A Phase I/II Study of Chemo Radiation Plus the Anti-Programmed Death-1 (Anti-PD-1) Antibody, Pembrolizumab (MK-3475) for Locally Advanced Laryngeal Squamous Cell Carcinoma
Phase: PHASE1
Conditions: Head and Neck Cancer
Sponsor: Vinita Takiar

 
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SPONSOR: University of Cincinnati 
 
TITLE:  A Phase I/ II Study of chemo radiation plus the Anti-PD-1 Antibody, 
Pembrolizumab (MK-3475) for Locally Advanced Laryngeal Squamous Cell Carcinoma 
 
IND NUMBER: 129364 
 
Protocol revision and date: Revision 5, 01SEP2017 
 
EudraCT NUMBER (Studies in Europe only): 
 
Principal Investigator: 
Vinita Takiar, MD 
University of Cincinnati  
Barret Center, ML 0757 
234 Goodman St. 
Cincinnati, Ohio, 45219 
Tel: 513-584-5327, Fax: 513-584-5680  
Email: takiarva@ucmail.uc.edu 
 
Sub-Investigators (alphabetic order) 
David Adelstein, MD 
Mustapha Bahassi, PhD 
William Barrett, MD 
Neal Dunlap, MD 
Bradley Huth, MD 
Tahir Latif, MD 
Jonathan Mark, MD 
John Morris, MD 
Yash Patil, MD 
Kevin Redmond, MD 
Keith Wilson, MD 
Cristina Rodriguez, MD 
Ammar Sukari, MD 
Vinita Takiar, MD, PhD 
Trisha Wise-Draper, MD, PhD 
 
 
Biostatistics: 
Lisa Rybicki, MS 
 
 

 
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1.0 TRIAL SUMMARY .......................................................... Error! Bookmark not defined. 
2.0 TRIAL DESIGN ................................................................ Error! Bookmark not defined. 
2.1 Trial Design ................................................................. Error! Bookmark not defined. 
2.1.1 2.1.1 Phase I run in ........................................... Error! Bookmark not defined. 
2.1.2 Phase II expansion ............................................................................................. 8 
Safety measurements that will be used in the study include physical examinations 
and clinical laboratory tests (hematology and blood chemistries). The 
adverse event will be graded for toxicity using the NCI CTC version 4.0. 
Toxicity assessment will occur at the start of each cycle, or more frequently 
if clinically indicated. Any adverse events leading to a treatment interruption 
or dose reduction along with all adverse events that are grade 3 and higher 
will be recorded in the CRF. .................................... Error! Bookmark not defined. 
2.2 Trial Diagram .............................................................. Error! Bookmark not defined. 
3.0 OBJECTIVE(S) & HYPOTHESIS(ES) ......................... Error! Bookmark not defined. 
3.1 Primary Objective(s) & Hypothesis(es) ............... Error! Bookmark not defined. 
3.1.1 Primary Objective & Hypothesis for phase 1 safety run-in portion: ... Error! 
Bookmark not defined. 
3.1.2 Primary Objective & Hypothesis for phase 2 portion: ................................. 10 
3.2 Secondary Objective(s) ........................................... Error! Bookmark not defined. 
3.3 Exploratory Objective............................................... Error! Bookmark not defined. 
4.0 BACKGROUND & RATIONALE .................................. Error! Bookmark not defined. 
4.1 Background ................................................................. Error! Bookmark not defined. 
4.1.1 Laryngeal cancer ............................................... Error! Bookmark not defined. 
4.1.2 Pharmaceutical and Therapeutic BackgroundError! Bookmark not defined. 
4.1.3 Preclinical and Clinical Trial Data ................... Error! Bookmark not defined. 
4.2 Rationale ...................................................................... Error! Bookmark not defined. 
4.2.1 Rationale for the Trial and Selected Subject PopulationError! Bookmark not 
defined. 

 
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4.2.2 Rationale for Dose Selection/Regimen/ModificationError! 
Bookmark 
not 
defined. 
4.2.3 Rationale for Endpoints .................................... Error! Bookmark not defined. 
5.0 METHODOLOGY ............................................................ Error! Bookmark not defined. 
5.1 Entry Criteria............................................................... Error! Bookmark not defined. 
5.1.1 Diagnosis/Condition for Entry into the Trial ... Error! Bookmark not defined. 
5.1.2 Subject Inclusion Criteria ................................. Error! Bookmark not defined. 
1.1.1 Subject Exclusion Criteria .............................. Error! Bookmark not defined.0 
5.2 Trial Treatments ......................................................... Error! Bookmark not defined. 
5.2.1 Dose Selection/Modification ........................................................................... 22 
5.2.2 Radiation Treatment ....................................... Error! Bookmark not defined.7 
5.3 Trial Blinding/Masking ........................................... Error! Bookmark not defined.0 
5.4 Randomization or Treatment Allocation ........... Error! Bookmark not defined.0 
5.5 Concomitant Medications/Vaccinations (allowed & prohibited) ........ Error! 
Bookmark not defined.0 
5.5.1 Acceptable Concomitant Medications ........................................................... 30 
5.5.2 Prohibited Concomitant Medications ............................................................. 31 
5.6 Rescue Medications & Supportive Care ........................................................ 31 
5.6.1 Pembrolizumab Supportive Care Guidelines ............................................... 31 
5.6.2 Cisplatin Supportive Care Guidelines .......... Error! Bookmark not defined.6 
5.7 Diet/Activity/Other Considerations .................................................................. 36 
5.7.1 Diet ..................................................................................................................... 36 
5.7.2 Contraception ................................................... Error! Bookmark not defined.7 
5.7.3 Use in Pregnancy ............................................ Error! Bookmark not defined.7 
5.7.4 Use in Nursing Women .................................. Error! Bookmark not defined.8 

 
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5.8 Subject Withdrawal/Discontinuation Criteria... Error! Bookmark not defined.8 
5.9 Subject Replacement Strategy ............................ Error! Bookmark not defined.8 
5.10 Clinical Criteria for Early Trial Termination ................................................ 39 
6.0 TRIAL FLOW CHART .................................................. Error! Bookmark not defined.0 
6.1 Study Flow Chart ..................................................... Error! Bookmark not defined.0 
7.0 TRIAL PROCEDURES ................................................. Error! Bookmark not defined.4 
7.1 Trial Procedures ...................................................... Error! Bookmark not defined.4 
7.1.1 Administrative Procedures ............................. Error! Bookmark not defined.4 
7.1.2 Clinical Procedures/Assessments ................................................................. 45 
7.1.3 Laboratory Procedures/Assessments .......... Error! Bookmark not defined.8 
7.1.4 Other Procedures ............................................ Error! Bookmark not defined.0 
7.1.5 Visit Requirements .......................................... Error! Bookmark not defined.0 
7.2 Assessing and Recording Adverse Events ...... Error! Bookmark not defined.1 
7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor and to Merck .............................. Error! Bookmark not defined.2 
7.2.2 Reporting of Pregnancy and Lactation to the Sponsor and to Merck Error! 
Bookmark not defined.3 
7.2.3 Immediate Reporting of Adverse Events to the Sponsor and to MerckError! 
Bookmark not defined.3 
7.2.4 Evaluating Adverse Events ............................ Error! Bookmark not defined.5 
7.2.5 Sponsor Responsibility for Reporting Adverse Events............................... 59 
8.0 STATISTICAL ANALYSIS PLAN ............................................................................ 59 
8.1 Statistical Analysis Plan Summary.................................................................. 59 
8.2 Statistical Analysis Plan ..................................................................................... 59 
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES .................................................................... Error! Bookmark not defined.0 

 
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9.1 Investigational Product .......................................... Error! Bookmark not defined.0 
9.2 Packaging and Labeling Information ................. Error! Bookmark not defined.0 
9.3 Clinical Supplies Disclosure ................................ Error! Bookmark not defined.0 
9.4 Storage and Handling Requirements ................. Error! Bookmark not defined.0 
9.5 Returns and Reconciliation .................................. Error! Bookmark not defined.0 
9.6 Cisplatin ..................................................................... Error! Bookmark not defined.1 
10.0 ADMINISTRATIVE AND REGULATORY DETAILSError! Bookmark not defined.1 
10.1 Confidentiality ........................................................ Error! Bookmark not defined.1 
10.2 Compliance with Financial Disclosure RequirementsError! 
Bookmark 
not 
defined.2 
10.3 Compliance with Law, Audit and Debarment Error! Bookmark not defined.2 
10.4 Compliance with Trial Registration and Results Posting Requirements
 ................................................................................... Error! Bookmark not defined.2 
10.5 Quality Management System ............................. Error! Bookmark not defined.2 
10.6 Data Management ................................................. Error! Bookmark not defined.2 
11.0 APPENDICES .............................................................. Error! Bookmark not defined.4 
11.1 ECOG Performance Status ................................. Error! Bookmark not defined.4 
11.2 Common Terminology Criteria for Adverse Events V4.0 (CTCAE) .. Error! 
Bookmark not defined.4 
11.3 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors ............ Error! Bookmark not defined.5 
11.4 Events of Clinical Interest Guidance DocumentError! Bookmark not defined.5 
11.5 References .............................................................. Error! Bookmark not defined.5 
 

 
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1.0 TRIAL SUMMARY 
Abbreviated Title 
MK-3475 in larynx cancer 
Trial Phase 
Phase I/II 
Clinical Indication 
Locally advanced stage III and IV larynx cancer 
Trial Type 
Open label single arm study 
Type of control 
None  
Route of administration IV 
Trial Blinding 
None  
Treatment Groups  
Single Arm Combination study 
Number of trial subjects 47 
Estimated 
enrollment 
period 
18 months 
Estimated duration of 
trial 
24 months 
Duration of Participation 24 months 
 
 
2.0 TRIAL DESIGN 
2.1 Trial Design 
This study is an open label, single arm study which will enroll patients with locally 
advanced squamous cell carcinomas of the larynx.  Positive tumor PDL1 expression by 
IHC will not be required for enrollment. 
 
All patients with receive Pembrolizumab and cisplatin in combination with radiation. 
Pembrolizumab 200 mg flat dose given Q21 days will begin 3 weeks prior to initiation of 
chemoradiation and continued through the 21-day cycle until completion of 
chemoradiation. Cisplatin will be given 100 mg/m2 every 21 days during radiation as per 
standard of care. 
 
Pembrolizumab has well defined toxicities as single agent and has non-overlapping 
mechanisms of action with cisplatin and radiation.  The safety of these agents used in 
combination has not been previously described, therefore the study will begin with a 
safety run-in phase 1 followed by the phase II design.  See statistical section for details. 
 
2.1.1 Phase I run in 
 
Both drugs are FDA approved for other disease indications, with safety and tolerability 
well described at the approved doses. Therefore the limited phase I portion of this study 
aims to assess the safety and tolerability of this drug combination at their established 
doses along with concurrent radiation.   There will be no dose escalation cohorts within 
this phase I run in group. 
 
The first six patients will constitute the phase I portion of this study. These initial 6 
patients will be assessed for dose limiting toxicities (DLTs, defined in Section 2.1.1.1) 

 
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from the start of study treatment until the start of cycle #2 concurrent cisplatin/radiation 
and pembrolizumab After these first 6 patients initiate cycle #1, enrollment to the study 
will be temporarily halted, and a formal DLT evaluation of all 6 patients will be 
conducted. 
 
If ≤ 2 of these six patients experience DLTs after completion of cycle #1 concurrent 
cisplain/radiation and Pembrolizumab, then the study will proceed to the phase II 
portion, using Pembrolizumab 200mg IV Q21 days and cisplatin 100mg IV each 
21 day cycle. 
 
If > 2 of these first 6 patients experience a DLT upon completion of cycle #1, the 
protocol will be amended to investigate use of pembrolizumab 200 mg IV Q 21 
days subsequent to completion of chemoradiation. (3-6 weeks after last dose of 
radiation) (upon Merck approval) 
 
Only upon completion of the DLT evaluation for these first 6 patients and the 
determination of appropriate Phase II dose, will enrollment reopen for the phase II 
expansion. 
 
If toxicity results are unclear, we will allow 6 additional patients into Phase I portion ( 6 + 
6) The second cohort will be assessed based on above definitions for DLTs. Unclear 
toxicity can include ( but not limited to) adverse effects that are considered secondary to 
cisplatin or radiation and per protocol are not considered DLT ( see section 2.1.1.1 for 
definition of DLT) , however, the investigator strongly feels they could be related to study 
drug or exacerbated by concurrent use of study drug and chemoradiation. This 
investigator initiated study will be under the oversight of the University of Cincinnati IRB 
and Data and Safety Monitoring committee.  
 
2.1.1.1  Definition of Dose-Limiting Toxicities  
 
All toxicities will be graded using National Cancer Institute (NCI) CTCAE Version 4.0 
(see Appendix). 
 
Dose limiting toxicity (DLT) is defined as the appearance of side effects during 
treatment that are severe enough to prevent continuation of planned treatment. Dose 
limiting toxicity is defined as grade 3 or 4 non-hematologic toxicities that is definitely, 
probably, or possibly related to study drug, excluding alopecia, nausea or vomiting, 
grade 3 tumor flare, rash, mucositis, radiation dermatitis, need for feeding tube, and 
grade 3 immune-related events that resolve to grade 1 or less within 28 days. However, 
Grade ≥3immune-mediated adverse events that include pneumonitis, renal failure 
nephritis, and elevation of AST, ALT, or bilirubin (with an exception for patients with liver 
metastases with baseline Grade 2 AST or ALT) should result in discontinuation of 
pembrolizumab and will be considered DLT ( please see Table 3 for details on dose 
modification) . 
 

 
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In addition, adverse effects that are considered secondary to cisplatin or radiation are not 
considered DLT (see sections 5.2.1.3 and 5.2.2.7) unless they develop after first dose of 
pembrolizumab and prior to initiation of cisplatin and radiation. Cisplatin or radiation 
adverse effects include (but are not limited to):  
Grade 3 or 4 renal impairment (with the exception of renal failure or 
nephritis determined to be immune-related, which will be considered a 
DLT). 
• 
 
 
Grade 2-4 neurotoxicity including ototoxicity (with the exception of 
myasthenia gravis and Guillain-Barre syndrome, which will be considered 
a DLT). 
 
• Grade 3 or 4 mucositis 
• 
Grade 3 or 4 myelosuppression 
 
Although the above should result in dose modifications or delays as stated in section 
5.2.1.3, they will NOT be considered DLTs for pembrolizumab on this study, and will NOT 
interfere with expansion to phase II portion of study. 
If a patient is taken off study due to the above and has not yet reached evaluation for 
toxicity attributed to pembrolizumab, that subject will be replaced with another patient on 
study. 
 
Non hematologic toxicities that will be attributed to pembrolizumab include: 
• 
Grade 3-4 Pneumonitis 
• 
Grade 3-4 diarrhea/colitis 
• 
Grade 3-4 hyperglycemia 
• 
Grade 3-4 hypophysitis 
• 
Grade 3-4 thyroid dysfunction ( hypothyroid or hyperthyroid) 
• 
Grade 3-4 hepatic failure ( elevation of AST, ALT, Bilirubin) 
• 
Grade 5 toxicity 
 
 
Any additional grade 3-4 non hematologic toxicity that is judged by the investigator to be 
possibly, probably or definitely related to study drug administration will be reviewed by 
study monitor and PI on an individual basis. 
 
Management and dose modifications associated with the above adverse events are 
outlined in Sections 5.2.1.2 and 5.6. 
 
 
2.1.2  Phase II expansion  
 
After the first 6 patients have been assessed for DLTs upon completion of cycle 1 of 
treatment, and the appropriate Cisplatin dose and Pembrolizumab dosing determined 

 
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for phase II expansion, an additional 41 patients with locally advanced larynx squamous 
cell carcinoma will be enrolled in this phase I/II study.  The entire cohort will be used to 
assess the safety and efficacy outcomes of interest.  Safety stopping rules will be 
applied in the event of excessive toxicity leading to inability of patients to receive at 
least 2 doses of cisplatin and complete radiation therapy. If radiation treatment breaks 
are required, greater than a 10 day radiation treatment break in 6 or more patients will 
also initiate early stop for safety evaluation. 
  
Patients will be evaluated 14 weeks after completion of radiation (14 ± 2 week after 
completion of radiation) with radiographic imaging to assess response to treatment.   All 
imaging will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 
1.1 Adverse events will be monitored throughout the trial and graded in severity according 
to the guidelines outlined in the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0.   
 
After the end of treatment, each patient will be followed for a minimum of 30 days for 
adverse event monitoring (serious adverse events will be collected for up to 90 days after 
the end of treatment).  Subjects will have post-treatment follow-up for laryngectomy event 
and survival status for two years.  
 
Participation in this trial will be dependent upon supplying tumor tissue from a formalin-
fixed specimen. Newly obtained formalin-fixed specimens are strongly encouraged 14-20 
days after first dose of Pembrolizumab prior to initiation of cisplatin and radiation unless 
clinically deemed unsafe by the treating physician. The specimen will be evaluated for 
expression status of PD-L1.   
 
2.1.2.1 Safety assessments during the Phase II expansion 
This investigator initiated study will be under the oversight of the University of Cincinnati 
Cancer Consortium IRB and Data and Safety Monitoring committee. The investigators 
are ultimately responsible for monitoring the safety of patients who have entered this 
study and for alerting the Consortium IRB to any event that seems unusual in 
accordance with IRB policy. The investigator is responsible for the appropriate medical 
care of patients during the study. The investigator remains responsible to follow, 
through an appropriate health care option, adverse events that are serious or that 
caused the patient to discontinue before completing the study. The patient should be 
followed until the event resolves or stabilizes. Frequency of follow-up is left to the 
discretion of the investigator.  
 
Safety measurements that will be used in the study include physical examinations and 
clinical laboratory tests (hematology and blood chemistries). The adverse event will be 
graded for toxicity using the NCI CTC version 4.0. Toxicity assessment will occur at the 
start of each cycle, or more frequently if clinically indicated. Any adverse events leading 
to a treatment interruption or dose reduction along with all adverse events that are 
grade 3 and higher will be recorded in the CRF. 
 

 
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The criteria for dose de-escalation for adverse events are outlined in Section 5.2.  Any 
patient who requires two dose modifications or de-escalations will be taken off study. 
 
2.2 Trial Diagram 
Please refer to timing of treatment administration (section 5.2.1.4) Trial Flow Chart (section 6.0) 
for details on timing flexibility of treatment administration. 
 
3.0 OBJECTIVE(S) & HYPOTHESIS(ES) 
3.1 Primary Objective(s) & Hypothesis(es) 
 
3.1.1 Primary Objective & Hypothesis for phase 1 safety run-in portion:  
Objective: Determine the safety and tolerability of Pembrolizumab in combination with 
cisplatin and radiation patients with LA-larynx SCC. 
 
Hypothesis:  The combination of Pembrolizumab with cisplatin and radiation is safe and 
well tolerated in patients with LA-larynx SCC. 
 
3.1.2 Primary Objective & Hypothesis for phase 2 portion:  
 
(1) Objective:  Determine the 18-month laryngectomy-free survival in locally advanced 
laryngeal squamous cell carcinoma (LA-larynx SCC).  

 
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Hypothesis:  Patients with LA-larynx SCC who receive Pembrolizumab combination 
with Cisplatin and radiation have a 15% improvement in 18-month laryngectomy-free 
survival. 
 
3.2 Secondary Objective(s)  
(1)   Objective: Estimate the one-year laryngectomy-free survival in locally advanced 
laryngeal squamous cell carcinoma (LA-larynx SCC). 
(2)    Objective: Estimate overall survival and progression free survival in patients enrolled 
in the study 
 (2) 
Objective: Estimate 3-month complete response rate (CR) in patients enrolled in 
the study 
 (3) 
Objective: Estimate event –free survival (events include death, persistent or 
progressive disease, laryngectomy) 
 
 
3.3 Exploratory Objective 
1. Objective: Explore peripheral T cell phenotype at baseline and after treatment 
with Cisplatin, radiation, and Pembrolizumab.  
Hypothesis: T cell phenotype is altered after exposure to Cisplatin, radiation, 
and Pembrolizumab, and will correlate with treatment response. 
2. Objective: Measure expression of the proteins in the PD-1 family on baseline 
tumor samples and on treatment biopsies. 
Hypothesis: There is a relationship between response to Pembrolizumab and 
PD-1 protein family expression in both pre- and post-treatment tumor samples.  
Cisplatin-radiation concurrent with Pembrolizumab impacts the expression of 
PD-1 family of proteins.  
3. Objective: Measure circulating tumor DNA in pre-treatment, during treatment, 
and post-treatment blood samples. 
Hypothesis: There is a relationship between response to Pembrolizumab and 
circulating tumor DNA level in both pre- and post-treatment tumor samples.  
4. Objective: Explore Tumor infiltrating immune cell phenotypes and global gene 
expression (including 12-gene signature) by RNAseq on baseline tumor 
samples and on treatment biopsies. 
Hypothesis: Tumor infiltrating immune cell phenotypes and global gene 
expression is altered after exposure to Pembrolizumab, and will correlate with 
treatment response. 
5. Objective: Explore patterns of disease recurrence after treatment with 
Cisplatin, radiation, and Pembrolizumab.  
Hypothesis: Patterns of recurrence of disease is altered after exposure to 
Pembrolizumab when added to standard Cisplatin and radiation therapy. 
6. Objective: Explore rates of speech and swallowing dysfunction after completion 
of treatment with Cisplatin, Radiation, and Pembrolizumab.  
Hypothesis: Rates of speech and swallowing dysfunction is improved after 
completion of treatment with Cisplatin, Radiation, and Pembrolizumab. 
7. Objective: Explore PET scan findings after completion of treatment with 
Cisplatin, Radiation, and Pembrolizumab 

 
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Hypothesis: There is a relationship between post treatment PET scan and 
clinical benefit in patients treated with Cisplatin, Radiation, and Pembrolizumab. 
 
4.0 BACKGROUND & RATIONALE 
4.1 Background 
4.1.1  Laryngeal cancer 
Laryngeal cancer represents one of the more common head and neck malignancies, 
accounting approximately for 20% of all cases, majority of them (85-90%) being 
squamous cell carcinomas [1, 2]. Up to 40% of patients present with advanced disease 
[3]. The term advanced laryngeal cancer generally denotes stage 3 or 4 laryngeal 
cancers according to the Union for International Cancer Control (UICC) / American Joint 
Committee on Cancer (AJCC) staging. Since larynx is essential in many physiologic 
functions including speech production, swallowing, airway protection, and breathing, 
disruption of any of these functions by either the tumor or the treatment may have 
devastating consequences for the patient and often associated with significant morbidity 
and mortality for the patient and a financial costs for society [4, 5]. Therefore, in addition 
to achieving tumor control, optimizing functional outcomes and organ preservation are 
very important in treatment of patients with laryngeal carcinoma.  
 
Management of advanced laryngeal cancer is complex and involves different treatment 
modalities [6].  Total laryngectomy (TL), alone or with neck dissection (ND), radiotherapy 
(RT) alone, TL followed by RT, and combined chemotherapy and RT (CRT) [6, 7]are 
considered standard treatment options. Prior to 1991, TL followed by adjuvant RT was 
widely considered the standard management option [8]. This approach would result in 
permanent tracheostoma in the neck, alterations in deglutition and loss of natural voice 
for the patients. The Veterans Administration (VA) study in 1991 sparked a major change 
in the management of advanced laryngeal cancer. [9]This randomized study involving 
332 patients found that induction chemotherapy followed by radiation therapy achieved 
an equivalent 2 year survival rate (68%) compared with total laryngectomy with 
postoperative radiation therapy. Moreover, the larynx could be preserved in 64% of 
patients undergoing chemoradiation therapy. Overall 64% of patients receiving 
chemoradiation achieved histologically confirmed complete response [9]. No significant 
difference in survival was reported after more than 10 years of follow up [10]. Patterns of 
recurrence differed significantly between the two groups with more local recurrences 
(12% vs 2%) and fewer distant metastases (11% vs 17%) in the chemotherapy group 
than in the surgery group. Thus addition of chemotherapy to radiation introduced new 
oncologic end points, namely organ preservation and laryngectomy-free survival (LFS). 
[9] 
The VA study was followed by another landmark study, the Radiation Therapy Oncology 
Group (RTOG) 91-11 trial reported by Forasteire and colleagues in 2003. This three arm 
randomized controlled trial in 547 locally advanced (stage III and IV – T2, T3 or low 
volume T4 ) resectable laryngeal cancer patients confirmed significantly lower rates of 
salvage laryngectomies in chemoradiation treated patients. [11]By the end of 2 years, the 
proportion of alive patients with intact larynx after radiotherapy with concurrent 
chemotherapy was 88% vs 75% in the group that received induction chemotherapy 
followed by radiotherapy vs 70% in the radiotherapy group alone, the differences being 

 
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statistically significant. Overall survival rates were similar at 75% at 2 years for all 
treatment groups [11]. In a recent update to the RTOG 91-11 study, composite end point 
of LFS for the concurrent chemotherapy group was 74% and 63% at 1 and 2 years 
respectively.  AT 10-year follow up, there is no significant difference between the 
concomitant cisplatin/ RT arm (23.5%) and the induction arm (28.9%). LFS was 
significantly worse for RT group (17.2%) versus both the induction group and the 
concomitant group, confirming role of systemic therapy in treatment of laryngeal cancer. 
[12] 
More recent studies that have introduced more aggressive induction chemotherapy 
regimens [TPF (taxane, cisplatin, and 5-fluorouracil)] to improve on laryngeal preservation 
rates compared to induction chemotherapy arm of RTOG 91-11 (3-year LFS 70% vs 
57%), however, these regimens carry higher adverse events without improvement if PFS 
or OS. [13] 
 
In the event of locally recurrent, residual disease, or dysfunctional larynx after completion 
of chemo radiation, salvage laryngectomy is considered standard treatment. However, 
there appears to be a significantly worse survival outcome for those patients undergoing 
laryngectomy after patients having been exposed to chemotherapy in combination with 
radiation [12].  
 
Thus, treatment paradigms for larynx cancer have continued to change since 1991 
resulting in variability in the treatment sequence and type of therapeutic modalities used. 
[14] . Unlike most other malignancies, a recent review of the latest National Cancer Data 
Base (NCDB) has demonstrated worsening survival outcome of larynx cancer patients in 
recent years with a 5-year survival at 59% compared to 67 % in 1985. These findings 
may, to some extent, reflect changes in practice patterns over the last two decades [1]. 
In addition, some other retrospective studies suggest a possible inferior oncologic 
outcome in patients who choose organ preservation compared to a more traditional 
upfront surgery (TL) with 2-year disease specific survival and overall survival (70% vs 
64%) and (64% vs 57%) respectively. [15]  
These findings suggest a need for further investigation and development of more 
successful curative organ preservation approaches. Despite multiple trials over the last 
two decades, overall rates of cure and organ preservation remain suboptimal without 
much improvement since introduction of concurrent chemo radiation in the landmark 
RTOG 91-11 study. 
 
4.1.2  Pharmaceutical and Therapeutic Background 
4.1.2.1 Pembrolizumab (MK-3475) 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ 
effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis 
and long-term survival in many solid tumors. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated 

 
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T-cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 which has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or 
PD-L2).  The structure of murine PD-1 has been resolved.  PD-1 and family members are 
type I transmembrane glycoproteins containing an Ig Variable-type (V-type) domain 
responsible for ligand binding and a cytoplasmic tail which is responsible for the binding 
of signaling molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling 
motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor 
tyrosine-based switch motif (ITSM).  Following T-cell stimulation, PD-1 recruits the 
tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, 
leading to the dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 
which are involved in the CD3 T-cell signaling cascade.  The mechanism by which PD-1 
down modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both 
molecules regulate an overlapping set of signaling proteins.  PD-1 was shown to be 
expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-
cells, T regs and Natural Killer cells.  Expression has also been shown during thymic 
development on CD4-CD8- (double negative) T-cells as well as subsets of macrophages 
and dendritic cells.  The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed 
or can be induced in a variety of cell types, including non-hematopoietic tissues as well 
as in various tumors.  Both ligands are type I transmembrane receptors containing both 
IgV- and IgC-like domains in the extracellular region and contain short cytoplasmic 
regions with no known signaling motifs.  Binding of either PD-1 ligand to PD-1 inhibits T-
cell activation triggered through the T-cell receptor.  PD-L1 is expressed at low levels on 
various non-hematopoietic tissues, most notably on vascular endothelium, whereas PD-
L2 protein is only detectably expressed on antigen-presenting cells found in lymphoid 
tissue or chronic inflammatory environments.  PD-L2 is thought to control immune T-cell 
activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell 
function in peripheral tissues.  Although healthy organs express little (if any) PD-L1, a 
variety of cancers were demonstrated to express abundant levels of this T-cell inhibitor.  
PD-1 has been suggested to regulate tumor-specific T-cell expansion in subjects with 
melanoma (MEL).  This suggests that the PD-1/PD-L1 pathway plays a critical role in 
tumor immune evasion and should be considered as an attractive target for therapeutic 
intervention. 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) 
of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its 
ligands, PD-L1 and PD-L2.  KeytrudaTM (pembrolizumab) has recently been approved in 
the United Stated for the treatment of patients with unresectable or metastatic melanoma 
and disease progression following ipilumumab and, if BRAF V600 mutation positive, a 
BRAF inhibitor. 
 
4.1.3 Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
 

 
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4.2 Rationale 
4.2.1 Rationale for the Trial and Selected Subject Population 
The Programmed death Ligand 1 (PD-L1) / programmed death receptor (PD-1) axis has 
been identified as an important regulator of the immune system across various solid 
tumors allowing cancer cells to escape immune response [16]. The normal function of 
PD -1, an Ig superfamily member related to CD 28 and CTLA-4, expressed on the cell 
surface of activated T- cells under healthy conditions, is to down modulate unwanted or 
excessive immune responses, including autoimmune reactions. The ligands for PD-1 
(PD- L1 and PD-L2) are constitutively expressed or can be induced in a variety of non-
hematopoietic tissues as well as in various tumors. Binding of either PD-1 ligand to PD-
1 inhibits T cell activation triggered through the T- cell receptor.  
 
Head and neck squamous cell carcinoma has a prominent immune escape in both HPV 
positive and negative settings [17, 18]. It has also been shown that in mouse model, 
blocking PD1/PDL1 interaction can result in tumor regression and survival 
extension.[19] In addition, it has been shown in pre-clinical models that following 
radiation, PD-L1 gets up-regulated in the tumor microenvironment and that anti-PD-L1 
therapy can improve the efficacy of radiation through a cytotoxic T cell-dependent 
mechanism, supporting the hypothesis that a PD-L1 / PD-1 inhibitor can restore anti-
tumor activity [32].  
 
Pembrolizumab (MK-3475) is a potent and highly selective humanized monoclonal 
antibody designed to block the interaction between PD-1 and its ligands PD-L1 and PD- 
L2. It has been shown to have a potent and durable anti-tumor activity in multiple tumor 
types, including single agent activity in HNSCC [20].  Preliminary data reported in 
abstract form in 2014 revealed that 78% of RMSCC screened for an ongoing MK-3475 
phase Ib study, expressed PD-L1.  There have been observations of disease responses 
in this cohort of 60 patients, many of whom have been heavily pretreated with prior 
systemic agents[20]. However, combination of Pembrolizumab and chemo radiation has 
not been examined in humans, which remains important in better understanding of the 
therapeutic utility of this agent in the vast majority of locally advanced HNSCC. 
Laryngeal squamous cell carcinoma is unique in the setting for which surgical options 
are less appealing due to long-term morbidities associated with a total laryngectomy 
(tracheostomy and loss of voice). Chemo-radiation alone may not be sufficient to avoid 
surgery and allow for a long-term survival of patients with a functional larynx. This 
disease is also unique in the setting that it is highly associated with smoking and genetic 
complexity, making it a favorable target for immune modulators. In addition, biologic 
correlative testing is feasible due to the accessibility of tumor tissue by biopsy and any 
specimens from patients undergoing laryngectomy for residual/ progressive or 
dysfunctioning larynx. 
 
We propose a single arm phase II study to test the hypothesis that the addition of 
Pembrolizumab to chemoradiation enhances the local effects of standard therapy in 
laryngeal HNSCC, ultimately allowing for higher rates of functional organ preservation in 
this population, and leading to improved quality of life. In addition, we hypothesize that 
adding Pembrolizumab to chemo radiation may result in immune-mediated regression 

 
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of micrometastatic disease and lower rates of systemic relapse, similar to what has 
previously been described in distant untreated melanoma lesions [21] Therefore, we will 
examine not only laryngectomy-free survival and event-free survival endpoints 
[including death, persistent disease or progression, laryngectomy (partial or total), and 
feeding tube dependence], but also pattern of in and out of field tumor growth in these 
patients. Finally, we will examine exploratory correlative studies that will provide 
valuable insight into the effects of chemo radiation in combination with PD1 inhibitor on 
laryngeal carcinoma microenvironment, and the association of tumor response and 
overall clinical benefit with adaptive PD-L1 tumor expression, immune infiltration, 
cytokine expression profiles, and genomic signature of tumors.  We hypothesize that 
chemo radiation affects expression of PD1/PD-L1 on tumor infiltrating immune cells 
detected by IHC and subsequently increases PD-L1 expression on the tumor cells, 
which will predict response to chemo radiation and PD-1 inhibitor.   
 
We hypothesize by inhibiting PD1 ligands, PDL1 and PDL2, we will activate immune 
system and allow for better anti-tumor effect, finally resulting in improved laryngectomy-
free survival with fewer side effects.   
 
 
4.2.2 Rationale for Dose Selection/Regimen/Modification  
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and 
clinical activity of single agent Pembrolizumab (MK-3475).  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 MK-3475 showed evidence of target engagement and objective evidence of 
tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W).  No MTD 
has been identified to date.  10.0 mg/kg Q2W, the highest dose tested in PN001, will be 
the dose and schedule utilized in Cohorts A, B, C and D of this protocol to test for initial 
tumor activity.  Recent data from other clinical studies within the MK-3475 program has 
shown that a lower dose of MK-3475 and a less frequent schedule may be sufficient for 
target engagement and clinical activity. 
 
PK data analysis of MK-3475 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 Q2W and Q3W dosing schedule.   
 
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 MK-3475 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.  MK-3475 has been found to 
have a wide therapeutic range based on the melanoma indication.  The differences in 

 
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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 MK-3475 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. 
 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab 
in solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed 
at either 2 mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response 
relationships of pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg 
Q3W to 10 mg/kg Q3W, 3) the lack of effect of tumor burden or indication on distribution 
behavior of pembrolizumab (as assessed by the population PK model) and 4) the 
assumption that the dynamics of pembrolizumab target engagement will not vary 
meaningfully with tumor type. 
 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is 
based on simulations performed using the population PK model of pembrolizumab 
showing that the fixed dose of 200 mg every 3 weeks will provide exposures that 1) are 
optimally consistent with those obtained with the 2 mg/kg dose every 3 weeks, 2) will 
maintain individual patient exposures in the exposure range established in melanoma as 
associated with maximal efficacy response and 3) will maintain individual patients 
exposure in the exposure range established in melanoma that are well tolerated and safe.  
 
A fixed dose regimen will simplify the dosing regimen to be more convenient for 
physicians and to reduce potential for dosing errors.  A fixed dosing scheme will also 
reduce complexity in the logistical chain at treatment facilities and reduce wastage. 
4.2.3 Rationale for Endpoints 
Cisplatin and pembrolizumab appear to be well tolerated as single agents and have FDA 
approved doses and indications.  These two drugs have non-overlapping mechanisms of 
action. Cisplatin in combination with radiation is well tolerated and considered standard 
treatment in laryngeal carcinoma patients who are treated with an organ preservation 
approach. There has been no reported clinical experience with the combination of 
cisplatin-radiation and pembrolizumab in locally advanced laryngeal carcinoma patients. 
Therefore a phase I/II design, wherein a limited phase I run in cohort is initially enrolled, 
was felt to be most appropriate to study this combination, with laryngectomy-free survival 
as a composite endpoint to reflect both oncologic and functional outcome as the primary 
endpoint of interest. 
 
4.2.3.1 Efficacy Endpoints  
 
There is intriguing preclinical and clinical data suggesting that combination of radiation 
and PD-1 inhibitor can augment the immunologic anti-tumor response to radiation. The 

 
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study explores whether chemoradiation combined with a PD-1 inhibitor have synergistic 
effects, resulting fewer salvage laryngectomies for persistent/ recurrent disease or 
dysfunctional larynx, and allow for improved quality of life in laryngeal cancer survivors. 
 
Specifically, this study hypothesizes that organ preservation will improve as a 
consequence of this synergistic effect.  
 
Therefore in addition to above, exploring objective response rates to the combination of 
pembrolizumab with chemoradiation will be secondary endpoints.  Overall survival and 
progression free survival will be examined as well.  If encouraging response rates, and 
overall and progression free survival are observed in this cohort of patients, further study 
of the combination in this disease will be justified. 
 
4.2.3.2  Biomarker Research 
1. Archived tumor tissue at diagnosis, during treatment tumor biopsies, salvage 
laryngectomy tissues, and potential biopsies from regional and systemic recurrent 
disease will be used to examine tumor PD-L1 expression, Tumor infiltrating 
immune cell phenotypes, global gene expression  by RNAseq, and whole genome 
sequencing in an attempt to define a gene set critical for clinical response to 
pembrolizumab and chemoradiation and correlate these with clinical benefit and 
emergence 
of 
resistance 
from 
combination 
of 
Pembrolizumab 
and 
chemoradiation. 
2. Examine peripheral blood mononuclear cell phenotypes in pre-treatment, during 
treatment, and post-treatment in blood samples using flow cytometric evaluation 
of CD3, CD4, CD8, CD14, PD-1, PD-L1, PD-L2, and correlate these with clinical 
benefit from combination of Pembrolizumab and chemoradiation. In addition to 
these specific protein biomarkers, both tissue and blood derivatives can be 
subjected to proteomic profiling studies using a variety of platforms that could 
include but are not limited to immunoassay, liquid chromatography/mass 
spectrometry. This approach could identify novel protein biomarkers that could aid 
in patient selection for pembrolizumab and chemoradiation. Combination therapy. 
3. Examine circulating tumor DNA in pre-treatment, during treatment, and post-
treatment blood samples, and correlate circulating tumor DNA levels as a potential 
biomarker for clinical benefit or emergence of early resistance from combination of 
Pembrolizumab and chemoradiation. 
4. Circulating tumor cells (CTCs) hold great promise as a readily available source 
material that can offer real-time insight into a tumor’s genomic architecture. CTCs 
can be detected in head and neck cancer patients and appear to have prognostic 
importance. We propose to collect CTCs and assess PD-L1 expression in CTCs 
and attempt to correlate PD-L1 expression in CTCs with patient’s primary tumor 
and with efficacy parameters.   
5. Examine rates of speech and swallowing dysfuncyion after completion of treatment 
with combination of Pembrolizumab and chemoradiation. 
6. Examine correlation of post treatment PET scan findings with clinical benefit in 
Pembrolizumab treated patients. 
 

 
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5.0 METHODOLOGY 
5.1 Entry Criteria 
5.1.1 Diagnosis/Condition for Entry into the Trial 
Patients with biopsy-proven laryngreal squamous cell carcinoma that are candidates for 
curative treatment with chemoradiation. 
 
5.1.2 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Biopsy-proven, previously untreated stage III or IV squamous cell carcinoma of the 
larynx, Primary tumor stage (T2, T3) and nodal stage ( N0,N1,N2,N3). 
2. Be willing and able to provide written informed consent/assent for the trial. 
3. Be ≥ 18 years of age on day of signing informed consent. 
4. Have measurable disease based on RECIST 1.1.   
5. Be willing to provide tissue from a newly obtained core or excisional biopsy of a 
tumor lesion.  Newly-obtained is defined as a specimen obtained up to 6 weeks 
(42 days) prior to initiation of treatment on Day 1.  Subjects for whom newly-
obtained samples cannot be provided (e.g. inaccessible or subject safety concern) 
may submit an archived specimen only upon agreement from the Sponsor. 
6. Have a performance status of 0 or 1 on the ECOG Performance Scale. 
7. Anticipated survival minimum 12 months. 
8. Patient is > 5 years free of another primary malignancy, except: a) if the other 
malignancy is basal cell carcinoma or cervical carcinoma in situ or b) if the other 
primary malignancy is not considered clinically significant and is requiring any 
active intervention 
 
9. Demonstrate adequate organ function as defined in Table 1, all screening labs 
should be performed within 10 days of treatment initiation.   
Table 1  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count 
(ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L without transfusion or 
EPO 
dependency 
(within 
7 
days 
of 
assessment) 
Renal 
 
Serum creatinine OR 
Measured or calculateda 
creatinine clearance 
(GFR can also be used in 
place of creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
 
≥60 mL/min for subject with creatinine levels 
> 1.5 X institutional ULN 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN OR 

 
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Direct bilirubin ≤ ULN for subjects with total 
bilirubin levels > 1.5 ULN 
AST (SGOT) and ALT 
(SGPT) 
≤ 2.5 X ULN  OR 
≤ 5 X ULN for subjects with liver metastases 
Albumin 
>2.5 mg/dL 
Coagulation 
International Normalized 
Ratio (INR) or Prothrombin 
Time (PT) 
 
Activated Partial 
Thromboplastin Time (aPTT) 
≤1.5 X ULN unless subject is receiving 
anticoagulant therapy 
as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants 
≤1.5 X ULN unless subject is receiving 
anticoagulant therapy 
as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 
 
10. Female subject of childbearing potential should have a negative urine or serum 
pregnancy within 72 hours prior to receiving the first dose of study medication.  If 
the urine test is positive or cannot be confirmed as negative, a serum pregnancy 
test will be required.   
11. Female subjects of childbearing potential should be willing to use 2 methods of 
birth control or be surgically sterile, or abstain from heterosexual activity for the 
course of the study through 120 days after the last dose of study medication 
(Reference Section 5.7.2).  Subjects of childbearing potential are those who have 
not been surgically sterilized or have not been free from menses for > 1 year.  
12. 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. 
 
5.1.3 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Patients with T1 primary tumor or T4 large volume tumor that has resulted in 
larynx dysfunction at baseline (for example tumor largely penetrating into base of 
tongue and resulting in inability to swallow at baseline) 
2. Prior radiation therapy to larynx area or involved neck. 
3. Distant metastasis. Small lesions (for example, small nodule in lung) that are not 
clinically or radiographically suggestive of metastasis do not require biopsy for 
confirmation. 
4. Prior complications from former therapies, such as history of radiation 
pneumonitis that, in the opinion of the investigator, may have risk of increasing 
toxicity with anti-PD1 therapy. 
5. Is currently participating and receiving study therapy or has participated in a study 
of an investigational agent and received study therapy or used an investigational 
device within 4 weeks of the first dose of treatment. 

 
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6. 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. 
 
7. Has a known history of active TB   (Bacillus Tuberculosis) 
8. Hypersensitivity to pembrolizumab or any of its excipients. 
9. Patients who have not recovered (i.e., ≤ Grade 1 or at baseline) from adverse 
events due to a previously administered agent. 
- 
Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion 
and may qualify for the study. 
- 
Note:  If subject received major surgery, they must have recovered 
adequately from the toxicity and/or complications from the intervention prior 
to starting therapy.   
10. Has a known additional malignancy that is progressing or requires active 
treatment.  Exceptions include basal cell carcinoma of the skin or squamous cell 
carcinoma of the skin that has undergone potentially curative therapy or in situ 
cervical cancer. 
11. Has known active central nervous system (CNS) metastases and/or 
carcinomatous meningitis.  Subjects with previously treated brain metastases may 
participate provided they are stable (without evidence of progression by imaging 
for at least four weeks prior to the first dose of trial treatment and any neurologic 
symptoms have returned to baseline), have no evidence of new or enlarging brain 
metastases, and are not using steroids for at least 7 days prior to trial treatment.  
This exception does not include carcinomatous meningitis which is excluded 
regardless of clinical stability.   
12. Has active autoimmune disease that has required systemic treatment in the past 
2 years (i.e. with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc.) is not considered a form of systemic treatment.  
13. Has known history of, or any evidence of active, non-infectious pneumonitis. 
14. Has an active infection requiring systemic therapy. 
15. 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.   
16. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
17. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit 
through 120 days after the last dose of trial treatment. 
18. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
19. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
20. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
21. Has received a live vaccine within 30 days of planned start of study therapy. 

 
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Note:  Seasonal influenza vaccines for injection are generally inactivated flu 
vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) 
are live attenuated vaccines, and are not allowed. 
 
5.2 Trial Treatments 
The treatment to be used in this trial is outlined below in Table 2 
Table 2 Trial Treatments  
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
pembrolizumab 200 mg  
Q3W 
IV infusion 
Starting 3W ( -1 w) 
prior to 
chemotherapy, 
then Day 1 of each 
3 week cycle 
Maximum 4 doses 
Experimental 
cisplatin 
100 mg /m2 
Q3W 
IV infusion 
Day 1 of each 3 
week cycle 
Maximum 3 dose 
Standard 
radiation 
70 Gy/35fx 
5 days /W 
radiation 
7 weeks 
Standard 
 
Trial treatment should begin on the day of randomization or as close as possible to the 
date on which treatment is allocated/assigned. 
5.2.1 Dose Selection/Modification 
5.2.1.1 Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 4.0 – 
Background and Rationale.   
Pembrolizumab will be dosed as a flat dose. 
Details on preparation and administration of pembrolizumab (MK-3475) are provided in 
the Pharmacy Manual.   
 
5.2.1.2 Dose Modification for Pembrolizumab  
Adverse events (both non-serious and serious) associated with pembrolizumab exposure 
may represent an immunologic etiology.  These adverse events may occur shortly after 
the first dose or several months after the last dose of treatment. Pembrolizumab must be 
withheld for drug-related toxicities and severe or life-threatening AEs as per Table 3 
below. See Section 5.6.1 and Events of Clinical Interest Guidance Document for 
supportive care guidelines, including use of corticosteroids. 
 
 
 
Table 3 
Dose Modification Guidelines for Pembrolizumab-Related Adverse Events 
 

 
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Toxicity 
Hold 
Treat
ment 
For 
Grade 
Timing for Restarting 
Treatment 
Discontinue Subject 
Diarrhea/Colitis 
2-3 
 
Toxicity resolves to 
Grade 0-1. 
Toxicity does not resolve within 6 weeks of 
last dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 6 
weeks. 
4 
Permanently 
discontinue 
Permanently discontinue 
AST, ALT, or 
Increased 
Bilirubin 
2 
Toxicity resolves to 
Grade 0-1 
Toxicity does not resolve within 6 weeks of 
last dose. 
3-4 
Permanently 
discontinue 
(see exception below)1 
Permanently discontinue 
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia 
T1DM 
or  
3-4 
Hold pembrolizumab for 
new 
onset 
Type 
1 
diabetes 
mellitus 
or 
Grade 
3-4 
hyperglycemia 
associated 
with 
evidence of beta cell 
failure.  
 
Resume pembrolizumab when patients are 
clinically and metabolically stable. 
Hypophysitis 
2-3 
Toxicity resolves to 
Grade 0-1 
Toxicity does not resolve within 6 weeks of 
last dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 6 
weeks. 
4 
Permanently 
discontinue 
Permanently discontinue 
Hyperthyroidism  
3 
Toxicity resolves to 
Grade 0-1 
Toxicity does not resolve within 6 weeks of 
last dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 6 
weeks. 
4 
Permanently 
discontinue 
Permanently discontinue 
Hypothyroidism 
2-4 
Therapy with 
pembrolizumab can be 
continued while 
treatment for the thyroid 
disorder is instituted 
Therapy with pembrolizumab can be 
continued while treatment for the thyroid 
disorder is instituted. 

 
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Toxicity 
Hold 
Treat
ment 
For 
Grade 
Timing for Restarting 
Treatment 
Discontinue Subject 
Infusion 
Reaction 
3-4 
Permanently 
discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to 
Grade 0-1 
Toxicity does not resolve within 6 weeks of 
last dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 6 
weeks. 
3-4 
Permanently 
discontinue 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to 
Grade 0-1 
Toxicity does not resolve within 6 weeks of 
last dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 6 
weeks. 
3-4 
Permanently 
discontinue 
Permanently discontinue 
All Other Drug-
Related 
Toxicity2 
3 or 
Severe 
Toxicity resolves to 
Grade 0-1 
Toxicity does not resolve within 6 weeks of 
last dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 6 
weeks. 
4 
Permanently 
discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or 
any life-threatening event. 
1 For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT 
increases by greater than or equal to 50% relative to baseline and lasts for at least 1 week then 
patients should be discontinued. 
2 Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at 
physician discretion.  Permanently discontinue study drug for persistent Grade 2 adverse 
reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 
within 6 weeks of the last dose.   
 
Dosing interruptions are permitted in the case of medical / surgical events or logistical 
reasons not related to study therapy (e.g., elective surgery, unrelated medical events, 
patient vacation, and/or holidays). Subjects should be placed back on study therapy within 
3 weeks of the scheduled interruption, unless otherwise discussed with the Sponsor. The 
reason for interruption should be documented in the patient's study record. 
 

 
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5.2.1.3 Dose Modification for Cisplatin 
1. Neutropenia: If on the day of scheduled treatment with cisplatin the absolute 
neutrophil count (ANC) is < 1200/mm3, hold the second chemotherapy treatment 
but not the radiation until ANC ≥ 1200/mm3, then treat at 100% dose. 
Neutropenic fever (i.e. any fever > 38.5°C with an ANC <1000/mm3) will require 
a 25% dose reduction of the next cisplatin dose. If neutropenic fever occurs with 
both the first and second dose, cisplatin should be discontinued. 
2. Thrombocytopenia: If on the day of scheduled treatment with cisplatin the platelet 
count is < 75,000/mm3, hold chemotherapy treatment but not the radiation until 
platelets are ≥ 75,000/mm3, then treat at 100% dose. Thrombocytopenia that 
results in bleeding will require a 25% dose reduction of the following cisplatin 
dose. 
3. Neurotoxicity: If grade 2 neurotoxicity develops, hold cisplatin (but continue RT) 
until toxicity improves to ≤ grade 1, then reduce the following cisplatin dose to 80 
mg/m2. If any signs of grade 3 or greater neurotoxicity occur, discontinue 
cisplatin, but continue RT.  
4. Renal Adverse Events: Cisplatin dose should be based on creatinine clearance 
immediately prior to the second and third cisplatin dose using the following 
guidelines:  
Note: Creatinine clearance must be calculated (Cockcroft-Gault) in order to make 
dose adjustment. If the calculated clearance is 50 mL/min or above, a 24-hour 
urine collection is not needed, but if the calculation is less than 50 mL/min, a 24-
hour urine collection is mandated, and the cisplatin dose will be determined as 
follows:  
Creatinine Clearance Cisplatin Dose 
> 50 ml/min then administer 100 mg/m2 
40-50 ml/min then administer 50 mg/m2 
< 40 ml/min Hold drug* 
*Cisplatin should be held (but the RT continued) and the creatinine measured 
weekly, until creatinine clearance is > 50 ml/min, and then the next and following 
doses of cisplatin should be given at the reduced dose of 50 mg/m2.  
5. Nausea and Vomiting: Maximum supportive therapy will be given, and cisplatin 
will be continued at full dose for ≤ grade 2 nausea and vomiting. For grade 3 
nausea and vomiting refractory to supportive therapy, cisplatin will be held until 
recovery to < grade 2. No dose reductions will be made.  
6. Mucositis: Significant mucositis (grade 3-4, CTCAE, v. 4) is expected from 
radiation and cisplatin and should not be a reason for a treatment break, unless it 
significantly interferes with fluid intake or nutrition. Aggressive supportive care is 
encouraged as well as consideration of a PEG tube if not already done.  
7. Ototoxicity: For clinical hearing loss not requiring a hearing aid, reduce cisplatin 
to 50 mg/m2. For hearing loss requiring a hearing aid, discontinue cisplatin. For 
grade 2-3 tinnitus (CTCAE, v. 4) at the time of retreatment, hold cisplatin until 
improvement to grade 1 or less and then reduce the following doses of cisplatin 
to 50 mg/m2. If tinnitus does not improve to grade 1 or less by the last day of 

 
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radiation therapy, discontinue cisplatin.  An audiogram is recommended when 
there is any report of significant change in hearing and/or an increase in tinnitus.  
8. Other Toxicities: For any other grade 3-4 adverse events, hold cisplatin until 
toxicities have recovered to grade 1 or less.  
If the second or third dose of cisplatin is delayed more than 21 days because of 
hematologic, neurologic, renal, or other adverse events, that dose will be omitted. 
If a weight change of ≥10% occurs, the following cisplatin doses should be 
adjusted. 
 
5.2.1.4 Timing of Dose Administration 
Trial treatment should be administered on Day 1 of each cycle after all 
procedures/assessments have been completed as detailed on the Trial Flow Chart 
(Section 6.0).  Trial treatment may be administered up to 2 days before or after the 
scheduled Day 1 of each cycle due to administrative reasons. Day 1 cisplatin and 
radiation can begin up to 7 days earlier (minimum 14 days after pembrolizumab 
administration) if patient and /or investigator prefer to expedite initiation of radiation. 
All trial treatments will be administered on an outpatient basis. 
Initiation of subsequent cycles of pembrolizumab therapy may be delayed for up to 6 
weeks to allow recovery from all drug-related toxicity. If the subsequent dose of 
pembrolizumab is delayed more than 6 weeks because of adverse events, 
pembrolizumab will be discontinued. Initiation of subsequent cycles of cisplatin therapy 
may be delayed for up to 3 weeks to allow recovery from all drug-related toxicity. If the 
subsequent dose of cisplatin is delayed more than 21 days because of adverse events, 
that dose will be omitted. Alternately, the Investigator may choose to administer 
supportive care (blood product transfusions) for retreatment criteria to be met. If the 
recovery criteria are not met after a 6-week delay, the patient will be discontinued from 
study treatment unless, in the opinion of the Investigator, the patient is experiencing a 
clinical benefit, in which case a decision regarding continuation of treatment will be 
made on an individual patient basis in consultation with the Merck medical monitor. 
Justification will be recorded in the source documents.  
 
In the setting of dose delays, neither cisplatin nor pembrolizumab will be 
administered following completion of radiation therapy. 
 
When initiating a subsequent cycle, a minimum interval of 21 days should be observed 
between pembrolizumab administrations and between cisplatin administrations. 
 
Cisplatin or pembrolizumab can be given either before or after the radiation therapy 
fraction that is given on the same day. If radiation is held for more than 2 days (for any 
reason), cisplatin may be held as well until radiation resumes.   
Note: pembrolizumab or cisplatin given within 48 hours of days 1 and 22 and 43 due to 
holidays, for example, is acceptable). Weekends count as days. Use the actual body 
weight for all patients. There should be no dose modifications because of obesity.  
 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.  
Sites should make every effort to target infusion timing to be as close to 30 minutes as 

 
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possible.  However, given the variability of infusion pumps from site to site, a window of -
5 minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
 
Cisplatin will be given as a bolus, infused over 1-2 hours along with appropriate 
hydration and anti-emetics. 
 
 
5.2.2 Radiation Treatment 
5.2.2.1 Dose Specifications  
The prescribed radiotherapy dose will be 70 Gy in 2 Gy once-daily fraction size (total of 
35 fractions). Radiotherapy should begin on a Monday, Tuesday or Wednesday. The daily 
dose of 2 Gy will be prescribed such that 95% of the PTV volume receives at least 95% 
of prescribed dose. The spinal cord dose may not exceed 45 Gy to any volume larger 
than 0.03 cc. 
 
5.2.2.2 Technical Factors 
Treatment Planning/Delivery: Megavoltage energy photon beam irradiation is required. 
IMRT treatment planning with simultaneous integrated boost (SIB) will be used, and 
treatment verification films must be taken daily (kv films or cone beam CT).   
 
5.2.2.3 Localization, Simulation, and Immobilization 
1. Patients must have an immobilization device (e.g., aquaplast mask extending to 
shoulders) made prior to treatment planning CT scan.  
2. All patients will undergo CT simulation for treatment planning. The treatment 
planning CT scan may be completed with or without IV contrast. The treatment 
planning CT scan must be performed with the immobilization device and in the 
treatment position. Slice thickness should be 0.3 cm or less.  
 
5.2.2.4 Target and Normal Tissue Volume Restrictions 
1. Definition of Target Volumes 
GTV70: This volume includes all gross tumor volume (primary tumor and nodal disease) 
based on clinical exam, PETCT scan and/or planning CT.   
CTV70: This volume will receive 2 Gy per fraction. CTV70 will include the primary tumor 
plus a 1.0 cm circumferential margin added for microscopic spread.  This volume may be 
decreased in size as appropriate around structures that represent barriers to anatomic 
spread of tumor, and up to 1.5 cm expansion may be added for suspicion on significant 
laryngeal movement with swallowing. 
 
CTV56: This will include all other regions felt to be at risk for harboring microscopic cancer 
that do not meet the criteria for CTV70. For example, this would apply to bilateral necks 
irradiated electively. This volume will receive 1.6 Gy per fraction.  
CTV63 Optional: This may be defined at the discretion of the treating radiation 
oncologist. This would include a region or regions felt to be at especially high risk for 
recurrence (e.g., first echelon nodal regions that are clinically negative). This area will be 
receiving a daily fraction size of 1.8 Gy.   
 

 
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Planning Target Volumes (PTVs): In general, the PTV should be pulled 3mm off of skin 
unless the skin is clinically involved with tumor.  
PTV Expansion The CTV-to- PTV expansion is 3 mm as daily image guidance will be 
employed. 
2. Definition of Normal Tissues/Organs at Risk (OARs) 
Spinal Cord: The cord begins at the cranial-cervical junction (i.e., the top of the C1 
vertebral body). Superior to this is brainstem and inferior to this is cord. The inferior border 
of the spinal cord is at approximately T3-4 (i.e., just below the lowest slice level that has 
PTV on it). The spinal cord shall be defined based on the treatment planning CT scan. In 
addition, however, a Planning Risk Volume (PRV) spinal cord shall be defined. The 
PRVcord = cord + 5 mm in each dimension.  
 
Brainstem: The inferior most portion of the brainstem is at the cranial-cervical junction 
where it meets the spinal cord. For the purposes of this study, the superior most portion 
of the brainstem is approximately at the level of the top of the posterior clinoid. The 
brainstem shall be defined based on the treatment planning CT scan. In addition, 
however, a Planning Risk Volume (PRV) brainstem shall be defined. The PRVbrainstem 
= brainstem + 3 mm in each dimension.  
 
Lips and Oral Cavity: These should be contoured as 2 separate structures as the goal is 
to keep the lip dose much lower than the oral cavity dose. The definition of lips is self-
explanatory. The oral cavity will be defined as a composite structure consisting of the 
anterior 1⁄2 to 2/3 of the oral tongue/floor of mouth, buccal mucosa, and palate.  
Parotid Glands: Parotid glands will be defined based on the treatment planning CT scan.  
 
OARpharynx: This will be defined as the posterior pharyngeal wall plus adjacent 
constrictor muscles. This extends from the superior constrictor region (the inferior 
pterygoid plates level) to the cricopharyngeal inlet (posterior cricoid cartilage level) 
excluding the PTVs.  
 
Cervical Esophagus: This will be defined as a tubular structure that starts at the bottom 
of OARpharynx and extends to the thoracic inlet, excluding the PTVs.  
Glottic/Supraglottic Larynx (GSL): This will be defined as a “triangular prism shaped” 
volume that begins just inferior to the hyoid bone and extends to the cricoid cartilage 
inferiorly and extends from the anterior commissure to include the arytenoids. This 
includes the infrahyoid but not suprahyoid epiglottis.  
 
Mandible: This includes the entire boney structure of the mandible from TMJ through the 
symphysis. It is recognized that for oral cavity cancers, this may overlap with CTVs and 
PTVs.  
 
Unspecified Tissue Outside the Targets: This will be defined as tissue located between 
the skull base and thoracic inlet that is not included in either the target volumes or the 
normal tissues described above.  
 

 
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5.2.2.5 Treatment Planning and Delivery 
1.  Dose Prescription to PTVs 
 As described above, prescribed radiotherapy dose will be 70 Gy in 2 Gy once-daily 
fraction size. For inverse planning IMRT, the goal is for 95% of the PTV70 to receive 95% 
of 70 Gy with a minimum dose (cold spot) of no less than 63 Gy.  
For IMRT prioritization, PTV70 will be the highest priority target structure. PTV63 and 
PTV56, if applicable, will be ranked in the IMRT planning as lower priority than PTV70 
although higher priority than normal structures other than spinal cord and brain stem.  
 
2.  Dose Constraints to Normal Structures  
Spinal Cord: The PRVcord should not exceed 45 Gy to any volume in excess of 0.03 cc 
(approximately 3 mm x 3 mm x 3 mm). The spinal cord PRV should not exceed 50 Gy to 
any volume in excess of 0.01 cc. In treatment planning, the spinal cord PRV should be 
given the highest priority.  
 
Brainstem: The PRVbrainstem should not exceed 50 Gy to any volume in excess of 0.03 
cc (approximately 3 mm x 3 mm x 3 mm). In treatment planning, the PRVbrainstem should 
be given less priority than the PRVcord but more priority than the other critical structures 
listed below.  
 
Lips: Reduce the dose as much as possible unless lips involved with primary tumor. The 
mean dose should be < 20 Gy. The maximum dose will be < 30 Gy.  
Oral Cavity: Reduce the dose as much as possible. The suggested mean dose should be 
< 30 Gy.  
 
Parotid Glands: In most cases, it will be easier to spare one parotid than the other. The 
treatment planning goal will be for this individual parotid gland to receive a mean dose of 
< 26 Gy. Additional planning goals may include: 1) At least 50% of one parotid will receive 
< 30 Gy; and/or 2) At least 20 cc of parotid tissue (from the combination of both glands) 
will receive < 20 Gy.  
 
OARpharynx: Reduce the dose as much as possible to uninvolved regions. Some 
recommended (but not mandatory) treatment goals include: 1) No more than 33% of the 
OARpharynx exceeds 50 Gy; 2) Mean dose < 45 Gy; 3) No more than 15% of the 
OARpharynx exceeds 60 Gy.  
 
Cervical Esophagus: Reduce the dose as much as possible to uninvolved regions. Some 
recommended doses (but not mandatory) treatment goals include: 1) No more than 33% 
of the esophagus exceeds 50 Gy; 2) Mean dose < 45 Gy; 3) No more than 15% of the 
esophagus exceeds 60 Gy.  
 
Mandible: Reduce the dose as much as possible; hot spots within the mandible should 
be avoided. It is recommended that maximum dose within the mandible be < 66 Gy. For 
tumors that were not clinically or pathologically involving the mandible, the CTV should 
be contoured off the mandible. 
 

 
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5.2.2.6 Compliance Criteria 
Treatment breaks must be clearly indicated in the treatment record along with the 
reason(s) for the treatment break(s). Treatment breaks, if necessary, ideally should not 
exceed five treatment days at a time and ten treatment days total. Treatment breaks 
should be allowed only for resolution of severe acute toxicity and/or for intercurrent illness 
and not for social or logistical reasons. 
 
5.2.2.7 Radiation Therapy Adverse Events  
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE), version 4.0 will be utilized for grading all adverse 
events.  Placement of a feeding tube should be recorded as should use of a feeding 
tube during and after treatment (e.g., greater than or less than 50% of nutrition by tube). 
Other common radiation adverse events include: fatigue, weight loss, regional alopecia, 
xerostomia, hoarseness, transient ear discomfort, and skin erythema and desquamation 
within the treatment fields. Less common long-term treatment adverse events include: 
hypothyroidism, loss of hearing, chronic swallowing dysfunction requiring permanent 
feeding tube, and skin/soft tissue fibrosis. Much less common radiation adverse events 
include: mandibular osteoradionecrosis, and cervical myelopathy (< 1% with restriction 
of spinal cord dose to max dose of 45 Gy). 
 
5.3 Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered. 
 
5.4 Randomization or Treatment Allocation 
All patients enrolled in this study will receive the combination of All patients enrolled in 
this study will receive the combination of pembrolizumab, cisplatin and radiation. 
 
5.5 Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other 
medications or vaccinations specifically prohibited during the trial, discontinuation from 
trial therapy or vaccination may be required.  The investigator should discuss any 
questions regarding this with the Merck Clinical team.  The final decision on any 
supportive therapy or vaccination rests with the investigator and/or the subject's primary 
physician.  
 
5.5.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards 
of medical care.  All concomitant medication will be recorded on the case report form 
(CRF) including all prescription, over-the-counter (OTC), herbal supplements, and IV 
medications and fluids.  If changes occur during the trial period, documentation of drug 
dosage, frequency, route, and date may also be included on the CRF. 
 

 
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All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded.  Concomitant 
medications administered after 30 days after the last dose of trial treatment should be 
recorded for SAEs and ECIs as defined in Section 7.2. 
 
5.5.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
• Antineoplastic systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab 
• Radiation therapy to any area other than specified in laryngeal carcinoma 
treatment  protocol 
• Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, 
the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, 
and typhoid vaccine.  
• Systemic glucocorticoids for any purpose other than to modulate symptoms from 
an event of clinical interest of suspected immunologic etiology.  Premedication with 
steroids may be administered on Cycle 1 Day 1, if required by institutional 
standards. However, due to their immunosuppressive effect, steroids are 
encouraged to be discontinued within 72 hours. The use of physiologic doses of 
corticosteroids may be approved after consultation with the Sponsor. 
 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  
Subjects may receive other medications that the investigator deems to be medically 
necessary. 
 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
 
5.6 Rescue Medications & Supportive Care 
5.6.1  Pembrolizumab Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by 
the treating investigator.  Suggested supportive care measures for the management of 
adverse events with potential immunologic etiology are outlined below and in greater 
detail in the ECI guidance document. Where appropriate, these guidelines include the 
use of oral or intravenous treatment with corticosteroids as well as additional anti-
inflammatory agents if symptoms do not improve with administration of corticosteroids.   
Note that several courses of steroid tapering may be necessary as symptoms may worsen 
when the steroid dose is decreased. For each disorder, attempts should be made to rule 
out other causes such as metastatic disease or bacterial or viral infection, which might 

 
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require additional supportive care. The treatment guidelines are intended to be applied 
when the investigator determines the events to be related to pembrolizumab.  
 
Note: if after the evaluation the event is determined not to be related, the investigator is 
instructed to follow the ECI reporting guidance but does not need to follow the treatment 
guidance (as outlined in the ECI guidance document). Refer to Section 5.2.1 for dose 
modification.  
 
It may be necessary to perform conditional procedures such as bronchoscopy, 
endoscopy, or skin photography as part of evaluation of the event. Suggested conditional 
procedures, as appropriate, can be found in the ECI guidance document. 
 
• Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  
Administer additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration. 
 
 
• Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis 
(such as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) 
and of bowel perforation (such as peritoneal signs and ileus).   
 
o All subjects who experience diarrhea/colitis should be advised to drink 
liberal quantities of clear fluids.  If sufficient oral fluid intake is not feasible, 
fluid and electrolytes should be substituted via IV infusion.  For Grade 2 or 
higher diarrhea, consider GI consultation and endoscopy to confirm or rule 
out colitis. 
o For Grade 2 diarrhea/colitis that persists greater than 3 days, administer 
oral corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis treat with intravenous steroids followed 
by high dose oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. 
 
 
• Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis 
[DKA]) or ≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or 
metabolic acidosis (DKA) 
 
o For T1DM or Grade 3-4 Hyperglycemia 

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

 
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o When symptoms improve to Grade 1 or less, a steroid taper should be 
started and continued over no less than 4 weeks. 
 
• Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks.  
 
• Management of Infusion Reactions: Signs and symptoms usually develop during 
or shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion.  
 
 
Table 4 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab (MK-3475). 
 
Table 4 Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated 
Increase monitoring of vital 
signs as medically indicated 
until the subject is deemed 
medically stable in the opinion 
of the investigator. 
None 
Grade 2 
Requires infusion 
interruption but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDS, narcotics, IV 
fluids); prophylactic 
medications indicated 
for < =24 hrs 
Stop Infusion and monitor 
symptoms. 
Additional appropriate 
medical therapy may include 
but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
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., 
Subject may be 
premedicated 1.5h (± 
30 minutes) prior to 
infusion of 
pembrolizumab (MK-
3475) with: 
 
Diphenhydramine 50 
mg po (or equivalent 
dose of 
antihistamine). 
 
Acetaminophen 500-
1000 mg po (or 
equivalent dose of 
antipyretic). 

 
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NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
from 100 mL/hr to 50 mL/hr).  
Otherwise dosing will be held 
until symptoms resolve and 
the subject should be 
premedicated for the next 
scheduled dose. 
Subjects who develop 
Grade 2 toxicity despite 
adequate premedication 
should be permanently 
discontinued from further 
trial treatment 
administration. 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not 
rapidly responsive to 
symptomatic 
medication and/or brief 
interruption of 
infusion); recurrence of 
symptoms following 
initial improvement; 
hospitalization 
indicated for other 
clinical sequelae (e.g., 
renal impairment, 
pulmonary infiltrates) 
Grade 4: 
Life-threatening; 
pressor or ventilatory 
support indicated 
Stop Infusion. 
Additional appropriate 
medical therapy may include 
but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital 
signs as medically indicated 
until the subject is deemed 
medically stable in the opinion 
of the investigator. 
Hospitalization may be 
indicated. 
Subject is permanently 
discontinued from further 
trial treatment 
administration. 
No subsequent 
dosing 
Appropriate resuscitation equipment should be available in the room and a 
physician readily available during the period of drug administration. 
 
 

 
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5.6.2 Cisplatin Supportive Care Guidelines 
• Fluid and Electrolyte Imbalance  
Patients must be vigorously hydrated and diuresed before cisplatin 
administration as per institutional standard regimens.  
 
• Nausea and Vomiting 
High dose cisplatin is a highly emetogenic regimen with significant incidence of 
delayed nausea and vomiting. The following guidelines will be followed:  
For acute nausea and vomiting, premedication should include a 5-HT3 antagonist, 
such as granisetron 1 mg iv; ondansetron, up to 16 mg iv; or palonosetron, 0.25 
mg iv; plus a corticosteroid, such as dexamethasone, up to 20 mg iv.  
 
Breakthrough nausea and vomiting should be managed at the discretion of the 
medical oncologist or radiation oncologist.  
 
Delayed nausea and vomiting (greater than 24 hours after chemotherapy 
administration) may be managed by the addition of aprepitant concurrently or with 
metoclopramide and dexamethasone.  
 
 
5.7 Diet/Activity/Other Considerations 
5.7.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an 
AE such as diarrhea, nausea or vomiting. 
 
5.7.2 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 study Visit 1 throughout the 
study period up to 120 days after the last dose of study therapy.  
 
The following are considered adequate barrier methods of contraception: diaphragm, 
condom (by the partner), copper intrauterine device, sponge, or spermicide.  Appropriate 
hormonal contraceptives will include any registered and marketed contraceptive agent 
that contains an estrogen and/or a progestational agent (including oral, subcutaneous, 
intrauterine, or intramuscular agents). 
 
Subjects should be informed that taking the study medication may involve unknown risks 
to the fetus (unborn baby) if pregnancy were to occur during the study.  In order to 

 
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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. 
 
5.7.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will immediately be removed from the study.  The site will contact the subject at 
least monthly and document the subject’s status until the pregnancy has been completed 
or terminated.  The outcome of the pregnancy will be reported to the Sponsor and to 
Merck without delay and within 24 hours to the Sponsor and within 2 working days to 
Merck if the outcome is a serious adverse experience (e.g., death, abortion, congenital 
anomaly, or other disabling or life-threatening complication to the mother or newborn).   
 
The study investigator will make every effort to obtain permission to follow the outcome 
of the pregnancy and report the condition of the fetus or newborn to the Sponsor.   If a 
male subject impregnates his female partner the study personnel at the site must be 
informed immediately and the pregnancy reported to the Sponsor and to Merck and 
followed as described above and in Section 7.2.2. 
 
5.7.4 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. 
 
5.8 Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at 
the discretion of the investigator should any untoward effect occur.  In addition, a subject 
may be withdrawn by the investigator or the Sponsor if enrollment into the trial is 
inappropriate, the trial plan is violated, or for administrative and/or other safety reasons.  
Specific details regarding discontinuation or withdrawal are provided in Section 7.1.4 – 
Other Procedures. 
 
A subject must be discontinued from the trial for any of the following reasons: 
• The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
• Confirmed radiographic disease progression 
Note: For unconfirmed radiographic disease progression, please see Section 
5.2.2 
• Unacceptable adverse experiences as described in Section 5.2.1.2 
• Intercurrent illness that prevents further administration of treatment 
• Investigator’s decision to withdraw the subject 
• The subject has a confirmed positive serum pregnancy test 
• Noncompliance with trial treatment or procedure requirements 

 
UCCI-HN-15-02, rev. 5 
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Pembrolizumab 
• The subject is lost to follow-up 
• 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. 
 
5.9 Subject Replacement Strategy 
Replacement of Patients in DLT Period 
Patients who received <90% of the pembrolizumab infusion in Cycle 1 (e.g., because the 
infusion had to be discontinued due to an infusion reaction) and did not experience a DLT 
will not be taken into account in the assessment of the overall DLT rate for the phase I 
run in cohort and need to be replaced. 
 
If a patient experiences a DLT in Cycle 1, study therapy may be discontinued following 
discussion and agreement between the Sponsor and Investigator.  An alternative 
consideration may be dose modifications of cisplatin and pembrolizumab as described in 
Section 5.2.1 with continued therapy. 
 
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures. 
 
5.10 Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a 
potential health hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
In the event of Merck decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made. 
 

 
UCCI-HN-15-02, rev. 5 
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Pembrolizumab 
6.0 TRIAL FLOW CHART 
6.1 Study Flow Chart 
Trial Period: 
Screening 
Phase 
Treatment Cycles End of Treatment 
 
Post-
Treatm
ent 
Post 
Progression 
or new anti-
cancer 
Therapy 
Treatment cycle/Title: 
Main 
Study 
Screening 
Visit 
C1 
D-
21 
C1 
D1 
C1 
D2
2 
C1 
D43 
Discon 
Safety 
Follow-
up 
Follow-
Up 
Survival 
Follow-Up 
Phase 
At time 
of 
Discon 
30 days 
post 
discon 
 
Every 
12 
weeks(
± 1 w) 
Every 12 
weeks (±1 w) 
Scheduling 
Window 
(Days): 
-28 to -1 
 -
21 
to -
14 ± 2 ± 2 ± 2 
  
  
 
  
Informed Consent 
x 
  
  
  
  
  
  
 
  
Inclusion/Exclusion 
Criteria 
x 
  
  
  
  
  
  
 
  
Standard 
Chemotherapy 
Administered 
Cisplatin-100 mg  
  
  
x 
x 
x 
  
  
 
  
Trial Treatment 
Administration 
Pembrolizumab 200 mg 
  
x 
x₠ 
x₠ 
x₠ 
  
  
 
  
Radiation- 70Gy/35 fx 
  
  
 x∆ x ∆  x∆ 
  
  
 
 
Survival Status 
  
  
  
  
  
 
 
x 
x ∞ 
Review Adverse Events 
  
x 
x 
x 
x 
x 
x  
x£ 
 

 
UCCI-HN-15-02, rev. 5 
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01-SEP-2017 
Pembrolizumab 
Trial Period: 
Screening 
Phase 
Treatment Cycles End of Treatment 
 
Post-
Treatm
ent 
Post 
Progression 
or new anti-
cancer 
Therapy 
Treatment cycle/Title: 
Main 
Study 
Screening 
Visit 
C1 
D-
21 
C1 
D1 
C1 
D2
2 
C1 
D43 
Discon 
Safety 
Follow-
up 
Follow-
Up 
Survival 
Follow-Up 
Phase 
At time 
of 
Discon 
30 days 
post 
discon 
 
Every 
12 
weeks(
± 1 w) 
Every 12 
weeks (±1 w) 
Scheduling 
Window 
(Days): 
-28 to -1 
 -
21 
to -
14 ± 2 ± 2 ± 2 
  
  
 
  
Directed Physical 
Examination 
 
 
 
 
X 
X 
X 
X 
X 
  
x¥ 
 
Full Physical Exam 
X 
 
 
 
 
 
 
 
 
Review of Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
 
Review Medical History 
X 
 
 
 
 
 
 
 
 
Subsequent Anti-
Cancer Therapy Status 
 
 
 
 
 
 
X 
 
 
Endoscopic 
Examination in Office 
x¢ 
  
x¢ 
  
  
 
  
 x£ 
 
Vital Signs and Weight 
x 
x 
x 
x 
x 
x 
  
 
 
Review Speech/swallow 
questionnaire ¢ 
x 
  
  
  
  
 
  
x¥ 
 
Review Nutrition 
questionnaire ¢ 
x 
  
  
  
  
 
  
 x¥ 
 

 
UCCI-HN-15-02, rev. 5 
Page 41 of 65 
 
 
 
01-SEP-2017 
Pembrolizumab 
Trial Period: 
Screening 
Phase 
Treatment Cycles End of Treatment 
 
Post-
Treatm
ent 
Post 
Progression 
or new anti-
cancer 
Therapy 
Treatment cycle/Title: 
Main 
Study 
Screening 
Visit 
C1 
D-
21 
C1 
D1 
C1 
D2
2 
C1 
D43 
Discon 
Safety 
Follow-
up 
Follow-
Up 
Survival 
Follow-Up 
Phase 
At time 
of 
Discon 
30 days 
post 
discon 
 
Every 
12 
weeks(
± 1 w) 
Every 12 
weeks (±1 w) 
Scheduling 
Window 
(Days): 
-28 to -1 
 -
21 
to -
14 ± 2 ± 2 ± 2 
  
  
 
  
ECOG Performance 
Status 
x 
x 
x 
x 
x 
x 
  
 
  
Functional Oral Intake ¢ 
X 
 
 
 
 
 
 
x¥ 
 
Pregnancy Test – Urine 
or Serum b-HCG if 
appropriate 
x 
  
  
  
  
  
  
 
  
CBC with Differential 
x 
x 
x 
x 
x 
  
  
 
  
Comprehensive Serum 
Chemistry Panel 
x 
x 
x 
x 
x 
  
  
 
  
T3, FT4 and TSH 
x 
  
 x 
  
 x 
  
  
 
  
Tumor Imaging  
( PET preferred) 
x 
  
  
  
  
  
  
 x£ 
 
Archival or Newly 
Obtained Tissue 
Collection 
x 
  
x¢ 
  
  
  
  
 
  

 
UCCI-HN-15-02, rev. 5 
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01-SEP-2017 
Pembrolizumab 
Trial Period: 
Screening 
Phase 
Treatment Cycles End of Treatment 
 
Post-
Treatm
ent 
Post 
Progression 
or new anti-
cancer 
Therapy 
Treatment cycle/Title: 
Main 
Study 
Screening 
Visit 
C1 
D-
21 
C1 
D1 
C1 
D2
2 
C1 
D43 
Discon 
Safety 
Follow-
up 
Follow-
Up 
Survival 
Follow-Up 
Phase 
At time 
of 
Discon 
30 days 
post 
discon 
 
Every 
12 
weeks(
± 1 w) 
Every 12 
weeks (±1 w) 
Scheduling 
Window 
(Days): 
-28 to -1 
 -
21 
to -
14 ± 2 ± 2 ± 2 
  
  
 
  
Correlative Studies 
Blood Collection 
x 
  
x 
  
  
 
 
x£ 
 
Urinalysis 
x 
 
x 
 
x 
 
 
 
 
 
 
¢ Recommended but not mandatory  
£ Only once 12-16 weeks after end of treatment 
¥ At 3, 6, 12 months after end of treatment 
∆ Continuous daily  
₠ If patient and clinician need to expedite initiation of chemoradiation, they are allowed to start cisplatin and radiation after 
a minimum of 14 from first dose pembrolizumab, however, there should be a minimum of 21 days ( +/- 2 days) between 
pembrolizumab doses, thereafter.  
∞ 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 

 
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Pembrolizumab 
7.0 TRIAL PROCEDURES 
7.1 Trial Procedures 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed 
at each visit.  Individual trial procedures are described in detail below.  It may be 
necessary to perform these procedures at unscheduled time points if deemed clinically 
necessary by the investigator. 
 
Furthermore, additional evaluations/testing may be deemed necessary by the 
Sponsor and/or Merck for reasons related to subject safety. In some cases, such 
evaluation/testing may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), 
and thus local regulations may require that additional informed consent be obtained 
from the subject.  In these cases, such evaluations/testing will be performed in 
accordance with those regulations. 
 
7.1.1 Administrative Procedures 
7.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 
 
7.1.1.1.1  General Informed Consent 
Consent must be documented by the subject’s dated signature or by the subject’s 
legally acceptable representative’s dated signature on a consent form along with the 
dated signature of the person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial. 
 
The initial informed consent form, any subsequent revised written informed consent 
form and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally 
acceptable representative should be informed in a timely manner if new information 
becomes available that may be relevant to the subject’s willingness to continue 
participation in the trial.  The communication of this information will be provided and 
documented via a revised consent form or addendum to the original consent form that 
captures the subject’s dated signature or by the subject’s legally acceptable 
representative’s dated signature. 
 
Specifics about a trial and the trial population will be added to the consent form 
template at the protocol level.   
 
 
The informed consent will adhere to IRB/ERC requirements, applicable laws and 
regulations and Sponsor requirements. 
 
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.  

 
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7.1.1.3 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical 
history will include all active conditions, and any condition diagnosed within the prior 
10 years that are considered to be clinically significant by the Investigator.  Details 
regarding the disease for which the subject has enrolled in this study will be recorded 
separately and not listed as medical history.   
 
7.1.1.4 Prior and Concomitant Medications Review 
7.1.1.4.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the 
subject within 28 days before starting the trial.  Treatment for the disease for which 
the subject has enrolled in this study will be recorded separately and not listed as a 
prior medication.  
 
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 
disease status.  
 
7.1.1.5.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
 
7.1.1.5.3 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy 
initiated after the last dose of trial treatment.  If a 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 Assignment of Screening Number  
Patients will be assigned a screening number upon consent. 
 
7.1.1.7 Assignment of Randomization Number 
There is no randomization number. 
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 Chart and more frequently if 

 
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Pembrolizumab 
clinically indicated.  Adverse experiences will be graded and recorded throughout the 
study and during the follow-up period according to NCI CTCAE Version 4.0 (see 
Section 11.2).  Toxicities will be characterized in terms regarding seriousness, 
causality, toxicity grading, and action taken with regard to trial treatment.  
 
For subjects receiving treatment with pembrolizumab all AEs of unknown etiology 
associated with pembrolizumab exposure should be evaluated to determine if it is 
possibly an event of clinical interest (ECI) of a potentially immunologic etiology 
(termed immune-related adverse events, or irAEs); see the separate ECI guidance 
document in Appendix 4 regarding the identification, evaluation and management of 
potential irAEs.   
 
Please refer to section 7.2 for detailed information regarding the assessment and 
recording of AEs.   
 
7.1.2.2 Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during 
the screening period.  Clinically significant abnormal findings should be recorded as 
medical history.  A full physical exam should be performed during screening,  
 
7.1.2.3 Directed Physical Exam 
For cycles that do not require a full physical exam per the Trial Flow Chart, the 
investigator or qualified designee will perform a directed physical exam as clinically 
indicated prior to trial treatment administration.   
 
7.1.2.4 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as 
specified in the Trial Flow Chart (Section 6.0).  Vital signs should include temperature, 
pulse, respiratory rate, weight and blood pressure.  Height will be measured at 
screening only. 
 
7.1.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 11.1) at 
screening, prior to the administration of each dose of trial treatment and 
discontinuation of trial treatment as specified in the Trial Flow Chart.   
 
7.1.2.6 Tumor Imaging and Assessment of Disease 
Radiologic assessments of measurable disease will be performed using PETCT 
imaging.  RECIST 1.1 will be used to assess response to therapy.  Radiologic imaging 
will be performed at baseline prior to initiation of treatment and subsequently after 
completion of s of therapy (14 +/- 2 weeks). Further imaging is not required unless 
clinically indicated.  
 

 
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7.1.2.7 Tumor Tissue Collection and Correlative Studies Blood Sampling 
 All patients will be required to submit archival tissue as part of study participation.  In 
patients who do not have archival tissue, a pretreatment tumor biopsy will be 
performed, unless deemed contraindicated by the treating physician.  An attempt to 
obtain additional tumor biopsies will be performed after 1 dose of treatment if felt safe 
and feasible. These samples will be submitted centrally for immunohistochemical 
expression studies involving proteins in the PD-1 family as well as CD3, CD69 and 
FOXP3. We will also attempt to perform Tumor infiltrating immune cell phenotypes, 
global gene expression by RNAseq, and whole genome sequencing if adequate tissue 
available. 
 
Research blood collections will be obtained for correlative research studies on the 
following time points: Prior to initiation of therapy (day -21 cycle 1), after 1 dose of 
treatment (day 1 cycle 1), at treatment discontinuation and 14 +/- 2 weeks follow up. 
We intend to perform flow cytometric evaluation of CD3, CD4, CD8, CD14, PD-1, PD-
L1, PD-L2 on peripheral blood mononuclear cells as well as measurement of 
circulating tumor cells and circulating cell-free DNA. 
 
Specimen Requirements: Submission for flow cytometry 
• 
A 7.5 mL specimen of peripheral blood in a lavender- (EDTA) or green- (sodium 
heparin) tube is acceptable for each draw. 
• 
Storage/Transport Temperature: Specimens can be transported with a cold 
pack or wet ice, but do not fix or freeze specimens. 
• 
Unacceptable Conditions: Frozen specimens, specimens greater than 48 hours 
old, specimens fixed in formalin for flow cytometry 
• 
Address for shipping specimens: Please refer to Standard Operating 
Procedures for details on blood and tissue shipment: 
 
 
Josette A. Robinson-Eaton, Sr. Research Assistant 
University of Cincinnati Retrovirology Reference Laboratory 
231 Albert Sabin Way, Rm. 6159 MSB, Cincinnati, Ohio 45267 
Lab: 513-558-4287 
Office: 513-558-4790 
Fax: 513-558-4711 
Email: robinsja@uc.edu 
 
 

 
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7.1.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this 
trial are provided below Laboratory Safety Evaluations (Hematology, Chemistry and 
Urinalysis) 
 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in 
Table 5.   
 

 
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Table 5  Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
 
Serum β-human chorionic 
gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase 
(ALT) 
 
 
WBC (total and differential) 
Aspartate aminotransferase 
(AST) 
 
 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
 
Total thriiodothyronine (T3) 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
 
Free tyroxine (T4) 
Absolute Lymphocyte Count   (CO2 or biocarbonate) 
Urine pregnancy test † 
Thyroid stimulating hormone (TSH) 
 
 
 
 
 
Calcium 
 
 
 
Chloride 
 
Blood for correlative studies 
 
Glucose 
 
  
 
 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin 
is elevated above the upper 
limit of normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy 
test will be required.   
‡ If considered standard of care in your region. 
 
 
 

 
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Pembrolizumab 
Laboratory tests for screening or entry into the Second Course Phase 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 72 hours prior to dosing.  Results must 
be reviewed by the investigator or qualified designee and found to be acceptable prior 
to each dose of trial treatment.  
 
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 may discontinue treatment with the option of restarting treatment if 
they meet the criteria specified in Section 7.1.5.5.  After discontinuing treatment 
following assessment of CR, these subjects should return to the site for a Safety 
Follow-up Visit (described in Section 7.1.5.3.1) and then proceed to the Follow-Up 
Period of the study (described in Section 7.1.5.4). 
 
7.1.5 Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-
related details are provided above in Section 7.1 - Trial Procedures. 
 
7.1.5.1 Screening 
The following assessments will be performed up to 28 days prior to initiation of 
study treatment: 
1. 
Full Physical Examination 
2. 
Vital Signs and weight 
3. 
Pregnancy test or Serum B-HCG in females of childbearing age (within 72 
hours of starting therapy) 
4. 
CBC  (within 10 days of starting therapy) 
5. 
Comprehensive Serum Chemistry panel (within 10 days of starting therapy) 
6. 
T3, FT4 and TSH (within 10 days of starting therapy) 
7. 
Imaging within 45 days of starting treatment. PET CT is preferred, but if not 
considered institution standard, CT head and neck and CT chest with 
contrast can be substituted. 
 
7.1.5.2 Treatment Period 
The following assessments will be performed on day of administration of study 
treatment and must be performed no more than 24 hours prior to treatment unless 
otherwise specified.  The only exception is for day 1 when the assessments will 
serve as baseline assessments and can be performed up to 3 weeks prior or as 
otherwise specified. 
1. Adverse event review 
3. Directed physical examination 

 
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4. Vital signs and weight 
5.  ECOG performance status 
5. CBC  
6. Comprehensive serum chemistry panel 
 
7.1.5.3 Post-Treatment Visits 
7.1.5.3.1  Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days 
after the last dose of trial treatment or before the initiation of a new anti-cancer 
treatment, whichever comes first.  All AEs that occur prior to the Safety Follow-Up Visit 
should be recorded.  
 
 Subjects with an AE of Grade > 1 will be followed until the resolution of the AE to 
Grade 0-1 or until the beginning of a new anti-neoplastic therapy, whichever occurs 
first.  SAEs that occur within 90 days of the end of treatment or before initiation of a 
new anti-cancer treatment should also be followed and recorded.   
 
7.1.5.4 Follow-up Visits 
Subjects who discontinue trial treatment for a reason other than disease progression 
will move into the Follow-Up Phase and should be assessed every 12 weeks (12± 1 
week) by exam to monitor disease status.  Imaging should be performed at 14 weeks 
(+/-2 weeks) since last treatment (radiation or drug therapy). Further imaging is per 
decision of treating clinician. 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. 
 
7.1.5.4.1 Survival Follow-up 
Once a subject experiences confirmed disease progression or starts a new anti-
cancer therapy, the subject moves into the survival follow-up phase and should be 
contacted by telephone every 12 weeks (12± 1 week) 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 
An adverse event is defined as any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product and which does 
not necessarily have to have a causal relationship with this treatment. An adverse 
event can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the 
use of a medicinal product or protocol-specified procedure, whether or not considered 
related to the medicinal product or protocol-specified procedure.  Any worsening (i.e., 
any clinically significant adverse change in frequency and/or intensity) of a preexisting 
condition that is temporally associated with the use of the Merck’s product, is also an 
adverse event. 
 
Changes resulting from normal growth and development that do not vary significantly 
in frequency or severity from expected levels are not to be considered adverse events.  

 
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Pembrolizumab 
Examples of this may include, but are not limited to, teething, typical crying in infants 
and children and onset of menses or menopause occurring at a physiologically 
appropriate time. 
 
Merck product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including 
placebo or active comparator medication) or marketed, manufactured by, licensed by, 
provided by or distributed by Merck for human use. 
 
Adverse events may occur during the course of the use of Merck product in clinical 
trials or within the follow-up period specified by the protocol, or prescribed in clinical 
practice, from overdose (whether accidental or intentional), from abuse and from 
withdrawal. 
 
Adverse events may also occur in screened subjects during any pre-allocation 
baseline period as a result of a protocol-specified intervention, including washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure. 
Progression of the cancer under study is not considered an adverse event unless it is 
considered to be drug related by the investigator. 
 
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. 
 
7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose 
to the Sponsor and to Merck 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose 
of 1,000 mg or greater (≥5 times the indicated dose).  No specific information is 
available on the treatment of overdose of pembrolizumab. Appropriate supportive 
treatment should be provided if clinically indicated. In the event of overdose, the 
subject should be observed closely for signs of toxicity.  Appropriate supportive 
treatment should be provided if clinically indicated. 
 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck 
product, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met. 
 
If a dose of Merck’s product meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose 
is reported as a non-serious Event of Clinical Interest (ECI), using the terminology 
“accidental or intentional overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 24 
hours to the Sponsor and within 2 working days hours to Merck Global Safety. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) 
 

 
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An overdose for cisplatin will be defined as any dose of study drug that is 10% or more 
over the prescribed dose per cycle as described in the study protocol. There is no 
specific antidote for cisplatin overdose. In the event of overdose, subsequent dose of 
cisplatin should be held unless approved by study Sponsor and Merck. Patient should 
be observed closely for signs of toxicity. As clinically indicated, appropriate supportive 
treatment should be provided, if applicable. 
 
7.2.2 Reporting of Pregnancy and Lactation to the Sponsor and 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 
the trial completing the trial, 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 outcome (health 
of infant) must also be reported. 
 
Such events must be reported within 24 hours to the Sponsor and within 2 working 
days to Merck Global Safety. (Attn: Worldwide Product Safety; 
 FAX 215 993-1220) 
 
7.2.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck 
7.2.3.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use 
of Merck’s product that: 
• Results in death; 
• Is life threatening; 
• Results in persistent or significant disability/incapacity; 
• Results in or prolongs an existing inpatient hospitalization; 
• Is a congenital anomaly/birth defect; 
• Is a new cancer (that is not a condition of the study); 
• Is associated with an overdose; 
• Is another important medical event  
 
Refer to Table 6 for additional details regarding each of the above criteria. 
Any serious adverse event, or follow up to a serious adverse event, including death 
due to any cause other than progression of the cancer under study that occurs to any 
subject from the time the consent is signed through 90 days following cessation of 
treatment, or the initiation of new anti-cancer therapy, whichever is earlier, whether or 
not related to Merck product, must be reported within 24 hours to the Sponsor and 
within 2 working days to Merck Global Safety.  

 
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Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety and will 
be handled in the same manner as SAEs.  
 
Additionally, any serious adverse event, considered by an investigator who is a 
qualified physician to be related to Merck product that is brought to the attention of the 
investigator at any time outside of the time period specified in the previous paragraph 
also must be reported immediately to the Sponsor and to Merck. 
 
SAE reports and any other relevant safety information are to be forwarded to the 
Merck Global Safety facsimile number:  +1-215-993-1220 
 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required 
by FDA, European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) 
or other local regulators. Investigators will cross reference this submission according 
to local regulations to the Merck Investigational Compound Number (IND, CSA, etc.) 
at the time of submission.  Additionally investigators will submit a copy of these reports 
to Merck & Co., Inc. (Attn: Worldwide Product Safety; FAX 215 993-1220) at the time 
of submission to FDA. 
 
All subjects with serious adverse events must be followed up for outcome. 
 
7.2.3.2 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical 
Interest (ECI) and must be recorded as such on the Adverse Event case report 
forms/worksheets and reported within 24 hours to the Sponsor and within 2 working 
days to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-
1220)Events of clinical interest for this trial include: 
 
1.  an overdose of Merck product, as defined in Section 7.2.1 - Definition of an 
Overdose for This Protocol and Reporting of Overdose to the Sponsor, that is not 
associated with clinical symptoms or abnormal laboratory results.  
 
2.  an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 2X 
the upper limit of normal and, at the same time, an alkaline phosphatase lab value 
that is less than 2X the upper limit of normal, as determined by way of protocol-
specified laboratory testing or unscheduled laboratory testing.* 
 
*Note:  These criteria are based upon available regulatory guidance documents. 
The purpose of the criteria is to specify a threshold of abnormal hepatic tests that 
may require an additional evaluation for an underlying etiology.  The trial site 
guidance for assessment and follow up of these criteria can be found in the 
Investigator Trial File Binder (or equivalent). 
1. Additional adverse events: 

 
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A separate guidance document has been provided entitled “Event of Clinical 
Interest Guidance Document” (previously entitled, “Event of Clinical Interest and 
Immune-Related Adverse Event Guidance Document”).  This document can be 
found in Appendix 4 and provides guidance regarding identification, evaluation and 
management of ECIs and irAEs.   
 
ECIs (both non-serious and serious adverse events) identified in this guidance 
document from the date of first dose through 90 days following cessation of 
treatment, or 30 days after the initiation of a new anticancer therapy, whichever is 
earlier, need to be reported within 24 hours to the Sponsor and within 2 working 
days to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-
1220), regardless of attribution to study treatment, consistent with standard SAE 
reporting guidelines. 
 
 
Subjects should be assessed for possible ECIs prior to each dose.  Lab results 
should be evaluated and subjects should be asked for signs and symptoms 
suggestive of an immune-related event.  Subjects who develop an ECI thought to 
be immune-related should have additional testing to rule out other etiologic causes.  
If lab results or symptoms indicate a possible immune-related ECI, then additional 
testing should be performed to rule out other etiologic causes.  If no other cause 
is found, then it is assumed to be immune-related. 
 
 
7.2.4 Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according 
to the NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any 
adverse event which changes CTCAE grade over the course of a given episode will 
have each change of grade recorded on the adverse event case report 
forms/worksheets. 
 
All adverse events regardless of CTCAE grade must also be evaluated for 
seriousness. 

 
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Table 6  Evaluating Adverse Events 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
V4.0 CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention 
not indicated. 
 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation or hospitalization indicated; disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the 
event as it occurred (Note: This does not include an adverse event that, had it occurred in a more severe form, 
might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct 
normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient 
admission, regardless of length of stay, even if the hospitalization is a precautionary measure for continued 
observation. (Note: Hospitalization [including hospitalization for an elective procedure] for a preexisting condition 
which has not worsened does not constitute a serious adverse event.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to 
diagnosis);or 
 
Is a new cancer; (that is not a condition of the study) or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered 
a serious adverse event. An overdose that is not associated with an adverse event is considered a non-serious 
event of clinical interest and must be reported within 24 hours. 
 
Other important medical events that may not result in death, not be life threatening, or not require 
hospitalization may be considered a serious adverse event when, based upon appropriate medical judgment, the 
event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time 
and units 
Action taken  Did the adverse event cause the Merck product to be discontinued? 

 
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Relationship 
to test drug  
Did the Merck product cause the adverse event? The determination of the likelihood that the Merck product 
caused the adverse event will be provided by an investigator who is a qualified physician. The investigator’s 
signed/dated initials on the source document or worksheet that supports the causality noted on the AE form, 
ensures that a medically qualified assessment of causality was done. This initialed document must be retained for 
the required regulatory time frame. The criteria below are intended as reference guidelines to assist the 
investigator in assessing the likelihood of a relationship between the test drug and the adverse event based upon 
the available information.  
The following components are to be used to assess the relationship between the Merck product and the 
AE; the greater the correlation with the components and their respective elements (in number and/or intensity), the 
more likely the Merck product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to the Merck product such as: reliable 
history, acceptable compliance assessment (pill count, diary, etc.), expected pharmacologic effect, 
or measurement of drug/metabolite in bodily specimen? 
 
Time 
Course 
Did the AE follow in a reasonable temporal sequence from administration of the Merck product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with 
investigational medicinal product)? 
 
Likely 
Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other 
drug(s)/vaccine(s), or other host or environmental factors 
 
 
 
 
Relationship The following components are to be used to assess the relationship between the test drug and the AE: 
(continued) 
to Merck 
product 
(continued)  
Dechallenge Was the Merck product discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the 
AE resolved/improved despite continuation of the Merck product; or (3) the trial is a single-dose 
drug trial); or (4) Merck product(s) is/are only used one time.) 
 
Rechallenge Was the subject re-exposed to the Merck product in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, 

 
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or (2) the trial is a single-dose drug trial); or (3) Merck product(s) is/are used only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS 
AND WHICH MAY HAVE BEEN CAUSED BY THE MERCK PRODUCT, OR IF REEXPOSURE 
TO THE MERCK PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE 
SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE U.S. 
CLINICAL MONITOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL. 
 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the 
Merck product or drug class pharmacology or toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician 
according to his/her best clinical judgment, including consideration of the above elements. 
Record one of the 
following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative 
of a Merck product relationship). 
Yes, there is a reasonable 
possibility of Merck 
product relationship. 
There is evidence of exposure to the Merck product.  The temporal sequence of the AE onset relative 
to the administration of the Merck product is reasonable.  The AE is more likely explained by the 
Merck product than by another cause. 
No, there is not a 
reasonable possibility 
Merck product relationship 
Subject did not receive the Merck product OR temporal sequence of the AE onset relative to 
administration of the Merck product is not reasonable OR there is another obvious cause of the AE.  
(Also entered for a subject with overdose without an associated AE.) 

 
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7.2.5 Sponsor Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and 
investigators in accordance with all applicable global laws and regulations.  
 
8.0 STATISTICAL ANALYSIS PLAN 
8.1 Statistical Analysis Plan Summary 
The primary endpoint is laryngectomy-free survival (LFS) at 18 month.  LFS for 
standard of care is approximately 70%; the trial hypothesis is that LFS at 18 month 
can be improved to at least 85% using the experimental agent. Forty seven patients 
are required to identify this improvement in 18 month LFS using a one-sided test with 
10% significance and 80% power.  This calculation is based on a non-parametric LFS 
distribution, and assumes that it will take 18 months to accrue all 47 patients, and that 
an additional 6 months of follow-up will be done after the last patient is enrolled. 
 
Study size was calculated using the SWOG calculator for “one-arm nonparametric 
survival”:   http://www.swogstat.org/statoolsout.html 
 
8.2 Statistical Analysis Plan 
Safety run-in phase: Although PD-1 inhibition is not expected to increase the toxicity 
of chemoradiation therapy, clinical trials of pembrolizumab combined with cisplatin 
and radiation for locally advanced head and neck carcinoma have not been 
conducted.  In order to protect against unexpected problems a run-in safety analysis 
will be performed prior to completing the rest of the first stage of study. This safety 
analysis will occur after 6 analyzable patients are entered into study.  Pembrolizumab 
will be administered initially at the recommended phase II dose of 200 mg q 3 weeks. 
If more than 2 dose-limiting toxicities (DLTs) in the cohort of 6 patients then 
pembrolizumab will be given subsequent to completion of chemoradiation. In the event 
of 0-2 DLT events, the study will proceed as planned. A DLT will be defined as a ≥ 
grade 3 (CTCAE, v.4) adverse event that is definitely, probably, or possibly related to 
study drug, excluding grade 3 tumor flare and toxicities that are strongly associated 
with concurrent radiation and cisplatin ( for example rash, mucositis, radiation 
dermatitis).  
 
LFS will be estimated using the Kaplan-Meier method.  The point estimate and 
standard error will be obtained from the Kaplan-Meier curve and a 95% confidence 
interval will be calculated to estimate 18-month LFS.  A z-test will be used to test the 
primary hypothesis of improvement in 18- month LFS from 70% to 85%.  
 
One-year LFS, Progression-free survival, overall survival, event-free survival, and 
patterns of failure will be estimated using the Kaplan-Meier method.  Complete 
response at 3 months will be estimated with an exact 95% confidence interval.   
For correlative studies, prognostic factors for complete response will be identified 
using logistic regression analysis.  Prognostic factors for outcomes will be identified 
using Cox proportional hazards analysis. 
 

 
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9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES 
9.1 Investigational Product  
The investigator shall take responsibility for and shall take all steps to maintain 
appropriate records and ensure appropriate supply, storage, handling, distribution and 
usage of investigational product in accordance with the protocol and any applicable 
laws and regulations. 
 
Clinical Supplies will be provided by Merck as summarized in Table 7. 
 
Table 7  Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
9.2 Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
 
9.3 Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor 
and/or designee are not blinded to treatment. Drug identity (name, strength) is 
included in the label text; random code/disclosure envelopes or lists are not provided. 
 
9.4 Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.   
Receipt and dispensing of trial medication must be recorded by an authorized person 
at the trial site. 
 
Clinical supplies may not be used for any purpose other than that stated in the 
protocol. 
 
9.5 Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies 
received from Merck or designee, the amount dispensed to and returned by the 
subjects and the amount remaining at the conclusion of the trial.  
 
Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per institutional policy. It is the 
Investigator’s responsibility to arrange for disposal of all empty containers, 
provided that procedures for proper disposal have been established according to 
applicable federal, state, local and institutional guidelines and procedures, and 
provided that appropriate records of disposal are kept. 
 

 
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9.6 Cisplatin 
Refer to the package insert for detailed pharmacologic and safety information 
 
1. Formulation: 
Each ml contains 1 mg cisplatin and 9 mg of sodium chloride in water for injection. 
Hydrochloric acid and/or sodium hydroxide is added for adjustment. Vials are multi-
dose, available as an aqueous solution, with a final concentration of 1 mg/1 mL 
cisplatin.  The pH range of aqueous product is 3.8 to 5.9. Vials should be stored at 
20-25ºC (68-77 ºF), and protected from light.  
 
2. Mechanism of Action:  
The dominant mode of action of cisplatin appears to be inhibition of the incorporation 
of DNA precursors, although protein and RNA synthesis are also inhibited. Although 
this drug seems to act as an alkylating agent, there are data to indicate that its mode 
and sites of action are different from those of nitrogen mustard and the standard 
alkylating agents. 
 
3. Administration:  
Cisplatin will be given as a bolus, infused over 1-2 hours along with appropriate 
hydration and anti-emetics. 
 
4. Storage and Stability:  
Reconstituted solution of cisplatin is stable for 20 hours when stored at 27°C and 
should be protected from light if not used within 6 hours. The vials and injection 
should not be refrigerated. Cisplatin has been shown to react with aluminum 
needles, producing a black precipitate within 30 minutes. 
 
5. Adverse Events:  
Human toxicity includes nausea, vomiting, renal toxicity (with an elevation of BUN 
and creatinine and impairment of endogenous creatinine clearance, as well as renal 
tubular damage, which appears to be transient), ototoxicity (with hearing loss that 
initially is in the high-frequency range, as well as tinnitus), and hyperuricemia. Much 
more severe and prolonged toxicity has been observed in patients with abnormal or 
obstructed urinary excretory tracts. Myelosuppression, often with delayed 
erythrosuppression, is expected. 
 
6. Supply:  
Cisplatin is commercially available. The use of drug(s) or combination of drugs in 
this protocol meet the criteria for IND exemption. 
 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
10.1 Confidentiality 
Patient records will be kept in a secure location at the University of Cincinnati 
accessible only to research authorized personnel. The patient identity will be kept as 
confidential as possible as required by law. Except as required by law, the patient will 
not be identified by name, social security number, address, telephone number, or any 

 
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other direct personal identifier. Study subjects will be assigned an ID code. Information 
about the code will be kept in a secure location and access limited to research study 
personnel. The results of this research study may be presented at scientific or medical 
meetings or published in scientific journals. However, the patient identity will not be 
disclosed. The patient's personal data which may be included in the investigator’s 
database shall be treated in compliance with all applicable laws and regulations. 
 
10.2 Compliance with Financial Disclosure Requirements 
Compliance standards established by University of Cincinnati will be followed. 
 
10.3 Compliance with Law, Audit and Debarment 
Compliance standards established by University of Cincinnati will be followed. 
 
10.4 Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and 
the Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial 
is solely responsible for determining whether the trial and its results are subject to the 
requirements 
for 
submission 
to 
the 
Clinical 
Trials 
Data 
Bank, 
http://www.clinicaltrials.gov.  Information posted will allow subjects to identify 
potentially appropriate trials for their disease conditions and pursue participation by 
calling a central contact number for further information on appropriate trial locations 
and trial site contact information.     
 
10.5 Quality Management System 
The protocol, the proposed informed consent and all forms of participant information 
related to the study (e.g. advertisements used to recruit participants) will be reviewed 
and approved by the Cancer Consortium IRB and Scientific Review Committee (SRC).  
Any changes made to the protocol will be submitted as a modification and will be 
approved by the IRB prior to implementation.   
 
The University of Cincinnati Consortium Data and Safety Monitoring Board (DSMB) 
will be the monitoring entity for this study in accordance with the Cancer Consortium’s 
Data Safety Monitoring Plan. 
 
10.6 Data Management 
The Protocol Director, or her designees, will prepare and maintain adequate and 
accurate participant case histories with observations and other data pertinent to the 
study.  Original source documents should be transcribed to Case Report Forms 
(CRFs) and used to analyze the study data.  Source documents include hospital 
records, clinical charts, laboratory and pharmacy records, and recorded electronic 
data. 
 
All data required by the trial will be entered onto paper and electronic case report 
forms. Any corrections to data required into the paper case report forms must be made 
in such a way that the original entry is not obscured. Only designated study staff will 

 
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enter data for study participants after study visits. Case report forms will be checked 
against source document data by study staff. 
 
Trial oversight will be carried out by the Protocol Director, Dr. Nooshin Hashemi 
Sadraei, and her research staff. They will meet weekly to review recently acquired 
data and adverse events. The data recorded within the research charts and protocol 
database is compared with the actual data that is available from the medical record 
and/or clinical histories. Data detailed in the research case report forms includes the 
nature and severity of all toxicities, which are also reported as described above. All 
investigators on the protocol will receive formal training in the ethical conduct of 
human research. Institutional support of trial auditing is provided in accordance with 
the Cancer Consortium’s Data and Safety Monitoring Plan. In addition, protocols are 
reviewed at least annually by the Scientific Review Committee (SRC) and the 
Institutional Review Board (IRB). 
 
 

 
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11.0 APPENDICES 
11.1 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. 
 
11.2 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) 
 
11.3 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. 

 
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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. 
 
In addition, volumetric analysis will be explored by central review for response 
assessment. 
 
11.4 Events of Clinical Interest Guidance Document 
Please refer to section 5.6.1  
 
11.5 References 
 
1. 
Hoffman, H.T., et al., The National Cancer Data Base report on cancer of the 
head and neck. Arch Otolaryngol Head Neck Surg, 1998. 124(9): p. 951-62. 
2. 
Chu, E.A. and Y.J. Kim, Laryngeal cancer: diagnosis and preoperative work-
up. Otolaryngol Clin North Am, 2008. 41(4): p. 673-95, v. 
3. 
Shah, J.P., et al., Patterns of care for cancer of the larynx in the United 
States. Arch Otolaryngol Head Neck Surg, 1997. 123(5): p. 475-83. 
4. 
Davis, G.E., et al., Cost comparison of surgery vs organ preservation for 
laryngeal cancer. Arch Otolaryngol Head Neck Surg, 2005. 131(1): p. 21-6. 
5. 
Starmer, H.M., D.C. Tippett, and K.T. Webster, Effects of laryngeal cancer on 
voice and swallowing. Otolaryngol Clin North Am, 2008. 41(4): p. 793-818, vii. 
6. 
Sessions, D.G., et al., Management of T3N0M0 glottic carcinoma: therapeutic 
outcomes. Laryngoscope, 2002. 112(7 Pt 1): p. 1281-8. 
7. 
Spector, G.J., et al., Management of stage IV glottic carcinoma: therapeutic 
outcomes. Laryngoscope, 2004. 114(8): p. 1438-46. 
8. 
Silver, C.E., et al., Current trends in initial management of laryngeal cancer: 
the declining use of open surgery. Eur Arch Otorhinolaryngol, 2009. 266(9): p. 
1333-52. 
9. 
Induction chemotherapy plus radiation compared with surgery plus radiation 
in patients with advanced laryngeal cancer. The Department of Veterans 
Affairs Laryngeal Cancer Study Group. N Engl J Med, 1991. 324(24): p. 1685-
90. 
10. 
Hong, W.K., S.M. Lippman, and G.T. Wolf, Recent advances in head and 
neck cancer--larynx preservation and cancer chemoprevention: the 
Seventeenth Annual Richard and Hinda Rosenthal Foundation Award 
Lecture. Cancer Res, 1993. 53(21): p. 5113-20. 
11. 
Forastiere, A.A., et al., Concurrent chemotherapy and radiotherapy for organ 
preservation in advanced laryngeal cancer. N Engl J Med, 2003. 349(22): p. 
2091-8. 
12. 
Forastiere, A.A., et al., Long-term results of RTOG 91-11: a comparison of 
three nonsurgical treatment strategies to preserve the larynx in patients with 
locally advanced larynx cancer. J Clin Oncol, 2013. 31(7): p. 845-52. 
13. 
Pointreau, Y., et al., Randomized trial of induction chemotherapy with 
cisplatin and 5-fluorouracil with or without docetaxel for larynx preservation. J 
Natl Cancer Inst, 2009. 101(7): p. 498-506. 

 
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14. 
American Society of Clinical, O., et al., American Society of Clinical Oncology 
clinical practice guideline for the use of larynx-preservation strategies in the 
treatment of laryngeal cancer. J Clin Oncol, 2006. 24(22): p. 3693-704. 
15. 
Megwalu, U.C. and A.G. Sikora, Survival outcomes in advanced laryngeal 
cancer. JAMA Otolaryngol Head Neck Surg, 2014. 140(9): p. 855-60. 
16. 
Zou, W. and L. Chen, Inhibitory B7-family molecules in the tumour 
microenvironment. Nat Rev Immunol, 2008. 8(6): p. 467-77. 
17. 
Lyford-Pike, S., et al., Evidence for a role of the PD-1:PD-L1 pathway in 
immune resistance of HPV-associated head and neck squamous cell 
carcinoma. Cancer Res, 2013. 73(6): p. 1733-41. 
18. 
Saloura V, Z.Z., Koeppen H, et al. , T cell-inflamed phenotype correlates with 
mesenchymal subtype, expression of PD-L1 and other immune checkpoints 
in head and neck cancer. J Clin Oncol. , 2014. 32(5s suppl): p. abstr 6009. 
19. 
Morales-Kastresana, A., et al., Combined immunostimulatory monoclonal 
antibodies extend survival in an aggressive transgenic hepatocellular 
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