 
• 
IV fluids 
Antihistamines 
NSAIDS 
• 
Acetaminophen 
• 
Narcotics 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate 
(e.g. from 100 mL/hr to 50 mL/hr). 
Otherwise dosing will be held until symptoms 
resolve and the subject should be 
premedicated for the next scheduled dose. 
Subjects who develop Grade 2 toxicity 
despite adequate premedication should 
be permanently discontinued from 
further trial treatment administration. 
Subject may be 
premedicated 1.5h (± 30 
minutes) prior to infusion 
of pembrolizumab with: 
• 
Diphenhydramine 
50 mg po (or 
equivalent dose of 
antihistamine). 
• 
Acetaminophen 500-
1000 mg po (or 
equivalent dose of 
antipyretic). 
Grades 3 or 4  
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; hospitalization 
indicated for other clinical 
sequelae (e.g., renal 
impairment, pulmonary 
infiltrates) 
 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Stop infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
• 
IV fluids 
• 
Antihistamines 
• 
NSAIDS 
• 
Acetaminophen 
• 
Narcotics 
• 
Oxygen 
• 
Pressors 
• 
Corticosteroids 
• 
Epinephrine 
 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued 
from further trial treatment 
administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available 
during the period of drug administration. For Further information, please refer to the Common Terminology 
Criteria for Adverse Events v4.0 (CTCAE) at http://ctep.cancer.gov 


Amendment 8, 07/26/2018 
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5.7.2 
Supportive Care Guidelines for Events of Clinical Interest and Immune-related 
Adverse Events (irAEs) 
Events of clinical interest of a potential immunologic etiology (irECIs) may be defined as an 
adverse event of unknown etiology associated with drug exposure and is consistent with an 
immune phenomenon. irAEs may be predicted based on the nature of the pembrolizumab 
compound, its mechanism of action, and reported experience with immunotherapies that have a 
similar mechanism of action. Special attention should be paid to AEs that may be suggestive of 
potential irAEs. An irAE can occur shortly after the first dose or several months after the last 
dose of treatment. Additional details are provided in the Event of Clinical Interest and Immune-
Related Adverse Event Guidance Document (Section 12). 
If an irAE is suspected, efforts should be made to rule out neoplastic, infectious, metabolic, 
toxin or other etiologic causes prior to labeling an adverse event as an irAE. Information on 
how to identify and evaluate irAEs has been developed and is included in the Event of Clinical 
Interest and Immune-Related Adverse Event Guidance Document (Section 12). Subjects who 
develop a grade 2 or higher irAE should be discussed immediately with the Sponsor. 
 
Recommendations to managing irAEs not detailed elsewhere in the protocol are detailed in 
Table 6. 
 
Table 6.  General Approach to Handling irAEs 
 
irAE 
Withhold/Discontinue 
Pembrolizumab? 
Supportive Care 
Grade 1 
No action 
Provide symptomatic treatment 
Grade 2 
May withhold pembrolizumab Consider systemic corticosteroids in addition to 
appropriate symptomatic treatment 
Grade 3 and Grade 4 
Withhold pembrolizumab 
Discontinue if unable to 
reduce corticosteroid dose to 
< 
10 mg per day prednisone 
equivalent within 12 weeks 
of toxicity 
Systemic corticosteroids are indicated in 
addition to appropriate symptomatic treatment. 
May utilize 1 to 2 mg/kg prednisone or 
equivalent per day. 
Steroid taper should be considered once 
symptoms improve to Grade 1 or less and 
tapered over at least 4 weeks. 
 
5.7.3 
Supportive Care Guidelines for Pneumonitis 
Subjects with symptomatic pneumonitis should immediately stop receiving pembrolizumab and 
have an evaluation. The evaluation may include bronchoscopy and pulmonary function tests to 
rule out other causes such as infection.  If the subject is determined to have study drug 
associated pneumonitis, the suggested treatment plan is detailed in Table 7. 
 
 
 


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Table 7.  Recommended Approach to Handling Pneumonitis 
 
Study Drug Associated 
Pneumonitis 
Withhold/Discontinue 
Pembrolizumab? 
Supportive Care 
Grade 1 (asymptomatic) 
No action 
Intervention not indicated 
Grade 2 
Withhold 
pembrolizumab, may 
return to treatment if 
improves to Grade 1 or 
resolves within 12 weeks 
Systemic corticosteroids are indicated. Taper if 
necessary. 
Grade 3 and Grade 4 
Discontinue pembrolizumab Systemic corticosteroids are indicated. The use of 
infliximab may be indicated as appropriate. Refer 
to the Event of Clinical Interest and Immune-
related Adverse Event Guidance Document 
(Section 12) for additional recommendations. 
For grade 2 pneumonitis that improves to ≤ grade 1 within 12 weeks, the following rules 
should apply: 
 
• First episode of pneumonitis 
o May increase dosing interval by one week (q 4 weeks) in subsequent cycles 
• Second episode of pneumonitis – permanently discontinue pembrolizumab if upon 
rechallenge subject develops pneumonitis ≥ grade 2 
 
5.8  Diet/Activity/Other Considerations 
 
5.8.1 
Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AEs 
such as diarrhea, nausea or vomiting, mucositis, or dysphagia. Consultation with nutrition 
during radiation therapy is strongly recommended. 
 
5.8.2 
Contraception 
Pembrolizumab may have adverse effects on a fetus in utero. Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm. Non-pregnant, non-
breast-feeding women may be enrolled if they are willing to use 2 methods of birth control or 
are considered highly unlikely to conceive. Highly unlikely to conceive is defined as 1) 
surgically sterilized, or 2) postmenopausal (a woman who is ≥45 years of age and has not had 
menses for greater than 1 year will be considered postmenopausal), or 3) not heterosexually 
active for the duration of the study. The two birth control methods can be either two barrier 
methods or a barrier method plus a hormonal method to prevent pregnancy. Subjects should 
start using birth control from the screening visit throughout the study period up to 120 days 
after the last dose of study therapy. 
 
The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide. Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents). 


Amendment 8, 07/26/2018 
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Subjects should be informed that taking the study medication may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study. In order to participate in the 
study they must adhere to the contraception requirement (described above) for the duration of 
the study and during the follow-up period defined in Section 7.2.2-Reporting of Pregnancy and 
Lactation to the Sponsor and to Merck. If there is any question that a subject will not reliably 
comply with the requirements for contraception, that subject should not be entered into the 
study. 
 
5.8.3 
Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will immediately be removed from the study. The site will contact the subject at least 
monthly and document the subject’s status until the pregnancy has been completed or 
terminated.   The outcome of the pregnancy will be reported to the sponsor and to Merck 
without delay and within 24 hours if the outcome is a serious adverse experience (e.g., death, 
abortion, congenital anomaly, or other disabling or life-threatening complication to the mother 
or newborn). The study investigator will make every effort to obtain permission to follow the 
outcome of the pregnancy and report the information to the sponsor and to Merck. If a male 
subject impregnates his female partner, the study personnel at the site must be informed 
immediately, and the pregnancy must be reported to the sponsor and to Merck, and followed as 
described above and in Section 7.2.2. 
 
5.8.4 
Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk. Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment. 
 
5.9  Subject Withdrawal, Replacement and Criteria for Early Trial Termination 
 
5.9.1 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur. In addition, a subject may be 
withdrawn by the Investigator if enrollment into the trial is inappropriate, the trial plan is 
violated, or for administrative and/or other safety reasons. Specific details regarding 
discontinuation or withdrawal are provided in Section 7.1.4 – Other Procedures. 
 
A subject must be discontinued from the trial treatment for any of the following reasons: 
 
• The subject withdraws consent. 
• Confirmed radiographic disease progression.  See Section 7.1.2.6 
• Unacceptable adverse events as described in Section 5.4.2 
• Intercurrent illness that prevents further administration of treatment 
• Investigator’s decision to withdraw the subject 
• The subject has a confirmed positive serum pregnancy test 
• Noncompliance with trial treatment or procedure requirements 
• The subject is lost to follow-up 


Amendment 8, 07/26/2018 
Page 36 
 
 
• Completed 24 months of treatment with pembrolizumab 
o Note: 24 months (104 weeks) of study medication is calculated from the date of 
first dose. Subjects who stop pembrolizumab after 24 months may be eligible 
for up to 12 months of additional study treatment if they progress after stopping 
study treatment provided they meet the requirements detailed in Section 
7.1.5.2.1. 
• Administrative reasons 
 
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Protocol Flow 
Chart) and Section 7.1.5 (Visit Requirements). After the end of treatment, each subject will be 
followed for 30 days for adverse event monitoring (serious adverse events will be collected for 
90 days after the end of treatment as described in Section 7.2.3.1).  Subjects who 
discontinue for reasons other than progressive disease will have post-treatment follow- up for 
disease status until disease progression, initiating a non-study cancer treatment, withdrawing 
consent or becoming lost to follow-up. After documented disease progression, each subject will 
be followed by telephone for overall survival until death, withdrawal of consent, or the end of 
the study, whichever occurs first. 
 
5.10 Subject Replacement Strategy 
A subject that withdraws from the trial for reasons other than toxicity, progression of disease or 
death and withdraws before the initial efficacy evaluation (PET/CT done at 3 months after 
completion of radiation) can be replaced. These cases will be recorded and accounted for in the 
report of the trial. 
 
5.11 Criteria for Early Trial or Performance Site Termination 
Early trial termination will be the result of meeting one of the criteria specified below: 
 
1 Quality or quantity of data recording is inaccurate or incomplete. 
2 Poor adherence to protocol and regulatory requirements. 
3 Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects. 
4 If acute radiation toxicity threshold is crossed by the first 20 patients enrolled as detailed 
in Section 8.0, discussion with Merck will ensue and trial may be closed early. 
5 Plans to modify or discontinue the development of the study drug. 
 
In the event of Merck’s decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made. 


Amendment 8, 07/26/2018 
Page 38 
 
 
6.0 TRIAL FLOW CHARTS 
 
6.1 Initial Treatment Phase 
 
Trial Period: 
Screening Day -
28 to -1 
Radiation + Pembrolizumab Treatment 1 
Pembrolizumab 
Monotherapy  
(Weeks 6-16)2 
3 Months 
Post 
Radiation 
Imaging3 
Radiation Treatment 
(1.2Gy BID Monday–Friday x25 days) 
Treatment with radiation 1.2Gy BID Monday –Friday X 25 
treatment days (weeks 1-5) 
Pembrolizumab Treatment 
(Day 1 of each 21 Day Cycle): 
Cycle 1, Day 1 
Cycle 2, Day 1 
Day 1, Cycles 3-6 
Week 17 
+/- 7 days 
Scheduling Window (Days): 
+ 1 day 
+1 day 
+/- 3 days 
Administrative Procedures 
Informed Consent 
X 
Inclusion/Exclusion Criteria 
X 
Demographics and Medical History 
X 
Prior and Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
SCCHN History and Treatment 
X 
Pembrolizumab Treatment Administration 
X 
X 
X 
X 
X 
X 
X9 
Clinical Procedures/Assessments 
Review Adverse Events1 
X 
X 
X 
X 
X 
X 
X 
X 
Full Physical Examination 
X 
X 
X 
Directed Physical Examination1 
X 
X 
X 
X 
X 
Vital Signs and Weight5 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
Dental Evaluation 6 
X 
12 Lead EKG 
X 
X 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 
Pregnancy Test – Urine or Serum β-HCG7 
X 
PT/INR and aPTT12 
X 
CBC with Differential8 
X 
X 
X15 
X 
X 
X 
X 


Amendment 8, 07/26/2018 
Page 40 
 
 
 
 
Trial Period: 
Screening Day -
28 to -1 
Radiation + Pembrolizumab Treatment 1 
Pembrolizumab 
Monotherapy 
(Weeks 6-16)2 
3 Months 
Post 
Radiation 
Imaging3 
Radiation Treatment 
(1.2Gy BID Monday–Friday x25 days) 
Treatment with radiation 1.2Gy BID Monday –Friday X 25 
treatment days (weeks 1-5) 
Pembrolizumab Treatment 
(Day 1 of each 21 Day Cycle): 
Cycle 1, Day 1 
Cycle 2, Day 1 
Day 1, Cycles 3-6 
Week 17 
+/- 7 days 
Scheduling Window (Days): 
+ 1 day 
+1 day 
+/- 3 days 
Comprehensive Serum Chemistry Panel14 
X 
X 
X15 
X 
X 
X 
X 
Urinalysis 
X 
X 
T3, FT4 and TSH 
X 
X 
Hepatitis C Ab16 
X 
HBsAg, HBsAb 
X 
HIV 1/2 Antibodies 
X 
Efficacy Measurements 
PET/CT 3 
X 
X9 
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood 
Archival or Fresh Tissue Collection10 
X 
X13 
Correlative Studies Blood Collection/Blood for 
Future Biomedical Research4, 10 
X 
X 
X 
Patient Reported Outcome Measures11 
EORTC QLQ C-30 
X 
X 
X 
X 
X 
X 
EORTC QLQ-H&N35 
X 
X 
X 
X 
X 
X 
 
1. 
During radiation treatment, patients will be evaluated weekly with a directed physical exam and toxicity evaluation (patients will be evaluated more frequently if clinically indicated). The first 
dose  of pembrolizumab should be given on the first day of radiation (+ 1 day) Radiation treatment can begin Monday through Wednesday. Doses of pembrolizumab during radiation treatment can be 
given before or after the first radiation treatment of the day. 
2. 
During the time period between completion of Radiation + Pembrolizumab Treatment and the 3 Months Post Radiation Imaging, the patient will be seen at Weeks 6 and 7, then at least once a 
month by a radiation oncologist. The patient will be seen before each pembrolizumab dose by a medical oncologist. 


Amendment 8, 07/26/2018 
Page 40 
 
 
3. 
Baseline tumor evaluation and tumor efficacy assessment at 3 months after completion of reirradiation will be with PET/CT. CT will include diagnostic CT with contrast of 
neck/chest/abdomen/pelvis. If the investigator feels that MRI will be the best way to follow the patients head and neck disease subsequently, then an MRI of the neck should be done at baseline as 
well. However, CT scan is encouraged over MRI. For the initial PET/CT done during the screening procedures, the diagnostic CT scans need to be done within 28 days of the start of therapy while the 
PET can be done within 42 days of start of therapy. 
4. 
Blood (approximately 2 teaspoons) will be drawn for correlative studies. Tumor and additional blood (approximately 2 teaspoons) for future biomedical research (FBR) is optional, but patient  
consent must be obtained be prior to sample collection. If a patient does not consent for FBR then only blood for correlative studies will be drawn. Blood draws for correlative studies and FBR will be 
into a Na Heparin “green top” tube (1 tube for each). They will be drawn prior to dosage of pembrolizumab at first and third cycle, and additionally at week 17 visit and at visit at time of progression. 
5. 
Vital signs to include temperature, pulse, respiratory rate, blood pressure, and oxygen saturation as measured by pulse oximeter. Height will be recorded at screening visit only. 
6. 
Prior to radiation therapy a dental evaluation will be done if recommended by treating radiation oncologist. Extraction of extensively diseased teeth should be carried out with conservation of 
restorable teeth where possible. At least 10 days should be allowed for healing of gingivae post-extraction. Because dental evaluation would be required for reirradiation as part of standard of care this 
evaluation/treatment can begin before consent for the trial. 
7. 
For women of reproductive potential, a urine pregnancy test will be performed within 72 hours prior to first dosage of pembrolizumab. If a urine pregnancy result can’t be confirmed as negative, 
then a serum pregnancy test will be required. Pregnancy testing may be repeated if pregnancy is suspected. 
8. 
CBC to include white blood cells, hgb/hct, platelets and differential. CBC as part of screening for organ function (Inclusion criteria # 13) is required to be done within 21 days of start date 
9. 
Tumor imaging will determine the subsequent study treatment plan. Definition of response is detailed in section 7.1.2.6. Subjects with a complete response (CR), partial response (PR), and 
progressive disease (PD) will require confirmation by repeat CT scan.  Subjects will remain on pembrolizumab following section 6.3 until response confirmation.  Subjects with confirmed CR will 
follow Chart 6.2. Subjects with confirmed partial response or who have stable disease will continue to follow Chart 6.3. Subjects with confirmed progressive disease will follow Chart 6.4. See 
section 
7.1.2.6 for all details on definitions of response. 
10. 
Provide adequate tissue (core or incisional/excisional biopsy) prior to starting study treatment. This tissue will be used for PD-L1 analysis. Fresh tissue or archival tissue sample can only be 
used. If adequate tissue cannot be safely obtained than the patient may still be able to be enrolled on the trial after discussion with the study principal investigator, as long as FNA was done to confirm 
recurrent/second primary HNSCCIf the subject signs the Future Biomedical Research (FBR) consent, any leftover tissue that would ordinarily be discarded at the end of the main study will be retained 
for FBR. 
11. 
Patient Reported Outcome Measures will be completed by the patient. The EORTC QLQ C-30 should be completed first. 
12. 
Coagulation studies will be repeated as clinically necessary. 
13. 
A repeat biopsy may be needed to confirm disease status.  See section 7.1.2.6.4 Assessment of Disease 
14. 
Comprehensive serum chemistry panel is done as part of screening for organ function (inclusion criteria #13) is required within 21 days of start date 
15. 
Starting with cycle 2 of pembrolizumab, CBC and CMP required prior to giving dosage can be done within 48 hours of dosage. 
16. 
If Hep C Ab is positive a Hep C virus RNA PCR can be checked. If the Hep C virus RNA PCR is negative then the patient does not have active Hep C and therefore would still qualify for the 
trial. 


Amendment 8, 07/26/2018 
 
Page 41 
 
 
6.2 Follow Up Phase for Patients Who Achieve a CR at Any Point During the Study or Who Complete Up to 24 Months of 
Pembrolizumab Without Progression of Disease. 1 
 
Trial Period: Follow Up 
Visits during the first year after the 
last dosage of pembrolizumab2 
Visits during the second year after 
the last dosage of pembrolizumab 3 
Annually after 24 M visit 
3M 
6M 
9M 
12M 
18M 
24M 
Annually 
Visit Window 
+/- 
2Wk 
+/- 2Wk +/- 2Wk +/- 2Wk 
+/- 2Wk 
+/- 2Wk 
+/- 2 weeks 
Clinical Procedures/Assessments 
Concomitant Medication Review 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
Directed Physical Examination 
X 
X 
X 
X 
X 
X 
X 
Vital Signs and Weight7 
X 
X 
X 
X 
X 
X 
X 
Efficacy Measurement 
Tumor Imaging4,5 
X 
X 
X 
X 
X 
X 
X8 
Laboratory Procedures/Assessments 
Comprehensive Serum Chemistry Panel 
X 
X 
X 
X 
X 
X 
X 
CBC with Differential 
X 
X 
X 
X 
X 
X 
X 
T3, FT4 and TSH 
X 
X 
X 
Patient Reported Outcomes 6 
EORTC QLQ C-30 
X 
X 
X 
X 
X 
X 
X 
EORTC QLQ-H&N35 
X 
x 
X 
X 
X 
X 
X 
1. 
Patients will undergo follow up as per this table until progression, withdrawal of consent, initiation of non-protocol anti-cancer treatment(s) or death, whichever occurs first. Definition of “first 
year” and “second year” are from the time of last pembrolizumab dosage. Patients who recur or progress may be eligible for retreatment discussed in section 7.1.5.2.1. 
2. 
During the first year of follow up patients will be seen at least every 3 months. The patient can be seen more frequently if clinically indicated. 


Amendment 8, 07/26/2018 
 
Page 42 
 
 
3. 
During the second year of follow up patients will be seen at least every 6 months. The patient can be seen more frequently if clinically indicated. 
4. 
During the first year of follow up patients will undergo neck CT with IV contrast every 3 months to evaluate for recurrence. CT chest with IV contrast or CXR PA/Lateral will be done at the 
discretion of the investigator, as clinically indicated. This will be obtained prior to each 3 month visit. If the patient has evidence of recurrence on CT scan, a biopsy will be done. If recurrence is 
confirmed, the patient can be treated with pembrolizumab again as per the treatment flow chart 6.3. Patients can be retreated with pembrolizumab for up to one year. If the investigator feels that 
MRI will be the best way to follow the patients head and neck disease subsequently, then an MRI of the neck should be done at baseline as well. However, CT scan is encouraged over MRI. 
5. 
During the second year of follow up patients will undergo neck CT with IV contrast every 6 months to evaluate for recurrence. CT chest with IV contrast or CXR PA/Lateral will be done at the 
discretion of the treating physician, as clinically indicated. This will be done prior to each 6 month visit. If the patient has evidence of recurrence on imaging, a biopsy will be done. If recurrence is 
proven, the patient may be eligible to be treated with pembrolizumab again as per table 6.3 below (Treatment phase for patients with PR/SD at 3 months post radiation). Patients can be retreated with 
pembrolizumab for up to one year. If the investigator feels that MRI will be the best way to follow the patient’s head and neck disease subsequently, then an MRI of the neck should be done at 
baseline as well.   However, CT scan is encouraged over MRI. 
6. 
Patient Reported Outcome Measures will be completed by the patient. The EORTC QLQ C-30 should be completed first. 
7. 
Vital signs to include temperature, pulse, respiratory rate, blood pressure, and oxygen saturation as measured by pulse oximeter. 
8. 
Imaging will be done as clinically indicated. 


Amendment 8, 07/26/2018 
 
Page 43 
 
 
6.3 Treatment Phase for Patients with a Partial Response (PR) or Stable Disease (SD) on Imaging 3 Months Post 
Completion of Radiation.1 
 
Trial Phase 
Treatment Cycle 
Treatment Cycle 
Treatment Cycle/Scheduled Time 
(Pembrolizumab Day 1 of each 3-week 
Cycle) 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 and beyond2 
Scheduling Window (days): 
+/- 3 days 
Clinical Procedures/Assessments 
Review Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Directed Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs and Weight6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Procedures/Assessments 
CBC with Differential 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Comprehensive Serum Chemistry Panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis3 
X 
X 
X3 
T3, FT4, TSH3 
X 
X 
X3 
Patient reported outcomes 
EORTC QLQ C-30 
X 
X 
X 
X 
X 
X4 
EORTC QLQ-H&N35 
X 
X 
X 
X 
X 
X4 
Efficacy Measurements 
Tumor Imaging5 
X5 
X5 
X5 
X5 
 
1. 
Patients that develop a complete response during this phase of treatment will be followed as per table 6.2. 
2. 
Patients will continue treatment with pembrolizumab for up to 24 months (from first dosage) or until progression of disease, complete response, discontinuation because of toxicity, or 
withdrawal from study. 
3. 
Urinalysis and T3, FT4, TSH to be drawn before every 4th cycle (i.e. Cycle 18, Cycle 22, etc.). 
4. 
EORTC QLQ C-30 and EORTC QLQ-H&N35 will be filled out by the patient every other cycle. The EORTC QLQ C-30 should be completed first. 
5. 
Tumor imaging with CT neck and chest with IV contrast will be obtained after each 3rd cycle (or sooner if clinically indicated) Imaging should be reviewed to determine disease status prior to 
giving every 4th cycle . Definition of response is as per section 7.1.2.6.4. If the investigator feels that MRI will be the best way to follow the patient’s head and neck disease subsequently, then an 
MRI of the neck should be done at baseline as well.  However, CT scan is encouraged over MRI. 
6. 
Vital signs to include temperature, pulse, respiratory rate, blood pressure, and oxygen saturation as measured by pulse oximeter. 


Amendment 8, 07/26/2018 
Page 46 
 
 
6.4 Follow Up Phase for Patients with Progressive Disease or Who Discontinue 
Treatment Because of Toxicity or Any Other Reason (other than completing all eligible 
cycles of pembrolizumab treatment). 
 
These patients will be taken off of pembrolizumab and enter the follow up phase. 
 
Trial Phase 
Safety Follow-up 
Follow-up 
Survival Follow-up1 
Time from Last pembrolizumab 
Dose 
30 days 
3 months 
6 months 
Starting at 9 months 
Visit 
Safety Follow up visit 
Follow up 
visit 1 
Follow up 
visit 2 
NA 
Scheduling Window 
+/- 3 days 
+/- 7 days 
+/- 7 days 
+/- 7 days 
Administrative Procedures 
Review Medications 
X 
X 
X 
Subsequent Antineoplastic Therapy 
X 
X 
X 
X 
Survival Status 
X 
Clinical Procedures/Assessments 
Review Adverse Events 
X 
X 
X 
ECOG Performance Status 
X 
X 
X 
Directed Physical Exam 
X 
X 
X 
Vital Signs and Weight3 
X 
X 
X 
Laboratory Procedures/Assessments 
CBC with Differential 
X 
X 
X 
Comprehensive Serum
Chemistry Panel 
X 
X 
X 
Patient Reported Outcomes2 
EORTC QLQ C-30 
X 
X 
X 
EORTC QLQ-H&N35 
X 
X 
X 
 
1. 
During survival follow-up patients should be contacted by telephone every 12 weeks to assess for survival status until death, withdrawal of 
consent, or the end of the study, whichever occurs first. 
2. 
The EORTC QLQ C-30 should be completed first. 
3. 
Vital signs to include temperature, pulse, respiratory rate, blood pressure, and oxygen saturation as measured by pulse oximeter. 
 
 


Amendment 8, 07/26/2018 
Page 47 
 
 
4. 
 
7.0 TRIAL PROCEDURES 
 
7.1 Trial Procedures 
The charts in Section 6.0 summarize the trial procedures to be performed at each visit. 
Individual trial procedures are described in detail below. It may be necessary to perform these 
procedures at unscheduled time points if deemed clinically necessary by the investigator. 
 
Furthermore, additional evaluations/testing may be deemed necessary by the investigator 
and/or Merck for reasons related to subject safety. In some cases, such evaluation/testing may 
be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may 
require that additional informed consent be obtained from the subject. In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
 
7.1.1 
Administrative Procedures 
 
7.1.1.1 
Informed Consent 
The study team must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 
 
Consent must be documented by the subject’s dated signature. A copy of the signed and dated 
consent form should be given to the subject before participation in the trial. 
 
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the subject must receive the Institutional Review Board’s 
(IRB’s) approval/favorable opinion in advance of use. The subject should be informed in a 
timely manner if new information becomes available that may be relevant to the subject’s 
willingness to continue participation in the trial. The communication of this information will be 
provided and documented via a revised consent form or addendum to the original consent form 
that captures the subject’s dated signature. 
 
7.1.1.2 
Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee to 
ensure that the subject qualifies for the trial. 
 
7.1.1.3 
Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that are 
considered to be clinically significant by the investigator. Details regarding the patients’ prior 
treatment for SCCHN will be recorded separately and not listed as medical history. 
 
7.1.1.4 
Prior and Concomitant Medications Review 
 
7.1.1.4.1 
Prior Medications 
The investigator or qualified designee will review prior medication use, including any protocol- 
specified washout requirement, and record prior medication taken by the subject within 30 days 


Amendment 8, 07/26/2018 
Page 48 
 
 
 
before starting the trial. Treatment for the disease for which the subject has enrolled in this study 
will be recorded separately and not listed as a prior medication. 
 
7.1.1.4.2 
Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial. All medications related to reportable SAEs and ECIs should be recorded as 
defined in Section 7.2. 
 
7.1.1.5 
Disease Details and Treatments 
 
7.1.1.5.1 
Disease Details 
The investigator or qualified designee will obtain prior and current details regarding the patient’s 
SCCHN, including all prior treatments received. 
 
7.1.1.5.2 
Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including systemic 
treatments, radiation and surgeries. 
 
7.1.1.5.3 
Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after 
the last dose of trial treatment. If  a subject initiates a new anti-cancer therapy within 30 days  
after the last dose of trial treatment, the 30 day Safety Follow-up visit must occur before the 
first dose of the new therapy. Once new anti-cancer therapy has been initiated, the subject will 
move into survival follow-up. 
 
7.1.1.6.4 Patient Reported Outcomes 
The EORTC QLQ C-30 and EORTC QLQ-H&N35 questionnaires will be administered by site 
personnel and completed by subjects at time points shown in the flow charts above. The EORTC 
QLQ C-30 will be completed first, followed by the EORTC QLQ-H&N35. 
 
7.1.1.6 
Assignment of Subject Number 
All consented subjects will be given a unique number. The performance site should contact the 
coordinating center to obtain each subject’s unique, sequential number.  That number will be 
used to identify the subject throughout the study. The number will not contain any direct 
subject identifiers. 
 
7.1.1.7 
Trial Compliance (Medication/Diet/Activity/Other) 
Administration of trial medication will be documented in the subject’s case record. The 
instructions for preparing and administering pembrolizumab will be provided in the 
Pharmacy Manual. 
 
Subjects who are unable to comply with protocol requirements (i.e. attend study visits 
within protocol prescribed windows, complete study assessments, etc.) may be removed 
from the protocol by the Investigator. 


 
Page 54 
Amendment 8, 07/26/2018 
 
 
7.1.2 
Clinical Procedures/Assessments 
 
7.1.2.1 
Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Trial Flow Charts and more frequently if clinically indicated. 
Adverse experiences will be graded and recorded throughout the study and during the follow-
up period according to NCI CTCAE Version 4.0 (see Section 12). Toxicities will be 
characterized  in terms of seriousness, causality, toxicity grading and action taken with regard 
to trial treatment. 
 
All AEs of unknown etiology associated with pembrolizumab exposure should be evaluated to 
determine if it is possibly an event of clinical interest (ECI) of a potentially immunologic 
etiology (irAE). See Section 5.7.2 and the separate guidance document in the study appendices 
regarding the identification, evaluation and management of AEs of a potential immunological 
etiology. 
 
Please refer to section 7.2 for detailed information regarding the assessment and recording of 
AEs. 
 
7.1.2.2 
Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the 
screening period and at other time points as documented in Section 6. Clinically significant 
abnormal findings should be recorded. 
 
7.1.2.3 
Directed Physical Exam 
For cycles that do not require a full physical exam per Section 6, the investigator or qualified 
designee will perform a directed physical exam as clinically indicated prior to trial treatment 
administration. 
 
7.1.2.4 
Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at other time points as specified in Section 6. 
Vital signs should include temperature, pulse, respiratory rate, blood pressure, pulse oximetry, 
and weight.  Height will be measured at screening only. 
 
7.1.2.5 
Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 12.1) at screening, 
prior to the administration of each dose of trial treatment and at all other time points as 
specified in Section 6.0. 
 
7.1.2.6 
Tumor Imaging and Assessment of Disease 
 
7.1.2.6.1 Initial Tumor Imaging 
Initial tumor imaging must be performed within 28 days prior to the start of radiation and 
pembrolizumab and at the time points indicated in Section 6.0. A PET/CT scan will be required 
for initial tumor imaging. CT scan should be a diagnostic CT including CT neck with IV 
contrast, CT chest with IV contrast, and CT abdomen/pelvis with IV and oral contrast to 


 
Page 55 
Amendment 8, 07/26/2018 
 
 
adequately rule out metastatic disease.  If the investigator feels that MRI will be the best way 
to follow the patients head and neck disease subsequently, then an MRI of the neck should be 
done at baseline as well.  However, CT scan is encouraged over MRI. 
 
Positron emission tomography (PET) in combination with systemic administration of a glucose 
analogue, fluorodeoxyglucose (FDG), is an imaging modality that measures metabolic activity 
of individual tissues. Tissues with large energy requirements, e.g. tumors, incorporate higher 
levels of FDG than surrounding normal tissue, allowing whole body tumor screening. PET in 
combination with diagnostic CT is now considered the standard of care in the initial staging 
and evaluation of treatment response or recurrence in SCCHN at most centers.77, 78 79 Using a 
multi- modality PET-CT scanner 3-D functional and anatomic images will be acquired and 
registered, and fused images will be viewed. A negative PET/CT done at 3 months after 
completion of treatment with radiation or chemoradiation has been shown to have a very high 
negative predictive value of 95-100%.78-82 For example, data at the University of Maryland 
Medical Center shows PET scan negativity, defined as an SUV of <1.5 compared to 
surrounding parenchyma, is 100% sensitive for the absence of disease in the post-treatment 
setting (Wartmann, Submitted). 
 
Standard FDG-PET isotope preparation and scanning techniques will be employed.  Regions 
from the base of the brain to the lower abdomen will be imaged approximately 60 minutes after 
FDG injection. Primary tumor metabolism will be measured by FDG PET using Standard 
Uptake Values (SUV). SUVs are determined by examining a specific region of interest (ROI) 
on the  scan defined as the maximum 50% activity contour and measuring radioactivity in this 
area as an average pixel display value (av). The calculation for SUV is: SUV = av ROI 
[mCi/mL]/injected radioisotope dose [mCi]/body wt [g]. 
 
The investigator must review baseline images to confirm the subject has measurable disease 
per RECIST 1.1. 
 
A PET/CT done as part of clinical practice prior to screening can be used if it meets the above 
qualifications and is within the stated time frame. 
 
7.1.2.6.2. Tumor Imaging at 3 Months Post Completion of Radiation 
A PET/CT scan will be required for imaging at 3 months post completion of radiation. CT scan 
should be diagnostic, including CT neck with IV contrast, CT chest with IV contrast, and CT 
abdomen/pelvis with IV and oral contrast.  PET imaging should be completed as discussed in 
7.1.2.6.1 above. If MRI neck has been done at baseline and will be the primary modality to 
follow the patient’s head and neck disease, then MRI neck should be done at 3 months as well. 
CT scan is encouraged over MRI. 
 
7.1.2.6.3 
Subsequent Tumor Imaging 
Subsequent tumor imaging will be with CT neck with IV contrast. Chest imaging will be with 
CT chest with IV contrast or chest X-ray PA/lateral as determined by response and time in 
follow up as detailed in section 6.0. MRI of the neck may be done as the primary means of 
following the patients’ disease if this is determined to be the most accurate study by the 
investigator.  If MRI of the neck will be used, then the CT neck can be omitted.  CT scans 


 
Page 56 
Amendment 8, 07/26/2018 
 
 
are encouraged over MRI. Unless clinically indicated, the same imaging modality (MRI neck 
or CT neck) should be used throughout the study. 
7.1.2.6.4 
Assessment of Disease  
7.1.2.6.4.1 Definitions 
Measurable Lesions: Lesions that can be accurately measured in at least one dimension with 
longest diameter at least >10 mm on CT scan (or >20mm by X-ray). Cystic lesions thought to 
represent cystic metastasis can be considered as measurable lesions. 
 
Malignant Lymph Nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be > 15 mm when assessed by CT scan. 
 
Non-measurable Lesions: All other lesions < 10 mm or lymph nodes <15mm by CT scan. 
 
Target Lesions: All measurable lesions up to a maximum of 2 lesions per organ and up to 5 
lesions in total, representative of all involved organs, should be identified as target lesions and 
recorded and measured at baseline. Target lesions should be selected on the basis of their size 
(lesions with the longest diameter), be representative of all involved organs, but in addition 
should be those that lend themselves to reproducible repeated measurements. It may be the case 
that, on occasion, the largest lesion does not lend itself to reproducible measurement. In this 
circumstance, the next largest lesion which can be measured reproducibly should be selected. 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. 
 
Non-target Lesions:  All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline. 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. 
 
7.1.2.6.4.2 
Evaluation of Disease Response 
Response determination will be defined based on RECIST 1.1. (Table 8). 
 
Table 8.  Definition of Response in Target Lesions. 
Response 
Definition 
Complete Response 
(CR) 
Disappearance of all target lesions* 
Partial Response 
(PR) 
At least a 30% decrease in the sum of the diameters of target lesions, taking as 
reference the baseline sum diameters 
Progressive Disease 
(PD) 
At least a 20% increase in the sum of the diameters of target lesions compared to baseline 
sum of target lesions, or any new lesions 
Stable Disease (SD) Neither sufficient decrease to qualify as a PR or sufficient increase to qualify as PD 
 


 
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*After treatment of SCCHN patients with radiation it may be difficult to distinguish residual 
disease from treatment effect/normal tissue. This will be a critical consideration at 3 months 
post completion of radiation. As detailed above PET/CT can play a significant role in 
determination of residual disease at 3 months post completion of radiation. If a target lesion 
has decreased in size but has not completely resolved and the lesion is not PET avid (defined 
as an SUV that is not higher than background soft tissue) then the patient is considered to have 
a complete response. If a target lesion has decreased in size, but has not completely resolved, 
and it has any PET activity a biopsy can be done at the discretion of the investigator. If a 
biopsy done and is negative then the patient will be considered to have a complete response. If 
the biopsy shows residual malignancy or a biopsy is not done then the patient will be 
considered to have a partial response or stable disease as determined by RECIST 1.1. 
 
Per RECIST 1.1, response should be confirmed by a repeat CT scan. The scan for confirmation 
of response may be performed at the earliest 4 weeks after imaging that showed response (if 
clinically indicated) or at the next scheduled scan. 
 
Lesions that can be measured clinically on physical exam (skin lesions or palpable lymph 
nodes) will be measured by the investigator with the longest axis recorded. These 
measurements can be used to guide clinical decision making, for example prompting an earlier 
CT scan to evaluate disease.  However, only measurements based on radiology will be used to 
determine response. 
 
Table 9.  Assessment of Non-Target Lesions 
Response 
Definition 
Complete Response (CR) 
Disappearance of all non-target lesions 
Incomplete Response/Stable Disease (SD) 
Persistence of one or more non-target lesions 
Progressive Disease 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target 
lesions 
 
Although a clear progression of “non-target” lesions only is exceptional, in such 
circumstances, the opinion of the treating physician should prevail. 
 
7.1.2.6.4.3 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence. 
 
Table  10. Best Overall Response 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
PR/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 


 
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Given the observed pattern of response with immunotherapy medications (anti-PD-1 mAb, 
anti- PD-L1 mAb, and Anti-CTLA4 mAb) where some patients develop evidence of 
progressive disease by RECIST 1.1, with significant increase in size of target lesions and/or 
new lesions, followed by regression of disease to SD or PR/CR2, all imaging showing 
progressive disease by RECIST 1.1, in the absence of significant clinic deterioration of the 
patient will be confirmed with a repeat CT scan at least 4 weeks from the initial imaging 
showing progression. Clinically stable patients will continue treatment in the interim before 
this scan. If progressive disease is confirmed on subsequent imaging, the patient will be 
defined as having progressive disease and will be taken off of the study. Progressive disease 
by RECIST 1.1 with clinical deterioration by the patient will be counted as progressive 
disease, and study treatment will be discontinued. 
 
Determination of clinical deterioration is at the discretion of the treating physician as defined 
by progression of disease at critical sites requiring urgent intervention (for example cord 
compression), or development of signs and symptoms of disease progression and/or 
significant decline in ECOG performance status. 
 
7.1.2.7 
Tumor Tissue Collection and Correlative Studies Blood Sampling 
 
7.1.2.7.1 
PD-L1 and p16 Expression in Tumor Samples 
PD-L1 expression and p16 status will be correlated with efficacy outcomes retrospectively. 
Frozen samples, plastic embedded samples, or formalin fixed samples that has been frozen at 
any point will not be accepted for analysis. Tumor samples that undergo analyses for research 
purposes will not contain any direct subject identifiers. Samples will be labeled with the 
participant study ID, tumor site and collection date. A Tissue Block Shipping Form (see 
protocol appendix) will need to be completed and submitted with each tumor block Tumor 
samples should be large enough to make about 10 slides. Archival tissue or formalin fixed 
paraffin embedded tissue should be sent to the Coordinating Center via 2 day shipping that 
maintains a documented chain of custody (e.g. Fed Ex). 
 
PD-L1Expression 
Tumor tissue for PD-L1 analysis from a formalin fixed paraffin embedded (FFPE) fresh biopsy 
or archival tissue sample of a tumor lesion will be obtained before treatment begins. Tumor 
tissue will be shipped to the Coordinating Center. The Coordinating Center will send tissue 
slides to the Merck designated lab for PD-L1 analysis. For archival or fresh biopsies, core 
needle or incisional/excisional biopsy should be used (fine needle aspiration is inadequate). 
Fixation time for samples should be 24 hours to 48 hours in 10% neutral buffered formalin.  
FFPE blocks will be sectioned by the Coordinating Center to make 5 positively charged slides. 
The same method of slide preparation will be used for archival tissue samples.  
 
“Positive” PD-L1 expression will be defined as >1% of tumor cells with PD-L1 expression. If 
a biopsy is required after treatment to confirm CR, this sample will also be sent to the 
Coordinating Center using the method above. The Coordinating Center will send slides to the 
Merck designated lab for exploratory PD-L1 expression analysis if malignant tissue remains. 
 
p16 
Additionally, for patients with oropharyngeal cancer (recurrence or second primary) pre- 


 
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treatment tumor tissue (archival or fresh biopsy) will be evaluated for p16 expression by 
immunohistochemistry at the treating institution. 
 
Other remaining tissue received by the Coordinating Center will be stored in the UPMC 
Hillman Cancer Center for at least 10 years. If the subject consents to future biomedical 
research, any leftover tissue(s) will be stored indefinitely at the UPMC Hillman Cancer Center 
in the Ferris lab. 
 
7.1.2.7.2 
Correlative Studies Blood Sampling 
For sites participating in correlative studies: Samples of patient’s blood will be collected at 
time points as detailed in Section 6.0. Approximately 2 teaspoons of blood will be drawn into a 
Na heparin ‘green top’ tube. The tube will be labeled with the study number (HCC 18-009), 
patient’s study ID number, date and time of blood draw. Samples drawn at the UPMC Hillman 
Cancer Center should be hand delivered to the Ferris Lab (Research Pavilion Lab 2.19, 5117 
Centre Avenue, Pittsburgh, PA 15213) within a half hour of collection. As detailed in section 
6.0, blood draws for correlative studies will be drawn prior to dosage of pembrolizumab at first 
and third cycle, and additionally at week 17 visit and at visit at time of progression. 
 
Blood samples from non-UPMC Hillman Cancer Center performance sites will either be sent 
unprocessed via courier on the date of collection to the Ferris Lab OR they will be processed 
on site and sent to the Ferris Lab using the instructions below. 
 
For sites doing on-site processing: Samples should be processed by the lab within four hours of 
blood draw. Once in the lab, blood will be diluted 1:1 with phosphate buffered saline (PBS) 
and then layered onto an equal volume of Lymphocyte Separation Media. The blood will then 
be centrifuged at 1500g for 30 minutes (no break) at room temperature within one hour of 
collection. The plasma will be removed, aliquoted, and labeled with the study number, 
subject’s study number, “plasma”, volume and date, and frozen at -80°C. The cells or “buffy 
coat” will then be removed, and placed into a new 15cc conical tube. Ten ml of ice cold PBS 
will be added to the cells in the tube and then the tube will be inverted 5 times and centrifuged 
(brake on) at 350g for 10-15 min at 4°C.  The tube will be gently inverted to pour off 
supernatant—the pellet should not be disturbed. Once the tube is upright the pellet will be 
dislodged by gently tapping the tube. Ten ml of ice cold phosphate buffered saline (PBS) will 
be added. The tube will be inverted five times, a 100ul aliquot removed for counting, then 
centrifuged one last time at 350g for 10-15 min at 4°C. Cells will be counted by trypan blue 
exclusion. After centrifugation, supernatant will be aspirated and the cells will be re-suspended 
to yield cells at 10-20 million cells per ml in freezing media (95% FBS / 5%DMSO). The 
viably frozen cells will be labeled with the study ID, subject’s study ID, date and number of 
cells. The cells should be placed in a Mr. Frosty, if possible, in a -80°C freezer until shipment. 
If shipment is longer than a few days after collection, transfer to liquid nitrogen or a -
150°C freezer. The frozen cells and plasma will be shipped to the Ferris Lab at the UPMC 
Hillman Cancer Center.  
 
 
 


 
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Future Biomedical Research 
If a patient consents to future biomedical research, then an additional 2 teaspoons of blood will 
be drawn at the same time points as detailed in section 6.0, prior to dosage of pembrolizumab 
at first and third cycle, and additionally at week 17 visit and at visit at time of progression. 
After drawing blood they will then be processed and labeled as detailed above. 
 
Specimens from non-UPMC Hillman Cancer Center performance sites should be transported 
via courier or shipped on dry ice via overnight delivery (Monday thru Thursday only) to the 
following address: 
 
Ferris Lab 
UPMC Hillman Cancer Center 
Research Pavilion Lab 2.19 
5117 Centre Avenue 
Pittsburgh, PA 15213 
Phone: 412-623-7738 
 
Overnight shipments must be sent Monday through Thursday only. 
 
Please contact the Ferris Lab (412-623-7738; reederc@upmc.edu) at the time of courier 
transport or shipment. 
 
After completion of the trial, the samples for correlative studies will be thawed. The 
following lymphocyte phenotypes will be analyzed by flow cytometry: cytotoxic T cells 
(CD8+CD3+CD28-CD57+), regulatory T cells (CD4+CD25+FOX-P3+) and myeloid 
derived suppressor cells (CD11b+HLA-DR[-]CD33+). These samples will be analyzed for 
these cell types to evaluate if there is any correlation with pre-protocol treatment levels of 
these cells, as well as changes over time and efficacy endpoints. These analyses will be done 
in the Ferris Lab at the UPMC Hillman Cancer Center. 
 
7.1.3 
Laboratory Procedures/Assessments 
 
7.1.3.1 
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 
Clinical laboratory tests for this trial are specified in Table 11. For these laboratory tests the 
total amount of blood/tissue to be drawn/collected over the course of the trial (from pre-trial to 
post- trial visits), are all standard of care. 


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Table 11.  Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human Chorionic 
Gonadotropin† 
Hemoglobin 
Alkaline Phosphatase 
Glucose 
(β-hCG)† 
Platelet Count 
Alanine Aminotransferase 
(ALT) 
Protein 
PT (INR) 
WBC (total and 
differential) 
Aspartate Aminotransferase 
(AST) 
Specific Gravity 
aPTT 
Red Blood Cell Count 
Lactate Dehydrogenase 
(LDH) 
Microscopic Exam (If 
abnormal 
results are noted) 
Total Thriiodothyronine (T3) 
Absolute Neutrophil 
Count 
Carbon Dioxide 
Free Tyroxine (T4) 
(CO2 or biocarbonate) 
Urine Pregnancy Test † 
Thyroid Stimulating Hormone 
(TSH) 
Uric Acid 
Calcium 
Chloride 
Glucose 
Phosphorus 
Potassium 
Sodium 
Magnesium 
Total Bilirubin 
Direct Bilirubin (If total 
bilirubin is elevated 
above the upper limit of 
normal) 
Total Protein 
Blood Urea Nitrogen 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a 
serum pregnancy test will be required. 
 
Laboratory tests for screening or entry should be performed within 10 days prior to the first 
dose of treatment. After Cycle 1, pre-dose laboratory procedures can be conducted up to 48 
hours prior to dosing. Results must be reviewed by the investigator or qualified designee 
and found to be acceptable prior to each dose of trial treatment. 
 
7.1.4 
Other Procedures 
 
7.1.4.1 
Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation. Any 
adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events. Subjects who a) attain a CR or b) complete 24 months of 
treatment with pembrolizumab will discontinue treatment with the option of restarting 
treatment if they meet the criteria specified in Section 7.1.5.2.1. After discontinuing 


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treatment following assessment of CR, these subjects should return to the site for a Safety 
Follow-up Visit (described in Section 7.1.5.3.1) and then proceed to the Follow-Up Period 
of the study (described in Section 7.1.5.4). 
 
7.1.4.2 
Blinding/Unblinding 
The investigators will not be blinded to the treatment received. 
 
7.1.5 
Visit Requirements 
Visit requirements are outlined in Section 6.0. Specific procedure-related details are 
provided in Section 7.1 - Trial Procedures. 
 
7.1.5.1 
Screening 
Within 28 days prior to initiation of treatment, the patient will be evaluated by the study 
team to determine if the patient is eligible for the trial. Clinical and radiologic tests will be 
done as per Section 6.0 and are required to be done within 28 (unless otherwise specified in 
Section 6.0) days of the first dosage of pembrolizumab. Prior tumor imaging can be used if 
determined to be adequate by the investigator and within time requirements for CT scan and 
PET/CT as per section 6.0. Because dental evaluation/treatment may be required treatment 
with radiation as part of standard of care, this evaluation can be started/completed before a 
patient is consented for the protocol. Laboratory tests for organ function screening (as per 
inclusion criteria #13) should be performed within 21 days prior to the first dose of 
treatment. All other required laboratory tests for screening as per section 6.0 can be done 
within 28 days. 
 
7.1.5.2 
Treatment Period 
Visit requirements are outlined in Section 6.0. Specific procedure-related details are 
provided in Section 7.1.  
7.1.5.2.1 
Retreatment with pembrolizumab 
Some patients who discontinue pembrolizumab may be eligible for retreatment with 
pembrolizumab for up to one year if this study remains open and the patient meets 
the following criteria: 
 
1. Stopped pembrolizumab after attaining a confirmed CR anytime during the study or 
had a CR, PR, or SD at time of completion of all 24 months of study treatment. 
2. Experienced a recurrence or disease progression on imaging study confirmed 
by the investigator. 
3. Has not been treated for recurrence/disease progression with other anti-cancer treatment. 
4. Still meets all inclusion/exclusion criteria (not including criterion that 
patient is a candidate for reirradiation). 
 
These patients will undergo trial screening procedures as per Section 6.1, with the 
following exceptions: 
 
• Patients will not have to sign another informed consent document. 
• Patients will not require PET/CT, but will require diagnostic CT, including CT 
neck and chest with IV contrast and CT abdomen/pelvis with IV and oral contrast 


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(MRI may be done at investigator discretion if previously used). 
• Patients will not require repeat biopsy for evaluation of PD-L1 expression. 
 
Patients will undergo serum collection for correlative studies before initiation of 
retreatment with pembrolizumab. Patients who meet criteria for retreatment will be treated 
and followed as per Section 6.3. 
 
7.1.5.3 
Post Pembrolizumab Treatment Visits 
 
7.1.5.3.1 
Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after 
the last dose of pembrolizumab or before the initiation of a new anti-cancer treatment, 
whichever comes first. All AEs that occur prior to the Safety Follow-Up Visit should be 
recorded. Subjects with an AE of grade > 1 will be followed until the resolution of the AE to 
grade 0-1 or until the beginning of a new anti-neoplastic therapy, whichever occurs first. 
SAEs that occur within 90 days of the end of treatment or before initiation of a new anti-
cancer treatment should also be followed and recorded. 
 
7.1.5.4  
Follow-up Visits 
Subjects who discontinue trial treatment for a reason other than disease progression or 
withdraw of consent will move into the Follow-Up Phase and should be assessed as per 
Section 6.2.  Every effort should be made to collect information regarding disease status   
until the start of new anti-neoplastic therapy, disease progression, death, end of the study or 
if the subject begins retreatment with pembrolizumab as detailed in Section 7.1.5.2.1. 
Information regarding post-study anti-neoplastic treatment will be collected if new treatment 
is initiated. If a new anti-neoplastic treatment is initiated during this phase, the patient will 
then be followed as per Section 6.4.  
7.1.5.4.1   Survival Follow-up 
Once a subject experiences confirmed disease progression or starts a new anti-cancer 
therapy, the subject will be followed per Section 6.4. Starting at 9 months from the last 
pembrolizumab dose, the patient will move into the survival follow-up phase. In this phase, 
patients should be contacted by telephone every 12 weeks to assess for survival status until 
death, withdrawal of consent, or the end of the study, whichever occurs first. 
 
7.2 Assessing and Recording Adverse Events 
 
7.2.1 
Definitions 
 
The following definitions of terms apply to this section: 
 
Adverse event: Any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. 
 
Life-threatening adverse event or life-threatening suspected adverse reaction: An adverse event 
or suspected adverse reaction is considered "life-threatening" if, in the view of either the 
investigator or sponsor, its occurrence places the patient or subject at immediate risk of death. It 


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Amendment 8, 07/26/2018 
 
 
does not include an adverse event or suspected adverse reaction that, had it occurred in a more 
severe form, might have caused death. 
 
Serious adverse event or serious suspected adverse reaction: An adverse event or suspected 
adverse reaction is considered "serious" if, in the view of either the investigator or sponsor, it 
results in any of the following outcomes: death, a life-threatening adverse event, inpatient 
hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or 
substantial disruption of the ability to conduct normal life functions, or a congenital 
anomaly/birth defect. Important medical events that may not result in death, be life-threatening, 
or require hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
 
Suspected adverse reaction: Any adverse event for which there is a reasonable possibility that 
the drug caused the adverse event. For the purposes of IND safety reporting, "reasonable 
possibility" means there is evidence to suggest a causal relationship between the drug and the 
adverse event. Suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug. 
 
Adverse reaction means any adverse event caused by a drug.  Adverse reactions are a subset of 
all suspected adverse reactions where there is reason to conclude that the drug caused the event. 
 
Unexpected adverse event or unexpected suspected adverse reaction: An adverse event or 
suspected adverse reaction is considered "unexpected" if it is not listed in the investigator 
brochure or is not listed at the specificity or severity that has been observed; or, if an investigator 
brochure is not required or available, is not consistent with the risk information described in the 
general investigational plan or elsewhere in the current application, as amended. For example, 
under this definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the 
investigator brochure referred only to elevated hepatic enzymes or hepatitis. Similarly, cerebral 
thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater specificity) 
if the investigator brochure listed only cerebral vascular accidents. "Unexpected," as used in this 
definition, also refers to adverse events or suspected adverse reactions that are mentioned in the 
investigator brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation. 
 
7.2.2 
Eliciting AE Information 
 
Research subjects will be routinely questioned about AEs at study visits. 
 
Recording Requirements 
All observed or volunteered adverse events (serious or non-serious) and abnormal test findings, 
regardless of study group or suspected causal relationship to the study drug(s) will be recorded in 


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the subjects’ case histories. For all adverse events, sufficient information will be pursued and/or 
obtained so as to permit 1) an adequate determination of the outcome of the event (i.e., whether 
the event should be classified as a serious adverse event) and; 2) an assessment of the casual 
relationship between the adverse event and the study drug(s). 
 
AEs or abnormal test findings felt to be associated with the investigational drug or study 
treatment(s) will be followed until the event (or its sequelae) or the abnormal test finding 
resolves or stabilizes at a level acceptable to the Sponsor-Investigator. 
 
7.2.3 
Abnormal Test Findings 
 
An abnormal test finding will be classified as an adverse event if one or more of the following 
criteria are met: 
 
• The test finding is accompanied by clinical symptoms. 
• The test finding necessitates additional diagnostic evaluation(s) or medical/surgical 
intervention; including significant additional concomitant drug treatment or other 
therapy. 
o Note: simply repeating a test finding, in the absence of any of the other listed 
criteria, does not constitute an AE. 
• The test finding leads to a change in study dosing or discontinuation of subject 
participation in the clinical study. 
 
All adverse events will be recorded from the time the consent form is signed through 30 
days following cessation of treatment and at each examination on the adverse event case 
report forms/worksheets. The reporting timeframe for adverse events meeting any serious 
criteria is described in section 7.2.3.1. 
 
Adverse events will not be collected for subjects as long as that subject has not undergone 
any protocol-specified procedure or intervention. If the subject requires a blood draw, fresh 
tumor biopsy etc., the subject is first required to provide consent to the main study, and AEs 
will be captured according to guidelines for standard AE reporting. 
 
7.2.3.1 Definition of an Overdose for This Protocol and Reporting of Overdose to 
Merck  
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed 
dose for pembrolizumab by 20% over the prescribed dose.  No specific information is 
available on the treatment of overdose of pembrolizumab. In the event of overdose, the 
subject should be observed closely for signs of toxicity. Appropriate supportive treatment 
should be provided if clinically indicated. 
 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, 
the adverse event(s) is reported as a serious adverse event, even if no other seriousness 
criteria are met. 
 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without 


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any associated clinical symptoms or abnormal laboratory results, the overdose is reported as 
a non-serious Event of Clinical Interest (ECI), using the terminology “accidental or 
intentional overdose without adverse effect.” 
 
All reports of overdose with and without an adverse event must be reported within 24 hours 
to the Sponsor and within 2 working days to Merck Global Safety (Attn: Worldwide 
Product Safety; FAX: 215 993-1220) using the protocol adverse event case report form 
(CRF). If the protocol adverse event CRF does not contain enough information, Merck may 
contact the performance site to request additional information. 
 
7.2.3.2 Reporting of Pregnancy and Lactation to Merck 
Although pregnancy and lactation are not considered adverse events, it is the responsibility 
of investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them), including the pregnancy of a male subject's female partner 
that occurs during the trial or within 120 days of completing protocol therapy, or 30 days 
following cessation of treatment if the subject initiates new anticancer therapy, whichever is 
earlier. All subjects and female partners of male subjects who become pregnant must be 
followed to the completion/termination of the pregnancy. Pregnancy outcomes of 
spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal 
death, intrauterine death, miscarriage and stillbirth must be reported as serious events 
(Important Medical Events). If the pregnancy continues to term, the pregnancy outcome 
must also be reported. 
 
Such events must be reported within 24 hours to the Sponsor and faxed within 2 working 
days to Merck Global Safety (Attn: Worldwide Product Safety; FAX: 215 993-1220) using 
the protocol adverse event case report form (CRF). If the protocol adverse event CRF does 
not contain enough information, Merck may contact the performance site to request 
additional information. 
 
7.2.4 
Immediate Reporting of Adverse Events 
 
7.2.4.1 
Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of 
Merck’s product that: 
 
• Results in death; 
• Is life threatening; 
• Results in persistent or significant disability/incapacity; 
• Results in or prolongs an existing inpatient hospitalization; 
• Is a congenital anomaly/birth defect; 
• Is a new cancer (that is not a condition of the study); 
• Is associated with an overdose; 
• Is another important medical event 
Refer to Table 12 for additional details regarding each of the above criteria. 
 


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Progression of the cancer under study is not considered an adverse event, unless it results in 
hospitalization or death. 
 
All events meeting the definition of a serious adverse event should be reported according to the 
departmental SAE checklist and SAE form. The initial SAE form should be sent to the following 
within 2 business days of the coordinating center Principal Investigator becoming aware: 
 
1. Dan Zandberg (zandbergdp@upmc.edu) 
2. CRSSafetySubmissions@upmc.edu 
3. Local Institutional Review Board when reporting requirements are met. 
 
NOTE: non-UPMC Hillman Cancer Center (UPMC HCC) sites should send the SAE to the 
addresses listed above in #1 and #2. The Coordinating Center (UPMC HCC) will report to Merck 
Global Safety (Attn: Worldwide Product Safety; Fax: 215-993-1220). 
 
In addition to completing appropriate patient demographic and suspect medication information, 
the report should include as applicable the following information that is available at the time of 
report within the Sections B and C of the departmental SAE form: 
 
• CTCAE term(s) and grade(s)  
• current status of study drug 
• all interventions to address the AE (testing and result, treatment and response) 
• hospitalization and/or discharge dates 
• event relationship to study drug 
 
Follow-up reports:   
Additional information may be added to a previously submitted report by adding to the 
original departmental SAE form and submitting it as follow-up or creating supplemental 
summary information and submitting it as follow-up with the original departmental SAE 
form.   
 
Non-serious Events of Clinical Interest and any other relevant safety information that does not 
meet SAE criteria are to be forwarded by the performance site to UPMC HCC (Dan Zandberg 
(zandbergdp@upmc.edu) and CRSSafetySubmissions@upmc.edu), who will forward to 
Merck Global Safety (Attn: Worldwide Product Safety; FAX: 215 993-1220) using the 
applicable study case report form. If the protocol CRF does not contain enough information, 
Merck may contact the performance site to request additional information. 
 
 
All subjects with serious adverse events must be followed up for outcome/resolution for at 
least 90 days after stopping protocol therapy. 
 
7.2.4.2 
Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical 
Interest (ECI) and must be recorded as such on the adverse event case report 
forms/worksheets and reported within 2 working days to UPMC HCC (Dan Zandberg 
(zandbergdp@upmc.edu) and CRSSafetySubmissions@upmc.edu), who will forward to 


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Merck Global Safety. (Attn: Worldwide Product Safety; FAX:  215 993-1220). 
 
Events of clinical interest for this trial include: 
 
1. An overdose of Merck product, as defined in Section 7.2.1 that is not associated 
with clinical symptoms or abnormal laboratory results. 
 
2. An elevated AST or ALT lab value that is greater than or equal to 3X the upper 
limit of normal AND an elevated total bilirubin lab value that is greater than or 
equal to 2X the upper limit of normal AND at the same time, an alkaline 
phosphatase lab value that is less than 2X the upper limit of normal, as determined 
by way of protocol-specified laboratory testing or unscheduled laboratory testing. 
 
3. In the event a subject develops any of the following AEs, a detailed narrative of the 
event should be reported as an ECI to Merck Global Safety within 2 working days 
of the event: 
• 
grade ≥ 3 diarrhea 
• 
grade ≥ 3 colitis 
• 
grade ≥ 2 pneumonitis 
• 
grade ≥ 3 hypo- or hyperthyroidism 
 
Potential skin events of clinical interest: 
 
Every attempt should be made by the study team to take photographs of the actual ECI skin 
lesion or rash as soon as possible.  If affected, photographs should be taken of: 
 
• the head (to assess mucosal or eye involvement) 
• the trunk and extremities 
• a close-up of the skin lesion/rash. 
 
If possible, a ruler should be placed alongside the site of the skin occurrence as a fixed 
marker of distance. 
 
• The time/date stamp should be set in the 'ON' position for documentation purposes. 
• Photographs should be stored with the subject’s study records. 
• Merck may request copies of photographs. 
 
In addition to the photographs, the following documents from the Merck Pembrolizumab 
Program Event of Clinical Interest Guidance Document (at the end of the  protocol) need to 
be completed and sent to UPMC HCC (Dan Zandberg (zandbergdp@upmc.edu) and 
CRSSafetySubmissions@upmc.edu), who will forward to to Merck Global Safety (Attn:  
Worldwide Product Safety, FAX: 215-993-1220) within 2 business day of the subject’s 
presentation with the dermatologic event: 
 
• Appendix 2—Past Medical History Related to Dermatologic Event 
• Appendix 3—Presentation of the Dermatologic Event 


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• Appendix 4—Focused Skin Examination 
 
A separate guidance document has been provided in the appendix entitled “Event of Clinical 
Interest and Immune-Related Adverse Event Guidance Document.” This document provides 
guidance regarding identification, evaluation and management of ECIs and irAEs. 
Additional ECIs are identified in this guidance document and also need to be reported to 
Merck Global Safety within 2 working days of the event. 
 
Subjects should be assessed for possible ECIs prior to each dose. Lab results should be 
evaluated, and subjects should be asked for signs and symptoms suggestive of an immune- 
related event. Subjects who develop an ECI thought to be immune-related should have 
additional testing to rule out other etiologic causes. If lab results or symptoms indicate a 
possible immune-related ECI, then additional testing should be performed to rule out other 
etiologic causes.  If no other cause is found, then it is assumed to be immune-related. 
 
ECIs that occur in any subject from the date of first dose through 90 days following 
cessation of pembrolizumab treatment, or the initiation of a new anticancer therapy 
(whichever is earlier) whether or not related to pembrolizumab, must be reported to Merck 
Global Safety within 2 working days. 
 
7.2.5 
Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to 
the NCI Common Terminology for Adverse Events (CTCAE), version5.0. Any adverse 
event which changes CTCAE grade over the course of a given episode will have each 
change of grade recorded on the adverse event case report forms/worksheets. 
 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 


Amendment 8, 07/26/2018 
 
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Table 12. Evaluating Adverse Events 
 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
 
V4.0 CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. 
Grade 3 
Severe or Medically Significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL. 
Grade 4 
Life Threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of the investigational condition that: 
†Results in death; or 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization [including hospitalization for an elective procedure] for a preexisting 
condition which has not worsened does not constitute a serious adverse event.); or 
†Is a congenital anomaly/birth defect (in offspring of subject exposed to the investigational condition regardless of time to diagnosis);or 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units. 
Action Taken 
Did the adverse event cause the study treatment to be discontinued? 
Relationship to 
Test Condition 
Did the investigational condition cause the adverse event? The determination of the likelihood that the investigational condition caused the adverse event will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality 
noted on the AE form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time 
frame. The criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the 
adverse event based upon the available information. 
The following components are to be used to assess the relationship between the investigational condition and the AE; the greater the correlation with the 
components and their respective elements (in number and/or intensity), the more likely the investigational condition caused the adverse event (AE): 
Exposure 
Is there evidence that the subject was actually exposed to the investigational condition such as: reliable history, acceptable compliance 
assessment (pill count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
Time Course 
Did the AE follow in a reasonable temporal sequence from administration of the investigational condition? 
Is the time of onset of the AE compatible with a study-induced effect (applies to trials with investigational medicinal product[s])? 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors? 


Amendment 8, 07/26/2018 
 
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Relationship 
The following components are to be used to assess the relationship between the test condition and the AE: (continued) 
To 
Investigational 
Condition 
(continued) 
Dechallenge 
Was the investigational condition discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation 
of the investigational condition; or (3) the trial is a single-exposure trial; or (4) The test condition is/are only used one time.) 
Rechallenge 
Was the subject re-exposed to the test condition in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single exposure trial); or 
(3) The test condition is/are used only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE INVESTIGATIONAL CONDITION, OR IF REEXPOSURE TO THE INVESTIGATIONAL CONDITION POSES 
ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE MERCK U.S. CLINICAL MONITOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL. 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the test condition? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements. 
Record One of the Following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a test condition relationship). 
Yes, there is a reasonable 
possibility of test condition 
relationship. 
There is evidence of exposure to the test condition. The temporal sequence of the AE onset relative to the administration of the test condition is 
reasonable. The AE is more likely explained by the test condition than by another cause. 
No, there is not a reasonable 
possibility of test condition 
relationship 
Subject was not exposed to the test condition OR temporal sequence of the AE onset relative to administration of the test condition is not 
reasonable OR there is another obvious cause of the AE. (Also entered for a subject with overdose without an associated AE.) 


 
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7.2.6 
Sponsor Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations. 
 
8.0 STATISTICAL ANALYSIS PLAN 
 
8.1 Statistical Analysis Plan Summary 
This study will test the efficacy of reirradiation combined with pembrolizumab, administered at 
200mg IV every 3 weeks, in patients with unresectable locoregional recurrence or second 
primary head and neck squamous cell carcinoma. In addition, the early toxicity profile and 
safety of the combination of the mAb with radiation therapy will be established. 
 
This is a single-arm phase II trial with continuous monitoring of acute non-hematologic 
toxicity. The primary efficacy endpoint is Progression-Free Survival (PFS). The efficacy 
outcome of the study will be summarized by the median time to progression or death. This will 
be related to experience reported in the literature. 
 
While the safety profile of pembrolizumab is well established when giving the drug as a single 
agent, the safety of the combination of pembrolizumab with high dose ionizing radiation needs 
to be established. In case the defined boundary for the incidence of severe non-hematologic 
toxicity is crossed, the trial will be stopped, and the available data at that point will be carefully 
reviewed in order to suggest potential modification of the drug-radiation combination that may 
warrant testing in a future, independent trial. 
 
8.2 Statistical Analysis Plan 
The design includes 1) continuous toxicity monitoring in the first 20 patients enrolled and 2) 
evaluation of toxicity and efficacy after the pre-specified target sample size is reached and the 
efficacy data have matured. 
 
8.2.1. Continuous Toxicity Monitoring in the First 20 Patients Enrolled (Stopping rule) 
The endpoint is severe (grade 4-5), non-hematologic toxicity that occurs during the radiation 
therapy plus 2 weeks (i.e. within the first 7 weeks of trial treatment). Based on the literature 
review, grade 4-5 acute radiation toxicity occurs in <20% of radiation-drug combinations tried 
in the reirradiation setting for SCCHN. Early stopping for unexpected, severe toxicity is based 
on continuous monitoring of grade 4-5 non-hematologic toxicity with the aim of keeping the 
probability of early stopping at around 5% if the true underlying rate of this toxicity is 20%. 
Following Ivanova et al. 83 we use the boundary proposed by Pocock. 84 If ≥bk patients with 
toxicity have been observed after enrolling the first k patients, then the study will be stopped as 
detailed above. Values of bk for the current design are given in Table 13. 
 


 
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Table 13. Pocock boundary for early stopping due to excessive grade 4+ toxicity with a 
probability of stopping of about φ = 0.05 and assuming the true toxicity rate is θ0 = 0.2 
 
k 
1 2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 15 16 17 18 19 20 
bk – – 
3 
4 
4 
4 
5 
5 
5 
6 
6 
6 
7 
7 
7 
8 
8 
8 
9 
9 
 
It is important for the validity and practical implementation of this strategy that the sequence 
of patients entered into the study is strictly recorded and preserved. Ideally, the design 
assumes that the outcome, i.e. the incidence of grade 4+ toxicity among the first i patients is 
known when entering patient i+1. However, the accrual rate is expected to be around two 
patients per month, and the time window for observing early toxicity in a patient is 
pragmatically defined as the time during and within two weeks after the completion of RT. 
Therefore, insisting on complete observations before entering the next patient will slow 
down accrual considerably. Instead we will allow staggered entry of cases. For patient safety 
reasons, no more than 5 patients will be allowed to be undergoing or be within 2 weeks of 
completing reirradiation treatment at any point during the enrollment of the first 20 patients. 
 
At the time when the boundary is crossed, the treatment with pembrolizumab will be 
discontinued in all patients on treatment at that point in time and toxicity data will be 
reviewed by the DSMB (Data and Safety Monitoring Board). 
 
If 20 patients are enrolled and have completed therapy (radiation plus 2 weeks) without 
crossing the toxicity boundary, toxicity data from those patients will be reported and 
reviewed by the DSMB. No further accrual will occur until after DSMB review. All 
subsequent accrual will be continued with respect to the efficacy question and although there 
will be no further toxicity boundary halting the study, toxicity will still be recorded and 
reported for the whole phase II cohort. 
 
 
An impression of the statistical power of the initial continuous toxicity monitoring phase 
may be achieved from a specific example. If 2 out of 20 patients develop grade 4+ early 
toxicity, the estimated incidence is 10%, and the upper limit of the exact 1-sided 95% 
confidence interval is 28%. 
Fig. 1. Hypothetical example of the timeline for enrolling and 
recording toxicity in the first 5 patients.  At time t1, 2 of the  first 
3 patients have developed grade 4+ toxicity and the trial should 
continue. At this point in time 3/4 and 3/5 patients have 
developed relevant toxicity and the boundary for stopping 
accrual at this dose level is still not crossed. At time t2, 4 of the 
first 4 patients enrolled have developed grade 4+ toxicity  which 
means accrual should stop at this point in time. The status of the 
5th patient at time t2 does not affect the decision as to whether the 
boundary is crossed or not. 


 
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8.2.2 Primary Efficacy Analysis 
All patients entered are evaluable with respect to the efficacy endpoint, which is the main trial 
endpoint. The primary endpoint is progression-free survival (PFS). Based on the literature 
review presented in the background section, we assume that reirradiation without 
pembrolizumab produces a median PFS of 8 months. 
 
The expected accrual rate is 2 patients per month for a total of 48 evaluable patients. A 12-
month maturation period after completing accrual has been added. All patients will be included 
in efficacy analysis irrespective of the dose of drug or radiation actually received. This follows 
a strict intention-to-treat principle. Subjects eligible for replacement are discussed in section 
5.10. We will use a 1-sided test with a 5% significance level (α) to test the uni-directional 
hypothesis that the median PFS is prolonged from 8 to 12 months by combining anti-PD-1 
mAb with reirradiation. We estimate that the power (1-β) of the study is 78%. The efficacy 
result will be summarized as a median PFS with a 1-sided 95% confidence interval. No early 
stopping rule for futility is planned due to the relatively rapid enrollment of patient in relation 
to the expected median PFS. 
8.2.3 
Efficacy 
Endpoints Primary 
Progression-free survival (PFS) – Progression free survival is defined as the time from the 
initiation of treatment to the first documented disease progression per RECIST 1.1 or death due 
to any cause, whichever occurs first. If a patient recurs and is eligible for retreatment, then only 
the time to the initial recurrence will be included in the evaluation of PFS. Patients who are 
alive with no evidence of disease at the time of last contact will be censored at that date. 
 
Secondary 
Overall Response Rate (ORR) – The overall response rate is defined as the percentage of the 
patients who have a complete response (CR) or partial response (PR) as defined by RECIST 
1.1. The patient’s best overall response rate defined as the best response recorded from the start 
of the treatment until disease progression will be recorded. 
 
Clinical Benefit Rate (CBR) - Clinical benefit rate is the percentage of patients that have 
achieved a complete response, partial response, and stable disease as defined by RECIST 1.1. 
 
Time to in-field progression – The time to in-field progression is defined as the time from 
initiation of treatment to progression of disease within the radiation field. 
 
Overall Survival – Overall survival is defined as the time from first treatment until death. 
Patients who are alive will be censored at the last date of patient contact. 
 
8.2.4. Biostatistical considerations in relation to proton therapy 
For the primary toxicity and efficacy analyses, toxicity and efficacy outcomes will be recorded 
and analyzed without stratification for radiation modality. While proton has some unique 


 
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qualities compared to photon (described in section 4.2.2.2), currently, there has not been a 
direct prospective comparison of photon and proton radiation, and therefore it is not known 
whether there is any difference in efficacy, toxicity, or immunogenicity between photons and 
protons in reirradiation of HNSCC. Therefore, pre-specified stratification is not required. 
Proton is also not an experimental treatment itself and therefore it does not need to be added as 
an additional experimental arm in this trial. 
 
In regards to the continuous toxicity evaluation (section 8.2.1 above) It is expected that early 
grade 4+ radiation toxicity will generally be observed in the high-dose region where radiation 
is given to gross disease. It should be noted that as described in section 4.2.2.2 above, the main 
difference between proton and photon is the dose to normal tissue rather than the high dose to 
the target volume ie high-dose region. However, in order to add extra safeguards with proton 
therapy, when 5 proton patients have been accrued and pass the 7 week mark on trial, the 
DSMB will review the data at that time and compare toxicity of proton patients to photon 
patients, to determine if further proton therapy should be allowed. The trial will continue to 
enroll photon patients during that review however proton patients will not be allowed until 
after the DSMB review.  If the first 5 patients are enrolled before a total of 20 patients have 
gone past week 7, then after this review of the proton patients, the trial will continue to accrue 
to the 20 initial patients as described above, with subsequent DSMB review either when the 
toxicity threshold is crossed or when 20 total patents (includes proton and photon) have gone 
past the 7 week mark. If the toxicity boundary is crossed, the independent DMSB will be 
charged with reviewing the data including whether there is any statistical reason to believe that 
the incidence of grade 4+ toxicities is less or more in the proton therapy cases. If this should be 
the case, the DMSB may advise as to whether only photon or only proton patients should 
continue accrual.  Similarly, when the 20 patients pass week 7 if the toxicity threshold is not 
met the DSMB will again evaluate toxicity for proton vs. photon patients. 
 
If the first 5 proton patients are not accrued until after the first 20 patients, then similarly when 
5 patients are accrued the DSMB will evaluate the data compared to photon to make a decision 
as to whether the option of proton therapy should still be allowed. 
 
In regards to the efficacy questions, the main hypothesis is that radiation will be synergistic 
with pembrolizumab because of the immunogenic effect of radiation detailed prior in the 
protocol. 
 
Proton radiotherapy induced cell death is the same mechanism as in photon radiation. 
Therefore, we would not expect a different effect on the target volume. There is a hypothetical 
difference in that less normal tissue exposure from proton may lead to less killing of 
lymphocytes and thus might be hypothetically more immunogenic than IMRT. However, this 
is only hypothetical, and it is unclear if this plays a significant role in the immunogenic effects 
of radiation in humans. 
Therefore, we assume that there is no effect of radiation modality on efficacy. The primary 
efficacy analysis will therefore not have a pre-specified stratification for radiation modality, 
nor is the study powered to allow for any formal comparison between radiation modalities. 


 
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However, provided that at least 10 patients each are treated with protons and photons, in 
addition to analyzing the entire cohort of patients, the toxicity profile and efficacy data will be 
retrospectively analyzed by radiation modality. 
 
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES 
 
9.1 Investigational Product 
The performance site principal investigator shall take responsibility for and shall take all steps 
to maintain appropriate records and ensure appropriate supply, storage, handling, distribution 
and usage of investigational product in accordance with the protocol and any applicable laws 
and regulations. 
 
Pembrolizumab will be provided to the performance sites by Merck as summarized in Table 
13. Sites will complete the Drug Request Form (provided as a document separate from this 
protocol), and send via email to Senthooran Selvarajah (senthooran.selvarajah@merck.com) 
and Tammy Moll (tammy.moll@merck.com). 
 
Table 13.  Product Description 
 
Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
9.2 Packaging and Labeling Information 
Clinical supplies will be affixed with a drug label in accordance with regulatory requirements. 
 
9.3 Clinical Supplies Disclosure 
This trial is open-label. The subject, the trial site personnel, the Sponsor and/or designee are not 
blinded to treatment. Drug identity (name, strength) is included in the label text. Random 
code/disclosure envelopes or lists are not provided. 
 
9.4 Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label. 
 
Receipt and dispensing of trial medication must be recorded by an authorized person at the trial 
site. 
 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
 
9.5 Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck or designee, the amount administered to subjects and the amount remaining at the 
conclusion of the trial. 
 


 
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Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the investigator’s 
responsibility to arrange for disposal of all empty containers, provided that procedures for 
proper disposal have been established according to applicable federal, state, local and 
institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 
 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
 
10.1 Compliance with Laws and Guidances 
This study will be conducted in accordance with current U.S. Food and Drug Administration 
(FDA) Regulations, Good Clinical Practices (GCPs) and International Counsel on  
Harmonization (ICH) E6 Guidelines. 
 
10.1.1 
Institutional Review Board (IRB) 
Site specific documents (e.g. HIPAA authorization, consent form, advertisements) should be 
submitted to the Coordinating Center for review and approval prior to IRB submission. The 
protocol and related study documents will be sent to the performance site IRB for review and 
approval per local practice. Study procedures may begin at the site once local IRB approval is 
secured and other details (e.g. study supplies, clinical trial agreements) are in place. All 
amendments, instances of reportable new information (i.e. unanticipated problems, data  
breaches, etc.) and continuing review reports will be submitted to the performance site IRB per 
local practices. All site specific IRB approved documents (e.g. consent, advertisement) and 
IRB approval letters should be forwarded to the Coordinating Center. 
 
10.1.2 
Clinical Trial Monitoring 
Data safety and verification monitoring will be conducted in accordance with the UPMC 
Hillman Cancer Center SOP HCC- CC-CRS-CLIN-027, the Code of Federal Regulations 
(CFR), and FDA and International Counsel on Harmonization (ICH) E6 Guidelines. 
 
10.1.3 
Data Safety and Monitoring Plan  
Investigator/Sub-investigators, regulatory, CRS management, clinical research coordinators, 
clinical research associates, data managers, and clinic staff meet regularly in disease center Data 
Safety Monitoring Boards (DSMB) to review and discuss study data to include, but not limited 
to, the following: 
 
• serious adverse events 
• subject safety issues 
• recruitment issues 
• accrual 
• protocol deviations 
• unanticipated problems 
• breaches of confidentiality 
 


 
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Minutes from the disease center DSMB meetings are available to those who are unable to attend 
in person. 
 
All toxicities encountered during the study will be evaluated on an ongoing basis according to 
the NCI Common Toxicity Criteria Version 4.0 . All study treatment associated adverse events 
that are serious, at least possibly related and unexpected will be reported to the IRB.  Any 
modifications necessary to ensure subject safety and decisions to continue, or close the trial to 
accrual are also discussed during these meetings. If any literature becomes available which 
changes the risk/benefit ratio or suggests that conducting the trial is no longer ethical, the IRB 
will be notified in the form of an Unanticipated Problem submission and the study may be 
terminated.  
 
All study data reviewed and discussed during these meetings will be kept confidential. Any 
breach in subject confidentiality will be reported to the IRB in the form of an Unanticipated 
Problem submission. The summaries of these meetings are forwarded to the UPMC Hillman 
Cancer Center DSMC which also meets monthly following a designated format. 
 
For all research protocols, there will be a commitment to comply with the IRB’s policies for 
reporting unanticipated problems involving risk to subjects or others (including adverse events). 
DSMC progress reports, to include a summary of all serious adverse events and modifications, 
and approval will be submitted to the IRB at the time of renewal. 
 
Protocols with subjects in long-term (survival) follow-up or protocols in data analysis only, will 
be reviewed bi-annually. 
 
Both the UPMC Hillman Cancer Center DSMC as well as the individual disease center DSMB 
have the authority to suspend accrual or further investigate treatment on any trial based on 
information discussed at these meetings. 
 
All records related to this research study will be stored in a locked environment. Only the 
researchers affiliated with the research study and their staff will have access to the research 
records. 
 
10.1.4 
Records Retention 
Essential documents should be retained by performance sites until notification is received 
from the Coordinating Center that the documents may be destroyed. In general, documents 
should be maintained at least 2 years after the last approval of a marketing application in an 
ICH region and until there are no pending or contemplated marketing applications in an ICH 
region or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. Records and documents pertaining to the conduct 
of this study and the distribution of investigational drug, including CRFs, consent forms, 
laboratory test results, and medication inventory records may be maintained in secure offsite 
storage after completion of study follow-up and data analysis. Performance sites should notify 
the Coordinating Center in writing of the new document location when documents are 


 
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transferred off site. 
 
10.2 Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements for 
submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. Information posted 
will allow subjects to identify potentially appropriate trials for their disease conditions and 
pursue participation by calling a central contact number for further information on appropriate 
trial locations and trial site contact information. 
 
10.3 Data Management 
Clinical data will be entered into the OnCore® database by the designated performance site 
personnel. Information can be entered into Oncore® in a way that is 21CRF11.10 (electronic 
medical records) compliant. OnCore® is equipped for HIPAA-compliant internet-based entry of 
protocol tracking and review information. 
 
All study data will be collected by the research team at each and every study visit and recorded 
in the research record. This data will then be entered in to the OnCore® study database. 
 
All source documents will be obtained and retained along with any study forms, 
and placed into the patient’s research record. 
 
 


 
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11.0  REFERENCES 
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patients (pts) with advanced melanoma (MEL) treated with the anti-PD-1 monoclonal 
antibody MK- 3475. J Clin Oncol 32:5s, 2014 (suppl; abstr 3006^) 
3. Wolchok JD, Hoos A, O'Day S, et al. Guidelines for the evaluation of immune therapy 
activity in solid tumors: immune-related response criteria. Clin Cancer Res 2009;15(23): 7412-
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4. Disis ML. Immune regulation of cancer. J Clin Oncol 2010;28(29): 4531-8. 
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apoptosis: a potential mechanism of immune evasion. Nat Med 2002;8(8): 793-800. 
6. Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nat Rev Immunol 2002;2(2): 116-26. 
7. Brown JA, Dorfman DM, Ma FR, et al. Blockade of programmed death-1 ligands on 
dendritic cells enhances T cell activation and cytokine production. J Immunol 2003;170(3): 
1257-66. 
8. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and 
autoimmunity. Immunol Rev 2010;236: 219-42. 
9. Thompson RH, Dong H, Lohse CM, et al. PD-1 is expressed by tumor-infiltrating immune 
cells and is associated with poor outcome for patients with renal cell carcinoma. Clin Cancer 
Res 2007;13(6): 1757-61. 
10. Talmadge JE, Donkor M, Scholar E. Inflammatory cell infiltration of tumors: Jekyll or 
Hyde. Cancer Metastasis Rev 2007;26(3-4): 373-400. 
11. Usubutun A, Ayhan A, Uygur MC, Ozen H, Toklu C, Ruacan S. Prognostic factors in 
renal cell carcinoma. J Exp Clin Cancer Res 1998;17(1): 77-81. 
12. Al-Shibli KI, Donnem T, Al-Saad S, Persson M, Bremnes RM, Busund LT. Prognostic 
effect of epithelial and stromal lymphocyte infiltration in non-small cell lung cancer. Clin 
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84. Pocock SJ. Group sequential methods in the design and analysis of clinical trials. 
Biometrika 1977;64(2): 192-99. 
 
 


 
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12.0 APPENDICES 
 
12.1 ECOG Performance Status 
 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 
50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined to 
bed or chair more than 50% of waking hours. 
4 
100%  bedridden.  Completely  disabled.  Cannot  carry  on  any self- 
care. Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative  Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative  Oncology Group, Robert Comis 
M.D., Group Chair. 
 
12.2 Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html). 
 
12.3 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for Evaluating 
Response in Solid Tumors 
 
RECIST version 1.1* will be used in this study for assessment of tumor response. While either 
CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this 
study. 
 
* As published in the European Journal of Cancer:        E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, 
S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe, J. Verweij. New response evaluation criteria 
in solid tumors: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 


 
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12.4 Tissue Block Shipping Form 
 
Protocol: A Phase II trial of reirradiation combined with open label Pembrolizumab  in patients 
with locoregional inoperable recurrence or second primary squamous cell carcinoma of the 
head and neck (SCCHN) 
 
Please complete one form for each tumor block.  Include a copy of the pathology report. 
 
 
Subject  Study ID:  
 
 
Date of Tumor Tissue Collection:  
 
 
FFPE Date of Fixation:  
 
 
Length of Fixation in Hours:  
 
 
Anatomical Location:  
 
 
Tumor Site (circle one): 
Primary 
Metastatic 
 
Shipment Tracking Number:  
 
 
Send tumor block to the Coordinating Center ATTN: 
Carly Reeder 
 
 
UPMC Hillman Cancer Center 
 
 
Research Pavilion Lab 2.19 
 
 
5117 Centre Avenue 
 
 
Pittsburgh, PA 15213 
 
 
Phone: 412-623-7738