Randomized Phase II Study of Immune Stimulation With Pembrolizumab and Radiotherapy in Second Line Therapy of Metastatic Head and Neck Squamous Cell Carcinoma (IMPORTANCE, Keynote-717, EudraCT NUMBER: 2017-002122-20 )
Phase: PHASE2
Conditions: Head and Neck Squamous Cell Carcinoma
Sponsor: University of Erlangen-Nürnberg Medical School

Product: Pembrolizumab 
1 
Protocol/Amendment No.: 717 
IMPORTANCE, Final Protocol 
v.1.6, 20.02.2023
Keynote-717; EudraCT-Nr.: 2017-002122-20 
Confidential 
Randomized phase II study of immune stimulation with 
Pembrolizumab and radiotherapy in second line therapy 
of metastatic head and neck squamous cell carcinoma 
(IMPORTANCE) 
EudraCT NUMBER: 
2017-002122-20 
Protocol code: 
IMPORTANCE (Keynote-717) 
Protocol version: 
1.6; 20.02.2023 
Sponsor: 
Dean of the Medical Faculty of the Friedrich-Alexander University 
Erlangen-Nürnberg 
Principal investigator: Prof. Dr. Rainer Fietkau 
University Hospital Erlangen, Radiation Oncology 
Universitätsstr. 27 
91054 Erlangen 
++49(0)9131-85-33968 
++49(0)9131-85-33996 
Email: rainer.fietkau@uk-erlangen.de 
Scientific leadership: 
Prof. Dr. Rainer Fietkau, University Hospital Erlangen, Radiation Oncology 
Prof. Dr. Wilfried Budach, University Hospital Düsseldorf, Radiation 
Oncology 
Prof. Dr. Markus Hecht, University Hospital Homburg/Saarland, Radiation 
Oncology 
Dr. Jan Haussmann, University Hospital Düsseldorf, Radiation Oncology 
Prof. Udo Gaipl, University Hospital Erlangen, Radiation Immunobiology 
Biostatistics: 
Dr. Axel Hinke 
Düsseldorf, Cancer Clinical Research Consulting (CCRC) 
Study Coordination: 
Dr. rer. nat. Annett Kallies. 
University Hospital Erlangen, Radiation Oncology 
Universitätsstr. 27 
91054 Erlangen 
++49(0)9131-85-33968 
++49(0)9131-85-33996 
Email: annett.kallies@uk-erlangen.de 

Product: Pembrolizumab 
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Protocol/Amendment No.: 717  
 
 
IMPORTANCE, Final Protocol 
 
 
 
 
 
 
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Keynote-717; EudraCT-Nr.: 2017-002122-20 
 
Confidential 
 
Detailed Protocol-specific Sponsor Contact information can be found in the Investigator Site File 
(ISF) (or equivalent). 
 

Product: Pembrolizumab 
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IMPORTANCE, Final Protocol 
 
 
 
 
 
 
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Keynote-717; EudraCT-Nr.: 2017-002122-20 
 
Confidential 
 
TABLE OF CONTENTS 
 
1.0 
TRIAL SUMMARY .................................................................................................. 10 
2.0 
TRIAL DESIGN ........................................................................................................ 12 
2.1 
Trial Design ........................................................................................................... 12 
2.2 
Trial Diagram ........................................................................................................ 13 
3.0 
OBJECTIVES & HYPOTHESES ........................................................................... 13 
3.1 
Primary Objective & Hypothesis ........................................................................ 13 
3.2 
Secondary Objectives & Hypotheses ................................................................... 14 
3.3 
Exploratory Objective .......................................................................................... 14 
4.0 
BACKGROUND & RATIONALE .......................................................................... 14 
4.1 
Background ........................................................................................................... 14 
4.1.1 Pharmaceutical and Therapeutic Background..................................................... 14 
4.1.2 Preclinical and Clinical Trial Data ...................................................................... 16 
4.1.2.1 Current treatment of metastatic head and neck squamous cell carcinoma .. 16 
4.1.2.2 Pembrolizumab in different tumor entities .................................................. 16 
4.1.2.3 Pembrolizumab in head and neck squamous cell carcinoma (HNSCC) ...... 17 
4.1.2.4 The medical challenge ................................................................................. 18 
4.2 
Rationale ................................................................................................................ 18 
4.2.1 Rationale for the Trial ......................................................................................... 18 
4.2.1.1 Abscopal effects of radiotherapy combined with immune therapy ............. 18 
4.2.1.2 Upregulation of Programmed cell death ligand 1 (PD-L1) by 
radiotherapy ................................................................................................. 19 
4.2.1.3 Radiotherapy and PD-1/ PD-L1 pathway blockade in vitro ........................ 19 

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4.2.1.4 Fractionation of radiotherapy ....................................................................... 19 
4.2.1.5 Timing of radiotherapy and pembrolizumab administration ....................... 20 
4.2.2 Rationale for pembrolizumab Dose Selection/ Regimen/ Modification ............. 20 
4.2.3 Rationale for Endpoints ...................................................................................... 21 
4.2.3.1 Efficacy Endpoints ....................................................................................... 21 
4.2.3.2 Safety endpoints ........................................................................................... 21 
4.2.3.3 Biomarker Research ..................................................................................... 21 
4.2.4 Risk-benefit analysis ........................................................................................... 21 
5.0 
METHODOLOGY ................................................................................................... 23 
5.1 
Entry Criteria ........................................................................................................ 23 
5.1.1 Diagnosis/ Condition for Entry into the Trial ..................................................... 23 
5.1.2 Subject Inclusion Criteria .................................................................................... 23 
5.1.3 Subject Exclusion Criteria .................................................................................. 25 
5.2 
Trial Treatments ................................................................................................... 28 
5.2.1 Treatment with pembrolizumab .......................................................................... 28 
5.2.1.1 Dose Selection ............................................................................................. 28 
5.2.1.2 Dose Modification and toxicity management for immune-related AEs 
associated with pembrolizumab and combination therapy .......................... 29 
5.2.2 Treatment with Radiotherapy.............................................................................. 35 
5.2.2.1 Technical factors of Radiotherapy ............................................................... 35 
5.2.2.2 
Immobilization and planning CT scan ......................................................... 35 
5.2.2.3 Target volumes ............................................................................................. 35 
5.2.2.4 Dose prescription and dose specification of Radiotherapy .......................... 36 
5.2.2.5 Dose modification of Radiotherapy ............................................................. 36 

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5.2.2.6 Documentation requirements and portal films ............................................. 36 
5.2.2.7 Critical normal structures and adverse events of radiotherapy .................... 36 
5.2.3 Adverse events of radiotherapy combined with pembrolizumab ........................ 38 
5.2.4 Timing of Administration of pembrolizumab and Radiotherapy ........................ 39 
5.2.5 Trial Blinding/ Masking ...................................................................................... 39 
5.3 
Randomization or Treatment Allocation ............................................................ 39 
5.4 
Stratification .......................................................................................................... 39 
5.5 
Concomitant Medications/ Vaccinations (allowed & prohibited) .................... 40 
5.5.1 Acceptable Concomitant Medications ................................................................ 40 
5.5.2 Prohibited Concomitant Medications/ Therapies ................................................ 40 
5.6 
Rescue Medications & Supportive Care ............................................................. 41 
5.6.1 Supportive Care Guidelines pembrolizumab ...................................................... 41 
5.6.2 Additional supportive Care Guidelines Radiotherapy ........................................ 45 
5.7 
Diet/ Activity/ Other Considerations ................................................................... 45 
5.7.1 Diet ...................................................................................................................... 45 
5.7.2 Contraception ...................................................................................................... 45 
5.7.3 Use in Pregnancy ................................................................................................ 47 
5.7.4 Use in Nursing Women ....................................................................................... 47 
5.8 
Subject Withdrawal/ Discontinuation Criteria .................................................. 48 
5.8.1 Discontinuation of Study Treatment after CR .................................................... 49 
5.9 
Subject Replacement Strategy ............................................................................. 49 
5.10 
End of the trial ...................................................................................................... 49 
5.11 
Clinical Criteria for Early Trial Termination ................................................... 49 

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6.0 
TRIAL FLOW CHART ........................................................................................... 50 
6.1 
Study Flow Chart .................................................................................................. 50 
7.0 
TRIAL PROCEDURES ........................................................................................... 55 
7.1 
Trial Procedures ................................................................................................... 55 
7.1.1 Administrative Procedures .................................................................................. 55 
7.1.1.1 
Informed Consent ......................................................................................... 55 
7.1.1.1.1 General Informed Consent .................................................................... 55 
7.1.1.2 
Inclusion/ Exclusion Criteria ....................................................................... 56 
7.1.1.3 Demographics and Medical History ............................................................ 56 
7.1.1.4 Prior and Concomitant Medications Review ............................................... 56 
7.1.1.4.1 Prior Medications .................................................................................. 56 
7.1.1.4.2 Concomitant Medications ..................................................................... 56 
7.1.1.5 Disease Details and Treatments ................................................................... 56 
7.1.1.5.1 Disease Details ...................................................................................... 56 
7.1.1.5.2 Prior Treatment Details ......................................................................... 56 
7.1.1.5.3 Subsequent Anti-Cancer Therapy Status .............................................. 57 
7.1.1.6 Assignment of Screening Number ............................................................... 57 
7.1.1.7 Assignment of Randomization Number ....................................................... 57 
7.1.2 Clinical Procedures/ Assessments ....................................................................... 58 
7.1.2.1 Adverse Event (AE) Monitoring .................................................................. 58 
7.1.2.2 Full Physical Examination ........................................................................... 58 
7.1.2.3 Directed Physical Examination .................................................................... 58 
7.1.2.4 Vital Signs .................................................................................................... 58 

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7.1.2.5 Electrocardiogram ........................................................................................ 58 
7.1.2.6 Eastern Cooperative Oncology Group (ECOG) Performance Scale ........... 59 
7.1.2.7 Tumor Imaging and Assessment of Disease ................................................ 59 
7.1.2.8 Tumor Tissue Collection and Correlative Studies Blood Sampling ............ 59 
7.1.3 
Laboratory Procedures/ Assessments .................................................................. 59 
7.1.4 Other Procedures ................................................................................................. 61 
7.1.4.1 Withdrawal/ Discontinuation from study ..................................................... 61 
7.1.4.2 Blinding/ Unblinding ................................................................................... 61 
7.1.4.3 Patient questionnaires .................................................................................. 61 
7.1.5 Visit Requirements .............................................................................................. 61 
7.1.5.1 Screening ...................................................................................................... 61 
7.1.5.2 Treatment Period .......................................................................................... 62 
7.1.5.3 End of Treatment Visit ................................................................................. 62 
7.1.5.4 Post-Treatment Visits ................................................................................... 63 
7.1.5.4.1 Safety Follow-Up Visit ......................................................................... 63 
7.1.5.4.2 Follow-up Visits ................................................................................... 63 
7.1.5.4.3 Survival Follow-up ............................................................................... 63 
7.1.5.5 Aftertreatment .............................................................................................. 63 
7.2 
Assessing and Recording Adverse Events .......................................................... 64 
7.2.1 Definition of an Overdose for this Protocol and Reporting of Overdose ........... 65 
7.2.2 Reporting of Pregnancy and Lactation ................................................................ 66 
7.2.3 
Immediate Reporting of Adverse Events ............................................................ 66 
7.2.3.1 Serious Adverse Events ............................................................................... 66 

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7.2.3.2 Events of Clinical Interest ............................................................................ 68 
7.2.3.3 Protocol-Specific Exceptions to Serious Adverse Event Reporting ............ 69 
7.2.4 Evaluating Adverse Events ................................................................................. 69 
7.2.5 Sponsor Responsibility for Evaluating and Reporting Adverse Events ............. 75 
7.2.6 Data Safety Monitoring Committee (DSMC) ..................................................... 75 
8.0 
STATISTICAL ASPECTS ....................................................................................... 75 
8.1 
Trial design and primary hypotheses .................................................................. 75 
8.2 
Sample size calculation ......................................................................................... 76 
8.3 
Evaluation categories of patients ......................................................................... 76 
8.4 
Methods of statistical analysis ............................................................................. 77 
8.5 
Statistical Analysis Plan ....................................................................................... 78 
9.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 78 
9.1 
Investigational Product ........................................................................................ 78 
9.2 
Packaging and Labeling Information ................................................................. 78 
9.3 
Clinical Supplies Disclosure ................................................................................. 78 
9.4 
Storage and Handling Requirements .................................................................. 78 
9.5 
Returns and Reconciliation .................................................................................. 79 
10.0 
ADMINISTRATIVE AND REGULATORY DETAILS ....................................... 79 
10.1 
Confidentiality ....................................................................................................... 79 
10.2 
Compliance with Financial Disclosure Requirements ....................................... 79 
10.3 
Compliance with Law, Audit and Debarment ................................................... 80 
10.4 
Compliance with Trial Registration and Results Posting Requirements ........ 80 
10.5 
Quality Management System ............................................................................... 80 

Product: Pembrolizumab 
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10.6 
Data Management and Data Archiving .............................................................. 80 
11.0 
TRANSLATIONAL RESEARCH .......................................................................... 82 
11.1 
Immune status in the peripheral blood ............................................................... 82 
11.2 
PD-L1 in combination with tumor-infiltrating lymphocytes ............................ 83 
12.0 
REFERENCES .......................................................................................................... 84 
13.0 
Abbreviations ............................................................................................................ 88 
14.0 
APPENDICES ........................................................................................................... 92 
14.1 
ECOG Performance Status .................................................................................. 92 
14.2 
Common Terminology Criteria for Adverse Events V4.0 (CTCAE) ............... 92 
14.3 
Response Evaluation Criteria iRECIST ............................................................. 92 
15.0 
Signatures .................................................................................................................. 94 
15.1 
Sponsor’s Representative ..................................................................................... 94 
15.2 
Investigator ............................................................................................................ 95 
 

Product: Pembrolizumab 
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1.0 TRIAL SUMMARY 
Title 
Randomized phase II study of immune stimulation with 
Pembrolizumab and radiotherapy in second line therapy of 
metastatic head and neck squamous cell carcinoma 
Abbreviated Title: 
Pembrolizumab and Radiotherapy in metastatic HNSCC  
EudraCT NUMBER: 2017-002122-20 
Protocol code: 
IMPORTANCE (Keynote-717) 
Sponsor: 
Dean of the Medical Faculty of the Friedrich-Alexander 
University Erlangen-Nürnberg 
Principal investigator:
 
 
 
Prof. Dr. med. Rainer Fietkau 
University Hospital Erlangen, Radiation Oncology 
Universitätsstr. 27 
91054 Erlangen 
++49(0)9131-85-33968 
++49(0)9131-85-33996 
Email: rainer.fietkau@uk-erlangen.de 
Scientific leadership 
Prof. Dr. Rainer Fietkau, University Hospital Erlangen, Radiation 
Oncology 
Prof. Wilfried Budach, University Hospital Düsseldorf, Radiation 
Oncology 
Prof. Markus Hecht, University Hospital Homburg/Saarland, 
Radiation Oncology 
Dr. Jan Haussmann, University Hospital Düsseldorf, Radiation 
Oncology 
Prof. Udo Gaipl, University Hospital Erlangen, Radiation 
Immunobiology 
Biostatistics: 
Dr. Axel Hinke 
Düsseldorf, Cancer Clinical Research Consulting (CCRC) 
Study Coordination: 
Dr. Annett Kallies 
University Hospital Erlangen, Radiation Oncology 
Universitätsstr. 27 
91054 Erlangen 
++49(0)9131-85-33968 
++49(0)9131-85-33996 
Email: annett.kallies@uk-erlangen.de 
Trial Phase 
Phase II 
 
 

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Clinical Indication 
 Metastatic HNSCC  
OR 
Locally recurrent HNSCC not suitable for local treatment (at 
least two lesions, e.g. primary tumor and lymph node) 
 
Progression to first line platinum-based or any second/ third line 
chemotherapy  
OR 
Progression within 6 months after platinum-based 
radiochemotherapy of locally advanced disease 
OR 
 First line treatment if PD-L1 CPS (combined positive score) ≥1 
Trial Type 
Multicenter prospective clinical trial 
Type of control 
Randomized trial 
Route of 
administration 
Pembrolizumab i.v. and percutaneous radiotherapy 
Trial Blinding 
none (open-label) 
Treatment Groups  
A: Pembrolizumab (200mg absolute, q3w) combined with 
radiotherapy (12x3Gy) of one, two or three tumor lesions. Only 
lesions that perspectively require radiotherapy will be treated. The 
irradiated tumor volume must be at least 2ml. Radiotherapy of 
brain metastases is not allowed.  
B: Pembrolizumab (200mg absolute, q3w) 
Primary endpoint 
Response to treatment according to iRECIST (irradiated lesion are 
excluded). 
Number of trial 
subjects 
130 
Estim. enrollment 
period 
24 months 
Estimated duration of 
trial 
36 months 
Duration of 
Participation 
12 months (treatment) 
Estimated average 
length of treatment 
per patient 
6 months 
 
 
 

Product: Pembrolizumab 
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Keynote-717; EudraCT-Nr.: 2017-002122-20 
 
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2.0 TRIAL DESIGN 
2.1 
Trial Design 
This is an open-label, randomized, prospective, multicenter phase II clinical trial of 
pembrolizumab with or without local radiotherapy in patients with recurrent and/ or metastatic 
HNSCC after progression to platinum-based therapy or as first line treatment if CPS≥1. 
All patients will receive pembrolizumab 200mg absolute dose administered every third week. 
Patients in treatment arm A will receive radiotherapy of one, two or three tumor lesions with a 
total tumor volume of at least 2ml intended to induce tumor cell death acting as an in situ 
vaccination. If possible, the irradiated tumor volume should be ≥5ml. Radiotherapy will be 
performed conventionally fractioned with single doses of 3Gy to a total dose of 36Gy. There 
will be a strict time schedule. Radiotherapy will always start on Wednesday. After application 
of the third radiation dose (Friday) the patients will receive pembrolizumab. After an 
interruption of radiotherapy for two days (Saturday, Sunday), radiotherapy will be continued. 
Pembrolizumab will be continued on an every three week schedule until confirmed disease 
progression according to iRECIST criteria, unacceptable toxicity, patient’s wish to stop 
therapy or a maximal treatment time of 12 months.  
Tumor assessment will be performed every 9 weeks and will be evaluated according to 
iRECIST and RECIST (see Appendix 14.3). For each patient the same assessment method will 
be used throughout the study. Toxicity will be assessed according to revised NCI Common 
Terminology Criteria for Adverse Events Version 4.0 (CTCAE 4.0) (see Appendix 14.2).  
 
 

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2.2 
Trial Diagram 
 
 
 
3.0 OBJECTIVES & HYPOTHESES 
3.1 
Primary Objective & Hypothesis 
(1) Objective: Assessment of the effect of local radiotherapy on systemic response to 
pembrolizumab 
Hypothesis: Local radiotherapy will significantly improve the overall response rate 
according to iRECIST  
 
 

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3.2 
Secondary Objectives & Hypotheses 
(1) Objective: Assessment of the effect of local radiotherapy on different response criteria 
to pembrolizumab 
Hypothesis: Local radiotherapy will tend to improve: 
• Response rate according to RECIST 
• changes of (not irradiated) target lesion  
• duration of response  
• progression free survival 
• overall survival 
 
(2) Objective: Assessment of safety and tolerability of the combination of pembrolizumab 
and radiotherapy 
Hypothesis: Local radiotherapy will not increase toxicity grade 3 or higher according to 
CTCAE 4.0 
3.3 
Exploratory Objective 
(1) 
Objective: Assessment of changes of the immunophenotype in peripheral blood after 
pembrolizumab without and with radiotherapy (longitudinal analysis) 
(2) 
Objective: Assessment of predictive value of PD-L1 in combination with tumor-
infiltrating lymphocytes 
 
4.0 BACKGROUND & RATIONALE 
4.1 
Background 
4.1.1 Pharmaceutical and Therapeutic Background 
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. 

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The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune responses, 
including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig superfamily 
member related to CD28 and CTLA-4 which has been shown to negatively regulate antigen 
receptor signaling upon engagement of its ligands (PD-L1 and/ or PD-L2). 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 cancer. 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 been approved by the US Food and Drug 
Administration (FDA) and the European Medicines Agency (EMA) for the treatment of 
patients with unresectable or metastatic melanoma and disease progression following 
ipilumumab and, if BRAF V600 mutation positive, a BRAF inhibitor and PD-L1 expressing 
non-small cell lung cancer (NSCLC) after first line chemotherapy. Recently, pembrolizumab 
200mg fixed dose administered every three weeks was approved in HNSCC by the FDA. 

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4.1.2 Preclinical and Clinical Trial Data 
4.1.2.1 Current treatment of metastatic head and neck squamous cell carcinoma 
Head and neck squamous cell cancer (HNSCC) is the 7th most common cancer worldwide. The 
current standard of care for palliative chemotherapy of metastatic HNSCC is a platinum 
combination mostly combined with cetuximab. The addition of cetuximab to cisplatin and 5-
fluorouracil was the most recent treatment change in metastatic HNSCC (EXTREME trial)1. 
But despite a high overall response rate of 36% and disease control rate of 81% median overall 
survival with this scheme is only 10 months. A further intensification with the addition of 
docetaxel did not improve treatment results (CEFCID trial)2. In a phase II trial the combination 
of cisplatin, docetaxel and cetuximab was safer and also seems to be effective3. This scheme 
is currently studied in the ongoing phase III TPExtreme trial (NCT02268695). In second line 
treatment methotrexate or taxanes are frequently used. Second line treatment with 
methotrexate alone or in combination with 5FU shows a median overall survival of only 
approximately 7 months4,5. The median overall survival of second line docetaxel is also only 
6 months6. New agents as the tyrosine kinase inhibitor gefitinib or the PI3-kinase inhibitor PX-
866 failed to improve treatment results4-6. 
4.1.2.2 Pembrolizumab in different tumor entities 
The strategy of releasing a suppressed immune reaction was successful in several tumor 
entities. As mentioned above pembrolizumab has been approved by the FDA and EMA for 
metastatic melanoma and PD-L1 NSCLC. The most important clinical trials are shown in table 
1. 
 
 

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Table 1: Most important clinical trials with pembrolizumab. 
Trial 
Entity 
Treatment 
Patients 
ORR 
Survival 
Response 
duration 
KEYNOTE-
001 
(Garon et al7) 
NSCLC 
Pem (2 or 10 
mg/kg in q2w 
or q3w) 
495 
19.4% 
Median 
OS: 12.0 
mo. 
Median: 
12.5 mo. 
KEYNOTE-
002 
(Ribas et al8) 
Melanoma 
after Ipi. / 
BRAFi 
Pem 2mg/kg 
vs. Pem 
10mg/kg vs. 
investigators 
choice 
chemotherapy 
180 / 
181 / 
179 
21% / 
25% / 
4% 
6-mo. 
PFS: 
34% / 
38% / 
16 % 
Median: 
not 
reached 
KEYNOTE-
006 
(Robert et al9) 
Melanoma Pem 10mg/kg 
q2w vs. q3w 
vs. Ipi. 
279 / 
277 / 
278 
33.7% / 
32.9% / 
11.9% 
OS 1year: 
74.1% / 
68.4% / 
58.2% 
Ongoing 
(FU 8mo) 
89%/97% 
/ 88% 
KEYNOTE-10 
(Herbst et al10) 
PD-L1+ 
NSCLC 
after 
platinum 
Pem 2mg/kg 
vs. Pem 
10mg/kg vs. 
Docetaxel 
344 / 
346 / 
343 
18% / 
18% / 
9% 
Median 
OS: 
10.4 mo. / 
12.7 mo. / 
8.3 mo. 
Median: 
n.r. / 
n.r./ 
8 mo. 
NCT02267603 
(Nghiem et 
al11) 
Merkel 
cell 
carcinoma 
Pem 2mg/kg 
q3w 
26 
56% 
PFS 
6 mo.: 
67% 
Range 
>2-7 mo. 
KEYNOTE-12 
(Muro et al12) 
PD-L1+ 
Gastric 
Cancer 
Pem 2mg/kg 
q2w 
39 
22% 
- 
Median: 
9.2 mo. 
KEYNOTE-12 
(Seiwert et 
al13) 
HNSCC 
Pem 200mg 
fix dose q3w 
132 
24,8% 
- 
Range 
>2-6 mo. 
 
In the large clinical trials in NSCLC and melanoma despite low objective response rates 
between 18% and 33%, overall survival improved significantly7-9.This is based on the finding 
that if a response appears, it is a long-lasting response. This observation has also been made 
with other immune therapies.  
4.1.2.3 Pembrolizumab in head and neck squamous cell carcinoma (HNSCC) 
Recently, in the KEYNOTE-12 clinical trial pembrolizumab was also effective in second line 
therapy of metastatic HNSCC. In this trial with 132 patients, the overall response rate to 
pembrolizumab was 24.8% and further 24.8% had stable disease. In interpreting these results, 

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it has to be considered, that 59.1% of the patients had at least two prior therapies. Interestingly, 
the responses to pembrolizumab were durable, with 86% of the patients still responding at the 
time point of the interim analysis (median follow-up duration 5.7 months)13. The similar PD-
1 inhibitor nivolumab was tested in the CHECKMATE-141 trial as second line therapy against 
investigator’s choice of chemotherapy. After 361 randomized patients this study was stopped 
because the PD-1 inhibitor significantly improved OS after 12 months from 16.6% to 36.0%. 
Interestingly, this overall survival benefit is based on a low overall response rate of only 13.3% 
and a stable disease in 22.9% of the patients14. Similar trials with pembrolizumab in second 
line (KEYNOTE-040/NCT02252042 or KEYNOTE-55/NCT02255097) and even first line 
therapy are currently ongoing (KEYNOTE-48/NCT02358031). Recently, Pembrolizumab has 
been approved in HNSCC by the FDA. 
4.1.2.4 The medical challenge 
It is generally assumed, that an improvement of the response rate will directly result in a further 
improvement of OS. Based on this assumption, pembrolizumab is combined with different 
agents in several clinical trials with the aim to improve the response rate. Most recent strategies 
are combinations of pembrolizumab with a histone deacetylase inhibitor, a bruton kinase 
inhibitor or even oncolytic viruses (NCT02538510, NCT02454179, NCT02626000). In a 
clinical trial with the other PD-1 inhibitor nivolumab in metastatic melanoma the combination 
with the CTLA-4 antibody ipilimumab increased the response rate to 57.6%. But with this 
treatment 68.7% of the patients suffered treatment related toxicities grade 3 or 4 15. Especially 
in the palliative setting, such severe toxicities should be avoided in respect of quality of life. 
Thus the current medical challenge is to find a combination treatment partner for PD-1 
inhibitors to improve the response rate without a severe increase of toxicity.  
 
4.2 
Rationale 
4.2.1 Rationale for the Trial  
4.2.1.1 Abscopal effects of radiotherapy combined with immune therapy 
Combination of radiotherapy with pembrolizumab is currently studied in locally advanced 
HNSCC (NCT02609503, NCT02586207) and in re-irradiations (NCT02289209) with the aim 
to improve local tumor control. But radiotherapy not only kills tumor cells, but also changes 
the tumor cell phenotype and the tumor microenvironment, which might result in induction of 
anti-tumor immune responses16. The latter act locally on the irradiated tumor and systemically 
on non-irradiated tumor masses, the so called “abscopal effect” of radiotherapy17. These 
systemic effects of local radiotherapy mostly occur in combination with further immune 
modulation18 and have already been reported in patients in combination with anti-CTLA-4 
therapy in different tumor entities19-21. In a retrospective analysis of 21 melanoma patients with 
progression under anti-CTLA-4, radiotherapy re-induced a systemic treatment response in 

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more than half of the patients22. This was not dependent of the location of the irradiated 
metastasis. In another retrospective clinical analysis of patients treated with CTLA-4 blockade 
shrinkage of not irradiated index lesions occurred more frequently if radiotherapy and 
immunotherapy was administered within 3 months compared to longer time intervals23 . 
Furthermore, in a prospective clinical trial with radiotherapy and granulocyte-macrophage 
colony-stimulating factor, systemic effects of local radiotherapy (10x3,5Gy) were achieved in 
11 of 41 patients with different solid tumors24. 
4.2.1.2 Upregulation of Programmed cell death ligand 1 (PD-L1) by radiotherapy 
PD-L1 is the ligand of PD-1 and can be found on cancer cells and immune cells. In a meta-
analysis of different tumor entities high cancer cell PD-L1 expression was associated with an 
improved response rate to pembrolizumab25. In the CHECKMATE-141 trial in HNSCC the 
PD-1 inhibitor nivolumab especially improved overall survival in the PD-L1 positive 
subgroup14. In vitro radiotherapy induces an up-regulation of PD-L126 (and own unpublished 
data). This up-regulation has recently been confirmed in cancer patients, when PD-L1 status 
was compared before and after radiotherapy27,28. In preclinical experiments fractionated 
radiotherapy induced a stronger up-regulation of PD-L1 than a single high dose (own 
unpublished data). The maximal increase of PD-L1 was detected three days after fractionated 
radiation in vitro26. 
4.2.1.3 Radiotherapy and PD-1/ PD-L1 pathway blockade in vitro 
In preclinical experiments the combination of radiotherapy and PD-1/ PD-L1 pathway 
blockade improved local tumor control26,29,30. But this combination also induced systemic 
tumor immunity. Consequently, metastases distant from the irradiated tumor responded after 
radiotherapy and the survival rate of the animals improved26,29. Thus, local radiotherapy, acting 
as in situ vaccination, is probably able to improve the response rate to pembrolizumab in 
recurrent and/ or metastatic HNSCC. 
4.2.1.4 Fractionation of radiotherapy 
As mentioned above, PD-L1 expression increases especially after fractionated radiation. In 
preclinical models the combination of CTLA-4 blockade induced more abscopal effects with 
fractionated radiotherapy compared to the application of one single high radiation dose31. 
Clinical analyses of patients treated with radiotherapy and CTLA-4 blockade revealed that 
radiation doses up to 3Gy more frequently induce abscopal effects than higher doses32. In a 
prospective clinical trial with radiotherapy and granulocyte-macrophage colony-stimulating 
factor, systemic effects of fractionated radiotherapy with 10x3,5Gy were induced in 11 of 41 
patients24. Thus in this trial a radiotherapy with 12 fractions of 3Gy (cumulative dose 36Gy) 
was chosen. This is a clinical standard dose for palliative radiotherapy of bone, lymphatic node 
or soft tissue metastases. This dose can also easily be delivered to organ metastases in lung, 
liver or the adrenal glands with a stereotactic technique and organ motion management. 

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4.2.1.5 Timing of radiotherapy and pembrolizumab administration 
To achieve a maximal immune stimulation after radiotherapy the timing of the administration 
of pembrolizumab must be critically reviewed. In a clinical analysis overall survival was best 
if a radiotherapy and immune therapy with CTLA-4 blockade was administered 
concomitantly33. Regarding the timing of PD-1 inhibitors only preclinical analyses exist. PD-
L1 expression peaked three days after fractionated radiation (5x2 Gy)26. In a preclinical setting 
survival of tumor bearing mice was better when PD-1/ PD-L1 blockade was administered 
during radiotherapy compared to after radiotherapy. Application with the first radiation 
showed a slight advantage compared to application with the last radiation26. Taken together, 
current preclinical and first clinical data indicate the best immune stimulating effect for early 
concomitant administration of the immune stimulating agent. Consequently, in this trial 
pembrolizumab is administered after the third fraction of radiotherapy consisting of altogether 
12 fractions. As radiotherapy always starts on Wednesday, after the administration of 
pembrolizumab will always be two days without radiotherapy (Saturday and Sunday). This 
ensures that radiotherapy does not impede the initiation of anti-tumor immunity.  
 
4.2.2 Rationale for pembrolizumab Dose Selection/ Regimen/ Modification  
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W).  Based 
on the totality of data generated in the Keytruda development program, 200 mg Q3W is the 
appropriate dose of pembrolizumab for adults across all indications and regardless of tumor 
type.  As outlined below, this dose is justified by: 
• Clinical data from 8 randomized studies in melanoma and NSCLC indications 
demonstrating flat dose- and exposure-efficacy relationships from 2 mg/kg Q3W to 10 
mg/kg  Q2W, representing an approximate 5- to 7.5-fold exposure range (refer to IB, 
Section 5.2.2) 
• Population PK analysis showing that both fixed dosing and weight-based dosing 
provides similar control of PK variability with considerable overlap in the distributions 
of exposures, supporting suitability of 200 mg Q3W 
• Clinical data showing meaningful improvement in benefit-risk including overall 
survival at 200 mg Q3W across multiple indications, and 
• Pharmacology data showing full target saturation in both systemic circulation (inferred 
from pharmacokinetic [PK] data) and tumor (inferred from physiologically-based PK 
[PBPK] analysis) at 200 mg Q3W 
 

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4.2.3 Rationale for Endpoints 
4.2.3.1 Efficacy Endpoints 
The primary endpoint of this clinical trial is overall response rate according to iRECIST. In the 
large clinical trials in NSCLC and melanoma despite low objective response rates between 
18% and 33%, overall survival improved significantly7-9. This is based on the finding that if a 
response appears, it is a long-lasting response. Consequently, the occurrence of a response is 
crucial for the further prognosis of a patient. Thus, the overall response rate seems to be a 
reasonable primary endpoint for this phase II clinical trial. The irradiated tumor lesion(s) will 
be excluded from the iRECIST evaluation. The response rate according to RECIST 1.1 criteria 
is a secondary endpoint of the trial. Further secondary endpoints are other parameters of a 
successful treatment as changes of (not irradiated) target lesion, duration of response, 
progression-free survival and overall survival. 
4.2.3.2 Safety endpoints 
Another aim of the trial is the assessment of safety and tolerability of the combination of 
pembrolizumab and radiotherapy. Consequently, this was chosen as a secondary endpoint. It 
is expected that local radiotherapy with pembrolizumab will not increase toxicity grade 3 or 
higher according to CTCAE 4.0 compared to the control arm with pembrolizumab only. In an 
interim analysis of an ongoing trial in which pembrolizumab was combined with 
chemoradiotherapy for locally advanced head and neck cancer, no increased toxicity was 
reported34. The current trial focuses both on the overall toxicity grade 3 or higher and on some 
special subsets. Both radiotherapy and pembrolizumab can cause pneumonitis. Consequently, 
pneumonitis grade 2 and pneumonitis grade 3 or higher will be compared separately in both 
arms. Pembrolizumab may also increase the severity of radiation dermatitis. Thus, skin toxicity 
is also evaluated separately as grade 2 toxicity and as grade 3 or higher toxicity in both arms. 
4.2.3.3 Biomarker Research 
See translational research 11.0. 
 
4.2.4 Risk-benefit analysis 
Currently, first line treatment of recurrent and/ or metastatic HNSCC consists of platinum-
based chemotherapy in combination with 5-fluorouracil and cetuximab1. In second line therapy 
taxanes or methotrexate are frequently used. The response rates to these treatments are below 
10% and the median overall survival is approximately 7 months4-6. In a phase 1 study with 
pembrolizumab 132 patients were included of whom 81.8% had at least one and 59.2% at least 
two prior therapies. In these heavily pretreated patients pembrolizumab achieved an overall 
response rate of 24.8% and further 24.8% had stable disease. The most common adverse events 

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(AE) (any grade) were fatigue (15.2%), hypothyroidism (9.1%), decreased appetite (7.6%) and 
rash (7.6%). Severe adverse (grade 3-5) events appeared in 9.8% of the patients. Thus 
pembrolizumab seems to be a new effective and safe drug for the treatment of recurrent and/or 
metastatic HNSCC. The other PD-1 inhibitor Nivolumab already improved significantly OS 
in second line therapy of metastatic HNSCC in another randomized clinical trial14. Clinical 
trials with the aim of the FDA approval of pembrolizumab in second line therapy are currently 
ongoing (KEYNOTE-040/NCT02252042 or KEYNOTE-55/NCT02255097).  
At ESMO 2018 the results of the randomized phase III KEYNOTE-48 trial (ESMO 2018, 
LBA8_PR, Burtness et al.) were presented for the patients with PD-L1 CPS≥1. In this cohort 
pembrolizumab was superior to standard treatment with platinum-based chemotherapy 
(EXTREME scheme) regarding overall survival. Furthermore, AEs were much lower in the 
pembrolizumab group. Consequently, the study protocol was amended (amendment 1), that 
patients with CPS≥1 can be included without prior platinum-based therapy. 
In clinical routine radiotherapy is frequently used in patients with symptomatic metastases. 
Furthermore, radiotherapy is first line treatment for brain metastases, spinal cord compression 
and bone metastases35. Radiotherapy is also safe and effective in the treatment of single lung, 
liver or adrenal metastases36-38. Radiotherapy of metastases in these locations is frequently 
performed in an oligometastatic situation in order to improve systemic tumor control39,40. In 
this study only metastases that will perspectively require radiation will be treated. These can 
be either metastases that are highly suspected to cause symptoms in the near future or 
metastases in an oligometastatic situation in order to improve systemic tumor control. 
Radiotherapy of brain metastases is not allowed in this study as this frequently requires a 
different dose or fractionation. In clinical routine radiotherapy is frequently performed during 
a PD-1 inhibitor treatment e.g. for melanoma or lung cancer without a defined fractionation or 
timing scheme. So far, no increase of toxicity has been reported. In this study the frequently 
used and easy to deliver treatment scheme of 12 fractions of 3 Gy will be used. As described 
in detail above, radiotherapy not only acts locally on the irradiated tumor but can also act 
systemically, the so called “abscopal effect” of radiotherapy17. Especially the predictive marker 
for anti-PD-1 treatment response PD-L125 is increased after radiotherapy26-28. In preclinical 
experiments the combination of local radiotherapy and PD-1/PD-L1 pathway blockade 
improved systemic tumor control26,29. Thus local radiotherapy, acting as in situ vaccination is 
probably able to improve the response rate to pembrolizumab in recurrent and/ or metastatic 
HNSCC. 
 

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5.0 METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 Diagnosis/ Condition for Entry into the Trial 
Patients with recurrent and/ or metastatic HNSCC after progression to first or any second line 
chemotherapy can be included in this trial. 
 
5.1.2 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Be willing and able to provide written informed consent/ assent for the trial. 
2. Be ≥ 18 years of age on day of signing informed consent. 
3. Metastatic HNSCC or metastatic squamous cell CUP (carcinoma of unknown 
primary) of the neck  (at least two distinct lesions: Lesion planned for radiotherapy 
with ≥2ml tumor volume, or ≥3 lesions: 1 lesion planned for radiotherapy with ≥2ml 
tumor volume or 2 lesions planned for radiotherapy with a cumulative tumor volume 
≥2ml) 
AND/ OR 
Locally recurrent HNSCC not suitable for curative local treatment within or outside 
the previously irradiated tissue (at least two distinct lesions: Lesion planned for 
radiotherapy with ≥2 ml tumor volume, or ≥3 lesions: 1 lesion planned for 
radiotherapy with ≥2 ml tumor volume or 2 lesions planned for radiotherapy with a 
cumulative tumor volume ≥2ml).  
 
At least in one of these lesions must be a need for radiotherapy in near future (as 
defined in inclusion criterion 4). 
 
4. Need for radiotherapy in near future as defined in the following. At least one of the 
following criteria must be fulfilled: 
• Primary tumor causing mild pain or swallowing problems 
• Lymph node or soft tissue metastasis with distance less than 1 cm to the skin 
(radiotherapy to prevent weeping tumor infiltration of the skin or fistula)  
• Bone metastases causing mild pain (without risk of fracture) 
• Lung metastases, lymph node metastases, liver metastases or adrenal gland 
metastases with a diameter above 1 cm in an oligometastatic situation (defined 
as a maximum of 5 tumor lesions) 
• Lung metastases or mediastinal lymph node metastases causing hemoptysis or 
permanent severe dry cough 

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• Lung metastases or mediastinal lymph node metastases close to trachea or 
main bronchus (radiotherapy to prevent tumor infiltration and bleeding) 
• Liver metastases causing intrahepatic bile duct obstruction. 
 
5. Progression after first line platinum-based or any second/ third line chemotherapy  
OR 
Progression within 6 months after platinum-based radiochemotherapy of locally 
advanced disease 
OR 
First line treatment if PD-L1 CPS (combined positive score) ≥1. 
 
6. Histological confirmation of HNSCC or squamous cell CUP (carcinoma of unknown 
primary) of the neck. 
7. Have at least one measurable lesion according to iRECIST that receives less than 10% 
of the prescribed dose of the irradiated lesion(s) (not considering doses from previous 
radiotherapy). 
8. Have a performance status of 0-1 on the ECOG Performance Scale. 
9. Demonstrate adequate organ function as defined in table 2, all screening labs should be 
performed within 10 days of treatment initiation.  
Table 2: Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute 
neutrophil 
count 
(ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L 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 
 
Direct bilirubin ≤ ULN for subjects with total 
bilirubin levels > 1.5 ULN 
AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR 

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≤ 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. A 
highly sensitive pregnancy test must be used. 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 (Section 5.7.2) must be willing to use a highly 
effective contraceptive measure as defined in the Clinical Trial Facilitation Group 
(CTFG) guideline (“Recommendations related to contraception and pregnancy testing 
in clinical trials.”) For details see Section 5.7.2 of the study protocol. Highly effective 
contraception is required for the course of the study through 120 days after the last dose 
of study medication. 
12. Generative male subjects (Section 5.7.2) must agree to use a highly effective method 
of contraception as outlined in Section 5.7.2- Contraception, starting with the first dose 
of study therapy through 120 days after the last dose of study therapy. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject. 
 
5.1.3 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. 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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2. Has need for palliative radiotherapy for symptomatic metastases. This includes the 
following situations:  
• New or progressive central nervous system metastases 
• Metastases causing significant pain 
• Instable bone metastases 
• Lung metastases or mediastinal lymph node metastases with active bleeding 
 
Other metastases that require prompt radiotherapy in the opinion of the investigator.  
3. Has only a tumor lesion perspectively requiring re-irradiation after prior radiotherapy 
less than three months ago. 
4. 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. 
 
5. Has a known history of active TB (Bacillus Tuberculosis). 
 
6. Hypersensitivity to pembrolizumab or any of its excipients. 
7. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study 
day 1 or who has not recovered (i.e., ≤ grade 1 or at baseline) from AEs due to agents 
administered more than 4 weeks earlier, with the exception of Cetuximab (here only a 
2 weeks intermission is required)  
8. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks prior to study day 1 or who has not recovered (i.e., ≤ grade 1 or at 
baseline) from AEs 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.  
9. Has known history or concurrent other malignancy. Exceptions include patients, who 
have been disease free for at least five years. Further exceptions are completely resected 
basal cell carcinoma or squamous cell carcinoma of the skin or successfully treated in 
situ carcinoma.  
10. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Subjects with previously treated brain metastases may participate provided 

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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.  
11. 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 (e.g., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form 
of systemic treatment.  
12. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required 
steroids or has current pneumonitis/interstitial lung disease. 
13. Has an active infection requiring systemic therapy. 
14. 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.  
15. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
16. 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. 
17. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent (One 
single administration of an anti-PD1, anti-PD-L1 or anti-PD-L2 agent as induction 
treatment in locally advanced disease is no exclusion criteria).  
18. Has a known history of human immunodeficiency virus (HIV) (HIV ½ antibodies). 
19. Has known active hepatitis B (e.g., HbsAg reactive) or hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
20. Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first 
dose of study drug.  Administration of killed vaccines is allowed. 
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. 

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21. Have a performance status of ≥2 on the ECOG Performance Scale. 
 
 
5.2 
Trial Treatments 
The treatment to be used in this trial is outlined below in table 3 
Table 3: Trial Treatment 
Drug 
Single 
dose 
Frequency / 
Cumulative 
dose 
Route of 
Administ-
ration 
Time 
schedule 
Use 
Pembrolizumab 200 
mg 
Q3W 
IV infusion* 
Day 3 of 
radiotherap
y (Friday), 
Q3W 
Experimental 
Radiotherapy 
3Gy 
5 days per 
week / 
36Gy 
percutaneous 
Day 1 on 
Wednesday 
clinical standard 
for symptomatic 
tumor lesions and 
oligometastatic 
situation 
*Pembrolizumab should be administered as IV infusion over 30 minutes. 
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 Treatment with pembrolizumab 
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.  
Details on preparation and administration of pembrolizumab (MK-3475) are provided in the 
Investigator’s Brochure (IB) for the investigational medicinal product or in the Summary of 
medicinal Product Characteristics (SmPC) for the authorized product.  

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5.2.1.2 Dose Modification and toxicity management for immune-related AEs 
associated with pembrolizumab and combination therapy 
AEs associated with pembrolizumab exposure, including coadministration with additional 
compounds, may represent an immunologic aetiology. These immune-related AEs (irAEs) 
may occur shortly after the first dose or several months after the last dose of 
pembrolizumab/combination treatment and may affect more than one body system 
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications.  Based on existing clinical study data, most irAEs were reversible and could 
be managed with interruptions of pembrolizumab/combination treatment, administration of 
corticosteroids and/or other supportive care. For suspected irAEs, ensure adequate evaluation 
to confirm etiology or exclude other causes. Additional procedures or tests such as 
bronchoscopy, endoscopy, skin biopsy may be included as part of the evaluation. Dose 
modification 
and 
toxicity 
management 
guidelines 
for 
irAEs 
associated 
with 
pembrolizumab/combination treatment are provided in Table 4. 
 

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Table 4: Dose modification and toxicity management guidelines for immune-related AEs associated with pembrolizumab 
monotherapy and IO Combinations  
General instructions: 
1. Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should 
begin if the irAEs are not controlled by corticosteroids. 
2. Study intervention must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not ≤10 mg/day within 12 weeks of 
the last study intervention treatment.  
3. The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks. 
4. If study intervention has been withheld, study intervention may resume after the irAE decreased to ≤ Grade 1 after corticosteroid taper. 
 
irAEs 
Toxicity 
Grade 
(CTCAE v5.0) 
Action With 
Pembrolizumab 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
Pneumonitis  
Grade 2 
Withhold  
•  Administer corticosteroids (initial dose of 
1 to 2 mg/kg prednisone or equivalent) 
followed by taper 
•  Add prophylactic antibiotics for 
opportunistic infections 
•  Monitor participants for signs and symptoms of 
pneumonitis 
•  Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment 
 
Recurrent 
Grade 2,  
Grade 3 or 4  
Permanently 
discontinue 
Diarrhea/Colitis  
Grade 2 or 3 
Withhold 
•  Administer corticosteroids (initial dose of 
1 to 2 mg/kg prednisone or equivalent) 
followed by taper 
•  Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, 
blood or mucus in stool with or without fever) 

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irAEs 
Toxicity 
Grade 
(CTCAE v5.0) 
Action With 
Pembrolizumab 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
Recurrent 
Grade 
3 
or 
Grade 4 
Permanently 
discontinue 
 
and of bowel perforation (ie, peritoneal signs 
and ileus) 
•  Participants with ≥Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis 
•  Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids. If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion 
AST or ALT 
Elevation 
or 
Increased 
Bilirubin 
Grade 2 a 
Withhold 
•  Administer corticosteroids (initial dose of 
0.5 to 1 mg/kg prednisone or equivalent) 
followed by taper 
•  Monitor with liver function tests (consider 
weekly or more frequently until liver enzyme 
value returned to baseline or is stable) 
Grade 3 b or 4 c 
Permanently 
discontinue 
•  Administer corticosteroids (initial dose of 
1 to 2 mg/kg prednisone or equivalent) 
followed by taper 
T1DM 
or 
Hyperglycemia 
New 
onset 
T1DM 
or  
Grade 3 or 4 
hyperglycemia 
Withhold d 
•  Initiate insulin replacement therapy for 
participants with T1DM 
•  Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes 

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irAEs 
Toxicity 
Grade 
(CTCAE v5.0) 
Action With 
Pembrolizumab 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
associated with 
evidence 
of 
β-cell failure 
•  Administer antihyperglycemic in 
participants with hyperglycemia 
 
Hypophysitis 
Grade 2 
Withhold 
•  Administer corticosteroids and initiate 
hormonal replacements as clinically 
indicated 
•  Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal 
insufficiency) 
Grade 3 or 4 
Withhold 
or 
permanently 
discontinue d 
Hyperthyroidism 
Grade 2 
Continue 
•  Treat with nonselective beta-blockers 
(eg, propranolol) or thionamides as 
appropriate 
•  Monitor for signs and symptoms of thyroid 
disorders 
Grade 3 or 4 
Withhold 
or 
permanently 
discontinue d 
Hypothyroidism 
Grade 2, 3 or 4 
Continue 
•  Initiate thyroid replacement hormones 
(eg, levothyroxine or liothyronine) per 
standard of care 
•  Monitor for signs and symptoms of thyroid 
disorders 
Nephritis: 
grading 
according 
to 
increased 
creatinine 
or 
acute 
kidney 
injury 
Grade 2 
Withhold 
•  Administer corticosteroids (prednisone 1 
to 2 mg/kg or equivalent) followed by 
taper 
•  Monitor changes of renal function 
Grade 3 or 4 
Permanently 
discontinue 

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irAEs 
Toxicity 
Grade 
(CTCAE v5.0) 
Action With 
Pembrolizumab 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
Neurological 
Toxicities 
Grade 2 
Withhold 
•  Based on severity of AE administer 
corticosteroids 
•  Ensure adequate evaluation to confirm etiology 
and/or exclude other causes 
Grade 3 or 4 
Permanently 
discontinue 
Myocarditis 
Grade 1 
Withhold 
•  Based on severity of AE administer 
corticosteroids 
•  Ensure adequate evaluation to confirm etiology 
and/or exclude other causes 
 
Grade 2, 3 or 4 
Permanently 
discontinue 
Exfoliative 
Dermatologic 
Conditions 
Suspected SJS, 
TEN, or DRESS 
Withhold 
•  Based on severity of AE administer 
corticosteroids 
•  Ensure adequate evaluation to confirm etiology 
or exclude other causes 
Confirmed SJS, 
TEN, or DRESS 
Permanently 
discontinue 
All Other irAEs 
Persistent Grade 2 Withhold 
•  Based on severity of AE administer 
corticosteroids 
•  Ensure adequate evaluation to confirm etiology 
or exclude other causes 
Grade 3 
Withhold 
or 
discontinue based 
on the event e  
Recurrent 
Grade 3 
or 
Grade 4  
Permanently 
discontinue 
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug 
Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; 
T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal. 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 
a AST/ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal;  
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal 
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if baseline normal; >3.0 to 10.0 x baseline 
if baseline abnormal 

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irAEs 
Toxicity 
Grade 
(CTCAE v5.0) 
Action With 
Pembrolizumab 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal;  
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal 
d The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. If control achieved or ≤ Grade 2, 
pembrolizumab may be resumed. 
e Events that require discontinuation include, but are not limited to: encephalitis and other clinically important irAEs. 
 
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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5.2.2 Treatment with Radiotherapy 
5.2.2.1 Technical factors of Radiotherapy 
Radiotherapy can be performed as three-dimensional radiotherapy (3D-RT), intensity-
modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT) or stereotactic 
radiotherapy (SRT). Megavolt equipment of 6 MeV or 12 MeV is essential. A multi-leaf 
collimator is necessary to allow customized blocking and intensity modulation, if necessary. 
The radiotherapy technique is chosen by the treating radiation oncologist depending on the 
anatomical location of the metastasis.  
5.2.2.2 Immobilization and planning CT scan 
The use of positioning devices depends on the treated anatomical region. Radiotherapy of 
tumor lesions in the head-and-neck region requires an individual rigid immobilization mask or 
equal non-rigid immobilization devices. A treatment planning CT scan is essential for defining 
the target volume. The use of intravenous contrast agent is recommended, but not essential. 
The CT scan slice thickness should not exceed 5mm. For the CT scan and radiotherapy the 
patient must be in the same position and use the same immobilization device. All anatomical 
areas receiving any irradiation must be included in the CT scan. In case of metastases in 
moving organs as lung or liver, repeated CT scans in the different breathing phases or a 4D-
CT scan with a continuous breathing detection has to be performed. 
5.2.2.3 Target volumes 
One, two or three tumor lesions with a total tumor volume of at least 2ml, which can easily be 
reached, will be irradiated. If possible, the irradiated tumor volume should be ≥5ml.  
Metastases in bones, muscles, subcutaneous tissue, lymphatic nodes, lung, liver or adrenal 
glands that will perspectively require radiotherapy can be treated. These can be either 
metastases that are highly suspected to cause symptoms in the near future or metastases in an 
oligometastatic situation in order to improve systemic tumor control (see definition in inclusion 
criterion 4). Radiotherapy of other metastases may be possible after consultation of the leading 
center. Radiotherapy of brain metastases is not allowed in this protocol, as this frequently 
requires different doses or fractionations. The gross tumor volume (GTV) should be outlined 
an all appropriate CT slices. If necessary, image fusion of additional imaging (e.g. MRI) should 
be used. The clinical target volume (CTV) consist of the GTV with a 3 mm anatomically 
adapted margin not reaching into cavities and uninvolved bony structures. An additional safety 
margin is required to generate the planning target volume (PTV) depending on the anatomical 
location, the used immobilization device, respiration induced movements of the CTV, and the 
employed verification system at the linear accelerator. In most cases, margins of 3-7 mm are 
adequate. In case of significant respiratory movements of the CTV, an internal target volume 
(ITV) should be shaped based on a 4D CT to generate the PTV. Alternatively, moving target 
can be irradiated by using respiratory gating of tracking techniques. Relevant organs at risk are 
contoured depending on the anatomical region. 

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5.2.2.4 Dose prescription and dose specification of Radiotherapy 
Radiotherapy will be performed conventionally fractioned with daily single doses of 3Gy to 
36Gy over approximately two and a half weeks. Radiation dose will be defined at the ICRU 
50 reference point. The isodose curve representing the 95% of the prescribed dose must include 
the entire PTV. Local dose maxima should not exceed 120%. 
5.2.2.5 Dose modification of Radiotherapy 
In this trial radiotherapy is used to induce dying tumor cells acting as in situ vaccination. If 
any radiotherapy related toxicity greater than grade 2 occurs, radiotherapy is stopped and not 
continued after toxicity resolved. Pembrolizumab will be continued as usual. 
5.2.2.6 Documentation requirements and portal films 
On the first day of radiotherapy portal image of each field or orthogonal images that localize 
the isocenter placement must be obtained. Treatment plans with isodoses, dose volume 
histograms (DVH) of the target volumes and critical risk organs are obligate for planning. 
Weekly positioning controls of the patients are essential. Image guided radiotherapy (IGRT) 
with daily positioning controls is possible, but not necessary. Radiotherapy documentation has 
to be stored for at least 30 years according to the German regulation for radiation protection 
(Strahlenschutzverordnung, StrlSchV § 85 Abs. 3). 
5.2.2.7 Critical normal structures and adverse events of radiotherapy 
The critical normal structures depend on the anatomical location of the metastasis. In the 
following the most common AEs are described for different anatomical regions. Acute side 
effects are usually transient and resolve within a few weeks following radiotherapy: 
Table 5: Possible acute adverse effects of radiotherapy (adapted from Wannemacher et al.41): 
Radiation dermatitis 
In the treatment of tumor lesions close to the skin, radiation 
dermatitis can appear. There is a range from erythema to weeping 
skin eczema. 
Mucositis 
Radiotherapy in the head-and-neck region can induce mucositis. A 
secondary oral thrush is possible. 
Dysphagia 
Radiotherapy in the head-and-neck mediastinal area can induce 
dysphagia. 
Pneumonitis 
Intrathoracic radiotherapy can induce pneumonitis with coughing, 
dyspnea or fever. A bacterial superinfection is possible. 
Diarrhea 
Abdominal radiotherapy can induce meteorism and diarrhea. Severe 
complications as ileus or bowl perforation are extremely rare. 
Cystitis 
Pelvic radiotherapy can induce cystitis with painful urination. 
Chronic AEs may appear later than three months after radiotherapy: 

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Table 6: Possible late adverse effects of radiotherapy (adapted from Wannemacher et al.41): 
Fibrosis 
Fibrosis can affect skin, subcutaneous tissue or muscles and lead to 
limited mobility and loss of strengths.  
Pulmonary fibrosis 
Pulmonary fibrosis can be a late complication of pneumonitis. Local 
fibroses are asymptomatic in most of the cases. Severe pulmonary 
fibroses requiring oxygen therapy are extremely rare. 
Lymphedema 
After radiotherapy of axillary, cervical or inguinal lymph nodes a 
lymphedema may appear. 
Impaired 
wound 
healing 
In irradiated areas wound healing can be impaired after injuries or 
surgical procedures. 
Renal insufficiency 
Radiotherapy induced renal insufficiency is extremely rare. 
Hepatic 
insufficiency  
Hepatic insufficiency after radiotherapy of hepatic metastases is 
extremely rare. 
Bowl stenosis, ileus, 
fistula 
Abdominal radiotherapy can lead to irregular adhesions of intestinal 
loops. Severe complications as fistula or ileus are extremely rare. 
Heart 
failure, 
arrhythmia, 
heart 
attack 
Cardiac complications as heart failure, arrhythmia of heart attack are 
extremely rare. 
 
Depending on the anatomical region the following dose limits must be respected: 
Table 7: Dose limits for critical normal structures  (adapted from Wannemacher et al41 and 
Hristow et al42 that base on RTOG guidelines). Dose limits were approved by the DEGRO 
Expertenkommission.  
Patients without prior radiotherapy. Dose limits for normal structures for single doses 
of 2Gy. 
Spinal cord (no previous radiotherapy) 
Dmax < 45 Gy 
brainstem (no previous radiotherapy) 
Dmax < 54 Gy 
lung 
V20 < 30% 
liver 
V30 < 35% 
kidney 
V18 < 20% 
 
Patients without prior radiotherapy. Calculated dose limits for normal structures for 
single doses of 3Gy. Calculated with a α/β-value of 3. 
Spinal cord (no previous radiotherapy) 
Dmax < 37,5 Gy 
brainstem (no previous radiotherapy) 
Dmax < 45 Gy 

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lung 
V16 < 30% 
liver 
V25 < 35% 
kidney 
V15 < 20% 
 
Patients with prior radiotherapy. Dose limits for normal structures for single doses of 
2Gy. These dose limits must be adapted for the 3Gy single doses used in the trial and 
possibly differing single doses of a previous radiotherapy by the treating radiation 
oncologist. A α/β-value of 3 is recommended for the calculations.  
 
Interval <6 months: 
interval ≥6 months: 
Previously irradiated spinal cord  
Cumulative  
Dmax < 54Gy 
Cumulative  
Dmax <60Gy 
Previously irradiated brainstem  
Cumulative  
Dmax < 54Gy 
Cumulative  
Dmax < 60 Gy 
irradiated bones, peripheral nerves, and soft 
tissues 
Cumulative  
Dmax < 110 Gy 
Cumulative  
Dmax < 120 Gy 
Previously irradiated lung 
Cumulative V20 < 30% 
Previously irradiated liver 
Cumulative V30 < 35% 
Previously irradiated kidney 
Cumulative V18 < 20% 
 
5.2.3 Adverse events of radiotherapy combined with pembrolizumab 
There exist only few clinical studies focusing on the toxicity of the combination of radiotherapy 
and pembrolizumab. Due to the frequent clinical use of pembrolizumab and palliative radiation 
therapy in patients with metastatic melanoma and NSCLC outside clinical trials and the lack 
of reported cases with severe toxicities, this combination seems to be feasible. However, some 
toxicities are probably increased. The risk of pneumonitis is probably increased in the 
combination as both intrathoracic radiotherapy and pembrolizumab can induce pneumonitis. 
In patients with history of prior thoracic radiotherapy pneumonitis occurred more frequently 
(6.9%) than in patients without prior thoracic radiotherapy (2.9%) (IB edition 15). 
Furthermore, the risk of diarrhea might be increased if abdominal metastases are irradiated in 
combination with pembrolizumab. A frequent late toxicity of chemoradiation of locally 
advanced HNSCC is hypothyreoidism43. As also pembrolizumab can induce hypothyroidism, 
the risk is probably increased in patients with history of prior radiotherapy of locally advanced 
HNSCC. Recently severe skin reactions including Stevens-Johnson syndrome or toxic 
epidermal necrolysis have been described in patients treated with pembrolizumab. As also 
radiotherapy can cause radiation dermatitis, the risk could be increased in combined treatment. 
However, in a recent trial combining chemoradiation of locally advanced HNSCC (radiation 
dose 70Gy) with pembrolizumab, no increased risk of severe radiation dermatitis was 
reported34. 
 

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5.2.4 Timing of Administration of pembrolizumab and Radiotherapy 
Day 1 of the study with the first radiation will always be Wednesday. Pembrolizumab will be 
administered on day 3 of the study (Friday) after radiotherapy. Radiotherapy is continued the 
following Monday. This time schedule for radiotherapy and the first pembrolizumab dose must 
not be changed. Trial treatment should be administered after all procedures/ assessments have 
been completed as detailed on the Trial Flow Chart (Section 6.0). The following 
pembrolizumab doses may be administered up to 3 days before or after the scheduled Day 1 of 
each cycle due to administrative reasons. 
All trial treatments will be administered on an outpatient basis. 
Pembrolizumab 200 mg will be administered as a 30-minute IV infusion every 3 weeks. Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible. 
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). 
The IB/ SmPC contains specific instructions for the preparation of the pembrolizumab infusion 
fluid and administration of infusion solution. 
 
5.2.5 Trial Blinding/ Masking 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered. 
 
5.3 
Randomization or Treatment Allocation 
A written informed consent has to be signed by every patient. A total of 130 patients will be 
enrolled into the study. All patients fulfilling the inclusion and exclusion criteria will be 
randomized 1:1 into two groups. Every patient will receive a study number representing the 
study site and the consecutive number of randomized patients. Patients will be randomized to 
either arm A (pembrolizumab with radiotherapy) or arm B (pembrolizumab without 
radiotherapy).  
 
5.4 
Stratification 
Randomization will be stratified according the following criteria: 

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- 
Local recurrence versus metastatic disease 
- 
ECOG performance score 0 versus 1 
 
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 treatment or 
vaccination may be required. The investigator should discuss any questions regarding this with 
the Sponsor. The final decision on any supportive therapy or vaccination rests with the 
investigator and/ or the subject’s primary physician.  
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. 
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 Serious 
Adverse Events (SAEs) and Events of Clinical Interest (ECIs) as defined in Section 7.2. 
 
5.5.2 Prohibited Concomitant Medications/ Therapies 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase 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 
• Further radiation therapy (If a patient requires radiotherapy without tumor progression 
according to iRECIST criteria, he must be dropped from the treatment period of the 
study.)  

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• 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, Bacillus 
Calmette–Guérin (BCG), and typhoid vaccine.  
• Systemic glucocorticoids for any purpose other than to modulate symptoms from 
suspected immunological AEs (as defined in Section 5.6.1). 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 abort treatment in this trial. These 
patients are still included in the statistical analysis (intent-to-treat analysis). Subjects may 
receive other medications that the investigator deems to be medically necessary. 
The exclusion criteria describe 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 Supportive Care Guidelines pembrolizumab 
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 5.2.1.2, Table 4.  Where appropriate, these guidelines include the use of oral or IV 
treatment with corticosteroids, as well as additional anti-inflammatory agents if symptoms do 
not improve with administration of corticosteroids.  Note that several courses of steroid 
tapering may be necessary as symptoms may worsen when the steroid dose is decreased.  For 
each disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care.  The treatment 
guidelines are intended to be applied when the Investigator determines the events to be related 
to pembrolizumab.  
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the Investigator does not need to follow the treatment guidance (as outlined below).  Refer to 
Table 4 in Section 5.2.1.2 for guidelines regarding dose modification and supportive care.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.  
Table 8 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab (MK-3475).  

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Table 8: 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 participant is deemed medically stable in the opinion of the 
investigator. 
None 
Grade 2 
Requires 
therapy 
or 
infusion interruption but 
responds 
promptly 
to 
symptomatic 
treatment 
(e.g., 
antihistamines, 
NSAIDs, narcotics, IV 
fluids); 
prophylactic 
medications indicated for 
≤24 hrs 
Stop Infusion. 
Additional appropriate medical therapy may include but is not 
limited to: 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically indicated until 
the participant is deemed medically stable in the opinion of the 
investigator. 
If symptoms resolve within 1 hour of stopping drug infusion, 
the infusion may be restarted at 50% of the original infusion 
Participant may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of study intervention 
with: 
Diphenhydramine 50 mg po (or 
equivalent 
dose 
of 
antihistamine). 
Acetaminophen 500-1000 mg po 
(or equivalent dose of analgesic). 

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rate (e.g. from 100 mL/hr to 50 mL/hr).  Otherwise dosing will 
be held until symptoms resolve and the participant should be 
premedicated for the next scheduled dose. 
Participants who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued from 
further study drug intervention 
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 
asectomiz 
support 
indicated 
Stop Infusion. 
Additional appropriate medical therapy may include but is not 
limited to: 
Epinephrine** 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
No subsequent dosing 

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Increase monitoring of vital signs as medically indicated until 
the participant is deemed medically stable in the opinion of the 
investigator. 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should be used 
immediately. 
Participant is permanently discontinued from further 
study drug intervention. 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of 
drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) at 
http://ctep.cancer.gov 
 
 

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5.6.2 Additional supportive Care Guidelines Radiotherapy 
Table 9: Supportive Care Guidelines Radiotherapy 
Radiation dermatitis 
grade 1: topical (e.g. Dexpanthenol) 
grade 2: topical (e.g. Polyhexanid) 
grade 3: topical (e.g. Silver sulfadiazine), consider antibiotics in case 
of bacterial superinfection 
Mucositis 
mouth rinsing solutions, consider local fungicides 
Dysphagia 
sip feed nutrition, analgesics 
Pneumonitis 
according to supportive care guidelines pembrolizumab, consider 
antibiotics in case of bacterial superinfection 
Diarrhea 
according to supportive care guidelines pembrolizumab 
Cystitis 
consider antibiotics in case of bacterial superinfection 
 
 
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.  
For this trial, male subjects will be considered to be of non-reproductive potential if they are 
permanently sterile by bilateral orchidectomy. 
Female subjects will be considered of non-reproductive potential if they are either:  
postmenopausal (defined as at least 12 months with no menses without an alternative medical 
cause; in women < 45 years of age a high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a post-menopausal state in women not using 
hormonal contraception or hormonal replacement therapy. In the absence of 12 months of 
amenorrhea, a single FSH measurement is insufficient.);  
OR  

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have had a hysterectomy and/ or bilateral oophorectomy and/ or bilateral salpingectomy, at 
least 6 weeks prior to screening;  
Female and male subjects of reproductive potential must agree to avoid becoming pregnant or 
impregnating a partner, respectively, while receiving study treatment and for 120 days after 
the last dose of study treatment by complying with one of the following:  
practice abstinence† from heterosexual activity;  
OR  
use (or have their partner use) contraception during heterosexual activity.  
†Abstinence (relative to heterosexual activity) can be used as the sole method of contraception 
if it is consistently employed as the subject’s preferred and usual lifestyle and if considered 
acceptable by local regulatory agencies and ERCs/ IRBs. Periodic abstinence (e.g., calendar, 
ovulation, asecto-thermal, post-ovulation methods, etc.) and withdrawal are not acceptable 
methods of contraception.  
Methods of contraception for female participants with child bearing potential must be highly 
effective. The following methods are allowed for female participants in the trial:  
• combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 
o oral 
o intravaginal 
o transdermal 
• progestogen-only hormonal contraception associated with inhibition of ovulation: 
o oral 
o injectable 
o implantable 
• intrauterine device (IUD) 
• intrauterine hormone-releasing system (IUS) 
• bilateral tubal occlusion 
• asectomized partner (after medical assessment of surgical success) 
 
For male participants in the trial with women with child bearing potential the following 
methods of contraception are allowed: 
• highly effective method of contraception of the women with child bearing potential 
(see above) 
• bilateral vasectomy (after medical assessment of surgical success) 
• Condoms 
 

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Highly effective contraception is required for the course of the study through 120 days after 
the last dose of study medication. 
 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate in 
the study subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of initiation of study treatment (or 14 days prior to the 
initiation of study treatment for oral contraception) throughout the study period up to 120 
days after the last dose of trial therapy. If there is any question that a subject of childbearing 
potential 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 without delay and within 1 working 
day 
to 
the 
Sponsor 
and 
to 
MSD 
Germany 
Pharmacovigilance 
(Email: 
arzneimittelsicherheit@msd.de, backup for fax: +49 89 / 456 11352) 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 MSD Germany Pharmacovigilance (Email: 
arzneimittelsicherheit@msd.de, backup for fax: +49 89 / 456 11352) 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. 
 

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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 discontinue trial treatment 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: A subject may be granted an exception to continue on treatment with 
confirmed radiographic progression if clinically stable or clinically improved, 
please see Section 7.1.2.7. 
• 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 
• The subject is lost to follow-up 
• Completed 12 months of uninterrupted treatment with pembrolizumab 
Note: 12 months of study medication is calculated from the date of first dose.  
• 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 AE monitoring (SAEs 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 

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for overall survival until death, withdrawal of consent, or the end of the study, whichever 
occurs first. 
 
5.8.1 Discontinuation of Study Treatment after CR  
Discontinuation of treatment may be considered for subjects who have attained a confirmed 
CR that have been treated for at least 24 weeks with pembrolizumab and had at least two 
treatments with pembrolizumab beyond the date when the initial CR according to iRECIST 
was declared.  
 
5.9 
Subject Replacement Strategy  
No subject replacement is planned in this trial. 
 
5.10 End of the trial 
The trial ends when the last patient completes the safety follow-up visit. Patients continue 
receiving Pembrolizumab for up to 1 year outside of the trial, which meets the general 
admission in this clinical indication.  
 
5.11 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 MSD decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made. 

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6.0 TRIAL FLOW CHART 
6.1 
Study Flow Chart 
Trial Period 
Screening 
Phase 
Treatment Phase 
Treatment outside of 
trial  
According to guidelines 
End of 
Treatment 
According to 
guidelines 
Post-Treatment 
According to 
guidelines 
Treatment 
Cycle m/Title: 
 
1 
(doses 
1 & 2) 
Last 
RT 
Safety  
Follow-up 
To be repeated beyond 4 
cycles 
 
Discontinuation b 
Follow 
Up 
Visits c 
Survival 
Follow-
Up d 
1 
(doses 3-
4) 
2 
3 
4 
Scheduling Window 
(Days): 
-28 to -1g 
 
 
30 days 
post dose 2 
± 3 
± 3 ± 3 ± 3 At time of discon. Every 12 
weeks 
post 
discon. 
Every 
12 
weeks 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
Demographics and 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Prior and 
Concomitant 
Medication Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Trial Treatment 
Administration 
 
X 
 
 
X 
X 
X 
X 
 
 
 

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Trial Period 
Screening 
Phase 
Treatment Phase 
Treatment outside of 
trial  
According to guidelines 
End of 
Treatment 
According to 
guidelines 
Post-Treatment 
According to 
guidelines 
Treatment 
Cycle m/Title: 
 
1 
(doses 
1 & 2) 
Last 
RT 
Safety  
Follow-up 
To be repeated beyond 4 
cycles 
 
Discontinuation b 
Follow 
Up 
Visits c 
Survival 
Follow-
Up d 
1 
(doses 3-
4) 
2 
3 
4 
Scheduling Window 
(Days): 
-28 to -1g 
 
 
30 days 
post dose 2 
± 3 
± 3 ± 3 ± 3 At time of discon. Every 12 
weeks 
post 
discon. 
Every 
12 
weeks 
Post-study 
anticancer therapy 
status 
 
 
 
X 
 
 
 
 
 
X 
 
Survival Status 
 
 
 
 
 
 
 
 
 
 
X 
Review AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Full Physical 
Examination 
X 
 
X 
X 
 
 
 
 
 
 
 
Directed Physical 
Examination 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
Vital Signs and 
Weight 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
12-lead ECG 
X 
 
 
X 
 
 
 
 
 
 
 
ECOG Performance 
Status 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 

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Trial Period 
Screening 
Phase 
Treatment Phase 
Treatment outside of 
trial  
According to guidelines 
End of 
Treatment 
According to 
guidelines 
Post-Treatment 
According to 
guidelines 
Treatment 
Cycle m/Title: 
 
1 
(doses 
1 & 2) 
Last 
RT 
Safety  
Follow-up 
To be repeated beyond 4 
cycles 
 
Discontinuation b 
Follow 
Up 
Visits c 
Survival 
Follow-
Up d 
1 
(doses 3-
4) 
2 
3 
4 
Scheduling Window 
(Days): 
-28 to -1g 
 
 
30 days 
post dose 2 
± 3 
± 3 ± 3 ± 3 At time of discon. Every 12 
weeks 
post 
discon. 
Every 
12 
weeks 
Pregnancy Test – 
Urine or Serum β 
HCG 
Xh 
 
 
X 
 
 
 
X 
 
 
 
HIV, Hepatitis B/C 
test 
Xk 
 
 
 
 
 
 
 
 
 
 
PT/INR and aPTT 
Xk 
 
 
 
 
 
 
 
 
 
 
CBC k 
X e, k 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Comprehensive 
Serum Chemistry 
Panel 
Xk 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Urinalysis 
Xk 
 
 
X 
 
 
 
 
 
 
 
FT3, FT4 and TSH 
Xk 
 
 
X 
 
 
 
X 
 
 
 
Tumor Imaging f 
X 
 
 
 
X 
X 
X 
X 
 
X 
 

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Trial Period 
Screening 
Phase 
Treatment Phase 
Treatment outside of 
trial  
According to guidelines 
End of 
Treatment 
According to 
guidelines 
Post-Treatment 
According to 
guidelines 
Treatment 
Cycle m/Title: 
 
1 
(doses 
1 & 2) 
Last 
RT 
Safety  
Follow-up 
To be repeated beyond 4 
cycles 
 
Discontinuation b 
Follow 
Up 
Visits c 
Survival 
Follow-
Up d 
1 
(doses 3-
4) 
2 
3 
4 
Scheduling Window 
(Days): 
-28 to -1g 
 
 
30 days 
post dose 2 
± 3 
± 3 ± 3 ± 3 At time of discon. Every 12 
weeks 
post 
discon. 
Every 
12 
weeks 
Archival Tissue 
Collection 
X 
 
 
 
 
 
 
 
 
 
 
Correlative Studies 
Blood Collection 
Xa 
X 
 
X 
Xa 
Xa Xa 
 
 
 
 
Patient 
questionnaires 
X 
 
 
 
Xl 
Xl 
 
 
 
 
 

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Trial Period 
Screening 
Phase 
Treatment Phase 
Treatment outside of 
trial  
According to guidelines 
End of 
Treatment 
According to 
guidelines 
Post-Treatment 
According to 
guidelines 
Treatment 
Cycle m/Title: 
 
1 
(doses 
1 & 2) 
Last 
RT 
Safety  
Follow-up 
To be repeated beyond 4 
cycles 
 
Discontinuation b 
Follow 
Up 
Visits c 
Survival 
Follow-
Up d 
1 
(doses 3-
4) 
2 
3 
4 
Scheduling Window 
(Days): 
-28 to -1g 
 
 
30 days 
post dose 2 
± 3 
± 3 ± 3 ± 3 At time of discon. Every 12 
weeks 
post 
discon. 
Every 
12 
weeks 
a at screening only for patients in treatment arm A (with RT); treatment cycles (only at doses P2, P3, P4, P8, P12): correlative study 
blood has to be collected before study treatment; a maximum of 8 samples will be collected 
b Discontinuation after unacceptable toxicity, tumor progression, patient’s wish or last dose of Pembrolizumab 
c if no tumor progression appeared 
d after tumor progression 
e with differential CBC 
f CT neck-thorax-abdomen (additional MRI of the brain if stable brain metastases have been diagnosed prior treatment), at doses P4, 
P7, P10, P13, P16 
g the screening phase can be prolonged for 7 days for radiotherapy treatment planning after consultation of the leading center 
h after informed consent of the patient in women with child bearing potential within 72 hours prior to the first dose of treatment 
k to be performed within 10 days prior to the first dose of treatment 
l only before third and seventh pembrolizumab administration 
m one cycle consists of 12 weeks with a maximum of 4 Pembrolizumab doses 

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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 
MSD 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.  

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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.  
7.1.1.3 Demographics and 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. Furthermore, demographics 
including smoking have to be recorded. 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 trial treatment. 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. 

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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  End of Treatment 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 
The screening number will be assigned to the patient after the pre-screening by consecutive 
numbers at every center. On the screening form in the ISF it has to be documented: 
- 
 date of written informed consent 
AND 
If the patient was randomized: 
- 
Study number of the patient assigned by the randomization service  
- 
Date of randomization 
If the patient was not randomized: 
- 
Reason for Not-Randomization 
7.1.1.7 Assignment of Randomization Number 
Subjects fulfilling all in-/ exclusion criteria, having provided written informed consent on the 
approved informed consent form, are eligible for participation in the study.  
Enrollment/ randomization is performed in secuTrial®. The following data must be provided: 
- 
Access code of person performing the randomization 
- 
Month/ year of patient’s birth 
- 
Sex of patient 
- 
Date of written informed consent 
- 
Stratification criteria 
The randomization result (patient no. and treatment allocation) is displayed online 
immediately. Furthermore, an email will be sent to defined persons that need to know about 
the randomization.  

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In case of technical problems or questions, please contact the study office at the leading center 
by email or phone. 
 
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 (Section 6.0) and more frequently if 
clinically indicated. Adverse experiences will be graded and recorded throughout the study and 
during the follow-up period according to NCI CTCAE 4.0. Toxicities will be characterized in 
terms regarding seriousness, causality, toxicity grading, and action taken with regard to trial 
treatment.  
Please refer to section 7.2 for detailed information regarding the assessment and recording of 
AEs.  
7.1.2.2 Full Physical Examination  
The investigator or qualified designee will perform a complete physical examination during 
the screening period. Clinically significant abnormal findings should be recorded as medical 
history. A full physical exam should be performed during screening, after the last dose of 
radiotherapy and in the Safety Follow-up Visit. 
7.1.2.3 Directed Physical Examination 
For cycles that do not require a full physical examination per the Trial Flow Chart (Section 
6.0), the investigator or qualified designee will perform a directed physical exam as clinically 
indicated prior to trial treatment administration. A directed physical examination will also be 
performed at the End of Treatment Visit. 
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, at treatment discontinuation and in the Safety 
Follow-up Visit 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 Electrocardiogram 
A 12-lead ECG will be performed in the screening phase and in the Safety Follow-up Visit. 

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7.1.2.6 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 14.1) at screening, 
prior to the administration of each dose of trial treatment, at discontinuation of trial treatment 
and in the Safety Follow-up Visit as specified in the Trial Flow Chart (Section 6.0).  
7.1.2.7 Tumor Imaging and Assessment of Disease 
Tumor imaging will be performed with a CT scan of the neck, thorax and abdomen. Contrast 
agent should be used unless renal function is substantially reduced or a present manifest 
hyperthyroidism is diagnosed. In patients with stable brain metastases prior treatment, an 
additional MRT-scan of the brain is necessary. Tumor imaging will be evaluated according to 
RECIST and iRECIST at the University Hospital Erlangen for all patients. Treatment duration 
of pembrolizumab bases on iRECIST criteria. During the treatment period, imaging will be 
performed every nine weeks or if a tumor progression is clinically suspected. In case of an 
unconfirmed progressive disease, the following imaging can be performed earlier (minimum 
time interval of 4 weeks). During the Follow-up, imaging will be performed every twelve 
weeks or if a tumor progression is clinically suspected. 
7.1.2.8 Tumor Tissue Collection and Correlative Studies Blood Sampling 
Tumor tissue will be collected by the Department of Pathology of the University Hospital 
Erlangen. The most recent achieved tissue sample will be requested from the local pathologist. 
Blood samples for the characterization of the immune status of the peripheral blood should be 
drawn during the Screening phase only for patients in treatment arm A (with radiotherapy) and 
prior to the first four administrations of pembrolizumab. Afterward blood samples will be 
drawn prior to the eighth and twelfth pembrolizumab administrations. One further blood 
sample should be drawn in the Safety Follow-up Visit. A maximum of eight samples will be 
collected. The blood samples will be collected in the Laboratory for Radiation-Immunobiology 
Erlangen. 
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 10.  

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Table 10: Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic 
gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
(β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
PT (INR) 
WBC (total and differential) Aspartate aminotransferase (AST) 
Specific gravity  
aPTT 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam  
(If abnormal)  
Free thriiodothyronine (FT3) 
ANC 
Uric Acid 
 
Free tyroxine (FT4) 
Absolute Lymphocyte Count Calcium 
Urine pregnancy test † Thyroid stimulating hormone (TSH) 
 
Chloride 
 
 
 
Glucose 
 
 
 
Phosphorus 
 
Blood for correlative studies 
 
Potassium  
 
  
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin 
is elevated above the upper limit of 
normal) 
 
  
 
Total protein 
 
  
 
Blood Urea Nitrogen 
 
 
† in women with child bearing potential within 72 hours prior to the first dose of treatment  

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Laboratory tests for screening 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 3 days 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 from study 
If a subject discontinues/ withdraws from study during the treatment period, all applicable 
activities scheduled for the End of Treatment Visit should be performed. Any AEs 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.  After 
discontinuing treatment, subjects should return to the site for a Safety Follow-up Visit 
(described in Section 7.1.5.4.1) and then proceed to the Follow-Up Period of the study 
(described in Section 7.1.5.4.2 and 7.1.5.4.3). 
If a patient withdraws from study during the follow up period, all procedures for the current 
follow up visit should be performed.  
7.1.4.2 Blinding/ Unblinding 
The study is performed open-label. There will be no blinding. 
7.1.4.3 Patient questionnaires 
Quality of life will be measured with the EORTC QLQ-C30 and EQ-5D-5L questionnaires 
during Screening and before the fourth and seventh application of pembrolizumab. 
 
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 screening investigations should be performed 28 to 1 day prior to the begin of radiotherapy 
or the administration of the first dose of pembrolizumab. In case of a required radiotherapy 
treatment planning the screening phase can be prolonged for 7 days after consultation of the 
leading center. Laboratory tests for screening should be performed within 10 days prior to the 
administration of the first dose of treatment. For women of child bearing potential a highly 

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sensitive pregnancy test should be performed within 72 hours prior to the first dose of 
treatment. Achieved tumor tissue for correlative studies is collected after informed consent of 
the patient. 
 
7.1.5.2 Treatment Period 
Treatment within the trial is finalized when the Safety Follow-Up visit is performed after 
administration of two doses of Pembrolizumab. 
Treatment in group A (with radiotherapy) starts with the first radiation on a Wednesday. The 
first pembrolizumab dose will be administered after the third radiation on Friday. After the last 
dose of radiotherapy, a full physical examination is required to detect all AEs. Furthermore, 
concomitant medication must be revised and a CBC and a comprehensive serum chemistry 
panel is required. 
In group B treatment comprises two doses of pembrolizumab followed by the Safety Follow-
Up.  
It is recommended to continue treatment with Pembrolizumab up to 1 year after start of 
treatment (Arm A and B). Pembrolizumab outside of the trial will be continued as usual every 
third week. Before every administration of pembrolizumab concomitant medication and AEs 
must be revised and vital signs, weight and ECOG have to be documented. Furthermore, a 
CBC and a comprehensive serum chemistry panel is required prior every administration of 
pembrolizumab.  
In both groups (A and B), tumor imaging with CT Neck-Thorax-Abdomen is performed every 
9 weeks. At these time points also a highly sensitive pregnancy test should be performed in 
women with child bearing potential. In case of stable brain metastases an additional MRI of 
the brain is required. Treatment is continued till unacceptable toxicity, tumor progression 
according to iRECIST criteria or patient’s wish to end treatment. 
As the trial includes patients with metastases perspectively requiring radiation, a patient may 
develop symptoms from a metastasis during the treatment period. If such a patient has no tumor 
progression according to iRECIST criteria, but requires palliative radiotherapy, he/ she must 
be dropped from the treatment period of the study. Thereafter a palliative radiotherapy can be 
done. 
7.1.5.3 End of Treatment Visit 
For all patients who discontinue/ withdraw from treatment or complete the treatment (including 
treatment with Pembrolizumab outside of the trial), the End of Treatment Visit should be 
conducted if the withdrawal/ completion does not coincide with an administration of 
pembrolizumab. AEs and concomitant medications must be revised and vital signs, weight and 

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ECOG have to be documented. Furthermore, a CBC and a comprehensive serum chemistry 
panel is required. 
7.1.5.4 Post-Treatment Visits 
7.1.5.4.1 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 within the trial or before initiation of a new anti-cancer 
treatment should also be followed and recorded. Concomitant medication must be revised and 
a full physical examination and a 12-lead ECG have to be performed. Furthermore, the post-
study anticancer therapy status should be recorded as well as vital signs, weight and ECOG 
performance status are required. Laboratory tests for hematology, chemistry, urinalysis, and 
others are specified in Table 10 (including a highly sensitive pregnancy test in women with 
child bearing potential). 
7.1.5.4.2 Follow-up Visits 
Follow-Up visits will be performed outside of the trial. Subjects will be seen within the follow-
up care in accordance with the guidelines. 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 by radiologic imaging to monitor disease status. Every effort should be made 
to collect information regarding disease status until the start of new anti-neoplastic therapy, 
disease progression, death or end of the study. Information regarding post-study anti-neoplastic 
treatment will be collected if new treatment is initiated. Follow-up Visits will be conducted up 
to 24 months after the last study treatment. 
7.1.5.4.3 Survival Follow-up 
Survival Follow-Up visits will be performed outside of the trial. Subjects will be seen within 
the follow-up care in accordance with the guidelines. 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 to assess for survival 
status until death, withdrawal of consent, or the end of the study, whichever occurs first. 
Survival Follow-up Visits will be conducted up to 24 months after the last study treatment. 
7.1.5.5 Aftertreatment 
Subjects who had no progression of disease and no unacceptable toxicity during the usual 
treatment period of the trial and are eligible for additional pembrolizumab therapy can be 

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treated with commercially available pembrolizumab. The investigator will prescribe 
pembrolizumab after evaluation of the individual medical patient need for the treatment with 
pembrolizumab. The data retrieved during the treatment will be properly captured in electronic 
case record forms (eCRF) and in the subject´s medical records until the last administration of 
pembrolizumab. Subjects who continue treatment will be treated at the same dose and dose 
interval as when they last received pembrolizumab until confirmed disease progression 
according to iRECIST criteria, unacceptable toxicity or patient’s wish to stop therapy and will 
proceed with Post-Treatment visits. 
 
7.2 
Assessing and Recording Adverse Events 
An AE 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 AE 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 MSD product, is also an AE. 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered AEs. 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. 
MSD 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 MSD for human use. 
AEs may occur during the course of the use of MSD product in clinical trials, or as prescribed 
in clinical practice, from overdose (whether accidental or intentional), from abuse and from 
withdrawal. 
Progression of the cancer under study and resulting symptoms are not considered AEs.  
All AEs that occur after the consent form is signed but before treatment allocation/ 
randomization must be reported by the investigator if they cause the subject to be excluded 
from the trial, or are the result of a protocol-specified intervention, including but not limited to 
washout or discontinuation of usual therapy, diet, placebo treatment or a procedure. 
From the time of treatment allocation/ randomization through 30 days following cessation of 
treatment, all AEs must be reported by the investigator. Such events will be recorded at each 

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examination on the AE case report forms/ worksheets. The reporting timeframe for AEs 
meeting any serious criteria is described in section 7.2.3.1. The investigator will make every 
attempt to follow all subjects with non-serious AEs for outcome. 
AEs will not be collected for subjects during the pre-screening period (for determination of 
archival tissue status) as long as that subject has not undergone any protocol-specified 
procedure or intervention. If the subject requires a blood draw, fresh tumor biopsy etc., the 
subject is first required to provide consent to the main study and AEs will be captured 
according to guidelines for standard AE reporting.  
 
7.2.1 Definition of an Overdose for this Protocol and Reporting of Overdose 
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 AE is associated with (“results from”) the overdose of a MSD product, the AE is reported 
as a SAE, even if no other seriousness criteria are met. 
If a dose of MSD 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 AE are to be forwarded within 1 working day to 
the Sponsor, Winicker Norimed and MSD. The report will be made by recording the necessary 
information in secuTrial®. In the event that the system is unavailable, the Event Reporting 
Form provided should be completed and submitted to Winicker Norimed (fax: +49 911 / 9260 
80 4444, backup for Email: safety@winicker-norimed.com) either by electronic or paper 
media. In this case, the reports will be forwarded to the Sponsor and MSD Germany 
Pharmacovigilance (Email: arzneimittelsicherheit@msd.de, backup for fax: +49 89 / 456 
11352) within 1 working day by Winicker Norimed. 
Once secuTrial® is available, all information will need to be entered and submitted via the 
system.  
 

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7.2.2 Reporting of Pregnancy and Lactation  
Although pregnancy and lactation are not considered AEs, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial. 
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/ randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure.  
Pregnancies and lactations that occur from the time of treatment allocation/ randomization 
through 120 days following cessation of treatment, or 30 days following cessation of treatment 
if the subject initiates new anticancer therapy, whichever is earlier, must be reported by the 
investigator. All reported pregnancies must be followed to the completion/ termination of the 
pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported. 
Such events are to be forwarded within 1 working day to the Sponsor, Winicker Norimed and 
MSD. The report will be made by recording the necessary information in secuTrial®. In the 
event that the system is unavailable, the Event Reporting Form provided should be completed 
and submitted to Winicker Norimed (fax: +49 911 / 9260 80 4444, backup for Email: 
safety@winicker-norimed.com) either by electronic or paper media. In this case the reports 
will be forwarded to the Sponsor and MSD Germany Pharmacovigilance (Email: 
arzneimittelsicherheit@msd.de, backup for fax: +49 89 / 456 11352) within 1 working day by 
Winicker Norimed. 
Once secuTrial® is available, all information will need to be entered and submitted via the 
system.  
 
7.2.3 Immediate Reporting of Adverse Events 
7.2.3.1 Serious Adverse Events 
A serious adverse event (SAE) is any AE occurring at any dose or during any use of MSD 
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; 

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• Is another important medical event  
• Note: In addition to the above criteria, AEs meeting either of the below criteria, 
although not serious per ICH definition, are reportable to MSD in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered 
serious by MSD for collection purposes. 
● 
Is a new cancer (that is not a condition of the study); 
● 
Is associated with an overdose. 
 
Refer to Table 11 for additional details regarding each of the above criteria. 
For the time period beginning when the consent form is signed until treatment allocation/ 
randomization, any SAE, or follow up to a SAE, including death due to any cause other than 
progression of the cancer under study (reference Section 7.2.3.3 for additional details) that 
occurs to any subject must be reported within 1 working day as described below if it causes 
the subject to be excluded from the trial, or is the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, placebo 
treatment or a procedure. 
For the time period beginning at treatment allocation/ randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any SAE, or follow up to a SAE, 
including death due to any cause other than progression of the cancer under study (reference 
Section 7.2.3.3 for additional details), whether or not related to the MSD product, must be 
reported within 1 working day as described below. 
Additionally, any SAE, considered by an investigator who is a qualified physician to be related 
to MSD product that is brought to the attention of the investigator at any time following consent 
through the end of the specified Safety Follow-up period specified in the paragraph above, or 
at any time outside of the time period specified in the previous paragraph also must be reported 
within 1 working day. 
All subjects with SAEs must be followed up for outcome. 
SAE reports and any other relevant safety information are to be forwarded within 1 
working day to the Sponsor, Winicker Norimed and MSD. 
The report will be made by recording the necessary information in secuTrial®. In the 
event that the system is unavailable, the SAE Reporting Form provided should be 
completed and submitted to Winicker Norimed (fax: +49 911 / 9260 80 4444, backup for 
Email: safety@winicker-norimed.com) either by electronic or paper media. In this case, 
the reports will be forwarded to the Sponsor and MSD Germany Pharmacovigilance (Email: 

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arzneimittelsicherheit@msd.de, backup for fax: +49 89 / 456 11352) within 1 working day by 
Winicker Norimed. 
Once secuTrial® is available, all information will need to be entered and submitted via 
the system.  
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 MSD Investigational Compound Number (IND, CSA, etc.) at the time of submission. 
Additionally investigators will submit a copy of these reports to MSD Germany 
Pharmacovigilance (Email: arzneimittelsicherheit@msd.de, backup for fax: +49 89 / 456 
11352). 
7.2.3.2 Events of Clinical Interest 
Selected non-serious and SAEs are also known as Events of Clinical Interest (ECI) and must 
be reported within 1 working day as described below.  
For the time period beginning when the consent form is signed until treatment allocation/ 
randomization, any ECI, or follow up to an ECI, that occurs to any subject must be reported 
within 1 working day as described below if it causes the subject to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure. 
For the time period beginning at treatment allocation/ randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, whether 
or not related to MSD product, must be reported within 1 working day to Winicker Norimed. 
Events of clinical interest for this trial include: 
1. an overdose of MSD 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.  

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Events of clinical interests are to be forwarded within 1 working day to the Sponsor, Winicker 
Norimed and MSD. The report will be made by recording the necessary information in 
secuTrial®. In the event that the system is unavailable, the Event Reporting Form provided 
should be completed and submitted to Winicker Norimed (fax: +49 911 / 9260 80 4444, backup 
for Email: safety@winicker-norimed.com) either by electronic or paper media. In this case the 
reports will be forwarded to the Sponsor and MSD Germany Pharmacovigilance (Email: 
arzneimittelsicherheit@msd.de, backup for fax: +49 89 / 456 11352) within 1 working day by 
Winicker Norimed. 
Once secuTrial® is available, all information will need to be entered and submitted via the 
system.  
 
7.2.3.3 Protocol-Specific Exceptions to Serious Adverse Event Reporting  
Efficacy endpoints as outlined in this section will not be reported as described in Section 7.2.3. 
Hospitalization related to convenience (e.g. transportation issues etc.) will not be considered a 
SAE. 
 
7.2.4 Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all AEs according to CTCAE 4.0. 
Any AE which changes CTCAE grade over the course of a given episode will have each change 
of grade recorded on the AE case report forms/ worksheets. 
All AEs regardless of CTCAE grade must also be evaluated for seriousness and relationship 
to MSD product or radiotherapy (if applicable). 

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Table 11: Evaluating AEs 
An investigator who is a qualified physician, will evaluate all AEs 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 Activities of Daily Living (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 SAE is any AE occurring at any dose or during any use of MSD & Co., Inc., Kenilworth, New Jersey, U.S.A. 
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 AE 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 

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†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, 
regardless of length of stay, even if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not worsened is not a SAE. A pre-
existing condition is a clinical condition that is diagnosed prior to the use of a MSD product and is documented in the 
patient’s medical history.); 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) (although not serious per ICH definition, is reportable to the 
Sponsor, Winicker Norimed and MSD within 1 working day to meet certain local requirements); or 
 
Is an overdose (whether accidental or intentional). Any AE associated with an overdose is considered a SAE for 
collection purposes. An overdose that is not associated with an AE is considered a non-serious event of clinical 
interest and must be reported within 1 working day to the Sponsor, Winicker Norimed and MSD. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization 
may be considered a SAE 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 AE. If less than 1 day, indicate the appropriate length of time and units 
Action 
taken  
Did the AE cause MSD product or radiotherapy to be discontinued? 
Relationship 
to MSD 
Product  
Did MSD product cause the AE? The determination of the likelihood that MSD product caused the AE 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. 

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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 AE based upon the available information. 
The following components are to be used to assess the relationship between MSD product and the AE; the 
greater the correlation with the components and their respective elements (in number and/ or intensity), the more 
likely MSD product caused the AE: 
 
Exposure 
Is there evidence that the subject was actually exposed to MSD 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 MSD product? Is the time 
of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal 
product)? 
 
Likely 
Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/ 
vaccine(s), or other host or environmental factors 
 
 
 

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Relationship 
to MSD  
The following components are to be used to assess the relationship between the test drug and the AE: 
(continued) 
Product 
(continued)  
Dechallenge 
Was MSD product discontinued or dose/ exposure/ frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; 
(2) the AE resolved/ improved despite continuation of the Sponsor’s product; or (3) the trial 
is a single-dose drug trial); or (4) Sponsor’s product(s) is/ are only used one time.) 
 
Rechallenge 
Was the subject re-exposed to MSD product in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent 
disability, or (2) the trial is a single-dose drug trial); or (3) Sponsor’s product(s) is/are used 
only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE WHICH WAS SERIOUS AND 
WHICH MAY HAVE BEEN CAUSED BY MSD PRODUCT, OR IF REEXPOSURE TO 
MSD PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE 
SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY 
THE SPONSOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL. 
 
Consistency with 
Trial 
Treatment 
Profile 
Is the clinical/ pathological presentation of the AE consistent with previous knowledge 
regarding MSD product or drug class pharmacology or toxicology? 

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The assessment of relationship will be reported on the case report forms/ worksheets by an investigator who is a qualified physician 
according to his/ her best clinical judgment, including consideration of the above elements. 
Record one of the following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative 
of MSD product relationship). 
Yes, there is a reasonable 
possibility of MSD product 
relationship. 
There is evidence of exposure to MSD product. The temporal sequence of the AE onset relative to 
the administration of MSD product is reasonable. The AE is more likely explained by MSD product 
than by another cause. 
No, there is not a reasonable 
possibility of MSD product 
relationship 
Subject did not receive the MSD product OR temporal sequence of the AE onset relative to 
administration of MSD product is not reasonable OR the AE is more likely explained by another 
cause than the MSD product. (Also entered for a subject with overdose without an associated AE.) 
 
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is an adverse reaction, which is suspected, serious and unexpected because the 
nature or severity of this event is not consistent with the applicable product information (e.g. SmPC for the authorized product or IB for the 
investigational medicinal product).

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7.2.5 Sponsor Responsibility for Evaluating and Reporting Adverse Events 
In addition to the first evaluation of AEs that is performed by the investigator, a second 
evaluation with respect to seriousness, causality and expectedness and a risk-benefit 
assessment is performed by the Sponsor. 
All AEs will be reported to regulatory authorities, IRB/ IECs and investigators in accordance 
with all applicable global laws and regulations: 
SUSARs will be reported to IRB/ IECs and competent authorities by Winicker Norimed as 
follows:  
• Non-fatal and non-life-threatening SUSARs latest within 15 calendar days 
• Fatal or life-threatening SUSARs latest within seven calendar days 
All involved investigators will also be informed by Winicker Norimed.  
Furthermore, an Annual Safety Report will be provided to IRB/ IECs and competent authorities 
by the Sponsor once a year or on request. This task maybe delegated to Winicker Norimed. 
As Reference Safety Information either the IB for unauthorized investigational medicinal 
product or the SmPC for the authorized product will be used. 
7.2.6 Data Safety Monitoring Committee (DSMC) 
A DSMC will be established to review accumulating safety data during the course of the trial. 
The DSMC may recommend discontinuation of the trial or modification of the protocol for 
safety reasons at any time during the trial. The decision to terminate is taken by the sponsor 
together with the coordinating investigator. The members of the DSMC will be chosen from 
different fields. The members will not be involved in the design of the study, its conduct other 
than through their role on the DSMC and will have no financial interest in the outcome of the 
study. The DSMC will have written operating procedures. 
 
8.0 STATISTICAL ASPECTS 
8.1 
Trial design and primary hypotheses 
The objective of this exploratory randomized phase II study is to obtain some evidence of a 
superior efficacy of pembrolizumab when combined with local radiotherapy, compared to 
pembrolizumab alone. Accordingly, the research hypothesis of the study is one-sided. The 
primary efficacy endpoint is the rate of patients achieving CR or PR as best response 
during/after treatment (ORR). Thus, the following hypotheses will be tested: 

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H0: ORR (radiotherapy) ≤ ORR (control) 
H1: ORR (radiotherapy) > ORR (control) 
According to these hypotheses, the test concerning the primary endpoint will be performed 
one-sided. 
 
8.2 
Sample size calculation 
Based on published results, the ORR after standard pembrolizumab therapy is assumed to be 
around 18%. The doubling of this ORR to 36% by adding radiotherapy seems to be a 
reasonable aim, and is unequivocally considered to be a major, clinically relevant advantage. 
In order not to miss such a distinct signal for improvement by the experimental treatment (if it 
actually exists) with a high level of confidence (power = 80%), 65 evaluable patients per arm, 
i.e. a total of n = 130, have to be observed, based on an alpha error rate of 0.1 (one-sided). The 
comparatively high alpha error level of 10% is acceptable within the framework of a phase II 
study44-46.  
 
8.3 
Evaluation categories of patients 
The primary population for the analyses consists of all randomized patients (intent-to-treat). 
However, patients who were enrolled although they unequivocally did not fulfil major 
selection criteria of the trial a priori “non-eligible”), will be excluded from the statistical 
analysis, in accordance with ICH recommendations. Only case reports will be provided for this 
group. The decision on exclusions will be made by the steering committee during a pre-analysis 
meeting in a blinded fashion.  
In the pre-analysis meeting, a per-protocol population will likewise be prospectively defined 
for sensitivity analyses, based on the amount of protocol treatment actually received.  
The population for safety analyses consists of all patients having received at least one 
application of protocol therapy. 
Eligible patients without any valid restaging procedure according to iRECIST are counted as 
failures in the primary analysis. 
 

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8.4 
Methods of statistical analysis 
The primary end-point of the trial (ORR) will be analysed confirmatively by Fisher’s exact test 
considering a level of p < 0.1 (one-sided) as significant.  
All other parameters will be evaluated in an explorative or descriptive manner, providing 
means, medians, ranges, standard deviations and/ or confidence intervals (CI). If additional p 
values are calculated, they will be presented explicitly without referring to hypotheses or a 
significance level. Usually, no error adjustment for multiple testing will be performed. Thus 
the p values will reflect the comparison-wise error and not the experiment-wise error. All p 
values will be two-sided if not stated otherwise. The statistical methods described in this 
section are suited for the data and distributions usually expected in this type of trials. The 
suitability will be checked after data entry. If necessary, the statistical method will be modified 
accordingly and the results of original and modifies analyses compared and strictly discussed.  
Demographic and prognostic baseline data will be checked for homogeneity between the study 
arms. In case of relevant imbalances of other important prognostic factors the statistical method 
may be adjusted in order to achieve best possible comparability of the groups, and the results 
will be critically reviewed in comparison to the unadjusted ones. 
Metric changes in (non-irradiated) target lesions will eventually be compared using the 
Wilcoxon rank sum test. Secondary endpoints of time-to-event type, such as duration of 
response, progression-free survival and overall survival, will be estimated according to 
Kaplan-Meier, and exploratively compared using the logrank test (PETO, 1972, 1977), 
stratified according to the protocol-defined strata. Hazard ratios (with Cis) will be derived from 
corresponding Cox proportional hazard models, eventually adjusting for important prognostic 
factors (sensitivity analysis). 
If the Peto logrank test is not appropriate because of violation of the proportional hazard 
assumption (HAYBITTLE 1988), Gehan’s generalization of the Wilcoxon rank sum test for 
censored data (GEHAN 1965) may be applied, preferably in its modification by PETO (1972) 
and PRENTICE (1978), as a sensitivity analysis.  
Comparisons of the categorical data will be performed using chi² tests, Fisher’s exact test or 
trend tests according to Cochran/Armitage, as appropriate. 
No interim analyses for efficacy will be performed. 
 

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8.5 
Statistical Analysis Plan 
Further details on the biostatistical methods will be described in a statistical analysis plan 
(SAP), to be written and approved by the steering committee of the study, prior to locking the 
data base and before any analyses on efficacy items are performed. 
 
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 MSD as summarized in Table 12. 
Table 12: Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/ 4ml 
Solution for Injection 
 
9.2 
Packaging and Labeling Information 
Clinical supplies will be affixed with a 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. 

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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 MSD 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. 
 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
10.1 Confidentiality 
The investigators and the Sponsor will preserve the confidentiality of all subjects taking part 
in the study, in accordance with Good Clinical Practice (GCP) and local regulations. 
The investigator must ensure that the subject’s pseudonymity is maintained. On the CRF or 
other documents submitted to the Sponsor and/ or agent, subjects should be identified by a 
unique subject identifier as designated by the sponsor.  
In compliance with Federal regulations/ ICH GCP Guidelines, it is required that the 
investigator and institution permit authorized representatives of the company, of the regulatory 
agency(s), and the Independent Ethics Committee (IEC) or Institutional Review Board (IRB) 
direct access to review the subject’s original medical records for verification of study-related 
procedures and data. The investigator is obligated to inform the subject that his/ her study-
related records will be reviewed by the above named representatives without violating the 
confidentiality of the subject. 
 
10.2 Compliance with Financial Disclosure Requirements 
All investigators have to sign a financial disclosure. 
 

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10.3 Compliance with Law, Audit and Debarment 
To conduct the study as outlined in the protocol and in compliance with GCP and with 
applicable regulatory requirements. 
 
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 
In addition to the initial visit for site-initiation, the monitor will contact and visit the 
investigator periodically to evaluate the study progress and the compliance of the study site 
with GCP, regulations and the study protocol as well as to verify and collect data reported in 
the eCRF. The investigator as well as any study staff member will cooperate with the monitor 
to ensure that any problem that may be identified is resolved. The investigator will make all 
study-related source data and documents available to the monitor or a quality assurance auditor 
mandated by the Sponsor, or to domestic or foreign regulatory inspectors, after appropriate 
notification. 
 
10.6 Data Management and Data Archiving 
All patient-related data are recorded in a pseudonymized way. Each patient is unequivocally 
identified by a trial subject number, attributed after randomization into the study. The 
investigator has to keep a patient identification log, including the full name and address of the 
subject and possibly additional relevant personal data such as hospital record number, home 
physician etc. Any patients, including those who were screened in order to be entered into the 
study, but who could not be recruited for whatever reason (i.e. not fulfilling selection criteria 
etc.) are recorded in a “patient screening log”. 
All the data retrieved during the conduct of the study are entered into the appropriate eCRF by 
the investigator or another person authorized by the investigator. The access to the eCRFs is 
provided by the Sponsor and is explained to the investigator by the study monitor. 

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All recorded data have to be plausible and complete. Please respect the following technical 
details when using the eCRFs: 
• All data fields have to be filled, except for those referring to open questions. If a specific test 
was not performed or an information item is definitely not available or applicable, information 
on this should be provided (not done = ND, not applicable = NA, unknown = UK). Exception: 
If a patient discontinues/ withdraws from study treatment earlier than 12 month, not applicable 
pembrolizumab trial visits in the eCRF must not be completed. 
• If a value or date is not known exactly, please explain in the comment field. 
• Screening Failures will not be entered in to the eCRF. 
The investigator is obliged to complete the case report forms within a reasonable time period 
after retrieval of the data (i.e. usually within 2 weeks). The study office or monitor checks the 
forms for completeness and plausibility. In case of queries the monitor fills out the query field. 
The investigator or a delegated person is responsible for clarification/ correction/ completion. 
Queries have to be handled within 4 weeks. 
After finalization of the data checks by the study office/ monitor the file or the database is 
closed. 
All relevant study documents including the eCRFs are stored at the office of the coordinating 
investigator/ sponsor for at least 10 years after completion of the final study report. The 
investigators have to archive major administrative documents (correspondence with ethical 
committee, authorities, sponsor etc.), the patient identification log, the signed informed consent 
forms, and the main study documents (protocol, amendments) for the same time period. The 
original patient records have to be archived according to the standard procedures of the 
respective institution, but at least for 10 years. 
 
 
 

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11.0 TRANSLATIONAL RESEARCH 
11.1 Immune status in the peripheral blood 
The effect of pembrolizumab on the immune phenotype of the peripheral blood has only 
marginally been studied so far, but is mandatory to deepen the knowledge on systemic and 
immune modulating effects of combinations of radiation therapy with immune checkpoint 
blockade. There exist no analyses about the combination of pembrolizumab with radiation 
therapy. In this trial pembrolizumab will be administered on day 3 of radiotherapy and repeated 
every third week. 
In treatment arm A (with radiotherapy) a blood sample will be analyzed on day 0 before the 
first fraction of radiation therapy. Thereafter, in both arms we will analyze blood before each 
of the first four pembrolizumab administrations. In the following time, blood samples will be 
analyzed prior to the eighth and twelfth pembrolizumab administrations. One further blood 
sample should be drawn in the Safety Follow-up Visit. This results in an average of 5 up to a 
maximum of eight blood samples. These closed meshed analyses will shed light on the answer 
of the immune system to pembrolizumab with and without radiotherapy and may identify early 
predictive markers for a future treatment response to pembrolizumab.  
We will collect non-clotted whole blood as well as clotted blood for the generation of serum. 
The patient’s material will be collected and stored at the Department of Radiation Oncology 
Erlangen. We have implemented a biobank which allows storing all blood samples (serum, 
plasma, and RNA) in a quality-controlled manner. All samples will be processed in the 
laboratory and stored in 2D Matrix coded tubes. The samples will be managed with sample 
storage software [LIMS] which allows adding an audit trail to every sample. This enables 
highest quality of sample storage and the spreading of the samples to all partners for further 
analyses. The technical equipment for the biobank system (ultra-cold fridges with temperature 
monitored 24/7, 2D plate barcode-scanner, centrifuges, LIMS software) is fully provided by 
the Department of Radiation Oncology Erlangen. 
In the non-clotted whole blood, a detailed immunophenotyping of all patients will be 
performed at the Department of Radiation Oncology in Erlangen. The laboratory of Radiation 
Immunobiology (Prof. Dr. Gaipl) has developed a set of highly modular multicolor flow 
cytometry protocols to analyze at least 40 different cell subsets including all major immune 
cells in peripheral blood47. These protocols have a special focus on the detection of the 
expression of activation markers on distinguished immune cells. Theses analyses can be 
performed on about 5 ml non-clotted whole blood.  
Further, RNA of the immune cells will be extracted and stored for following analysis. Focus 
will be set on immunological activation markers, cytokine production and pathways of the 
immunological synapse. 

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Blood of the patients will be analyzed on the amount of pembrolizumab-induced antibody 
dependent cellular cytotoxicity (ADCC) by analyzing common danger signals correlating with 
ADCC. In particular messengers correlating with immunogenic cell death (HMGB1, HSP70, 
IL-34) or onset of ADCC (LDH, IFN-y, MCP-1, TNF-a) will be studied.  
 
11.2 PD-L1 in combination with tumor-infiltrating lymphocytes 
The immunosuppressive potential of a cancer is of great interest. PD-L1 is a major player in 
the immunosuppression of inflammatory cells, however there are several other potential 
immunosuppressive cells like regulatory T cells and M2 macrophages. Another question is 
whether the inflammatory cells like cytotoxic cells (CD8, M1 macrophages) or antigen 
presenting cells (dendritic cells, B cells) are functional or immunosuppressed. We have 
developed a multiparameter and multislice assay to analyze the immunosuppressive potential 
of the inflammatory cells and the functional activity of the antigen presenting and cytotoxic 
cells. We use serial sections of the tumor tissue sections and stain it mostly by double stainings 
shown in table 13. The overall set of slides is scanned by a whole slide scanner. By the use of 
an image analysis software each image is as accurately as possible aligned to each other. The 
tumor epithelium and stromal areas are identified and the inflammatory cells and tumor cells 
are marked by the software. The positions of the tumor and stromal mass and the coordinates 
of the inflammatory cells are transferred to a database. Now from these data sets the 
distribution pattern and the distance from each cell to the next cell can be calculated. The 
calculated cell to cell distances can compared to simulated distances showing whether cells are 
randomly distributed and therefore not functional or have shorter distances than the simulated 
distances and are assessed to be functional due to their interactions with other inflammatory or 
tumor cells48-50. Additionally it is possible to calculate an immunosuppressive score or 
cytotoxicity score or other multiparameter scores. 
Table 13: Multislice staining strategy 
 
Marker 1 
Marker 2 Identified characteristics 
by marker 1 
Identified characteristics by 
marker 2 
1 
H3K9me3 
Premature senescence 
2 CleavedCaspase3 
Ki67 
Apoptosis 
Proliferation 
3 
E-Cadherin 
HE 
Cell-in-cell, budding 
Cancer cells 
4 
CD68 
CD163 
M1 macrophages 
(cytotoxic) 
M2 macrophages 
(immunosuppressive) 
5 
FoxP3 
CD8 
Regulatory T cells 
Cytotoxic T cells 
6 
PD-L1 
Programmed death-ligand 1 
7 
CD1a 
CD20 
Dendritic cells 
B cells 
8 
CD45RO 
CD4 
Memory T cells 
T helper cells 
9 
PD1 
Programmed cell death 
protein 1 

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43. 
Rivelli TG, Mak MP, Martins RE, da Costa e Silva VT, de Castro G, Jr. Cisplatin based 
chemoradiation late toxicities in head and neck squamous cell carcinoma patients. Discov Med 
2015;20:57-66. 
44. 
Gray R, Manola J, Saxman S, et al. Phase II clinical trial design: methods in translational 
research from the Genitourinary Committee at the Eastern Cooperative Oncology Group. Clinical 
cancer research : an official journal of the American Association for Cancer Research 2006;12:1966-9. 
45. 
Korn EL, Arbuck SG, Pluda JM, Simon R, Kaplan RS, Christian MC. Clinical trial designs for 
cytostatic agents: are new approaches needed? Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology 2001;19:265-72. 

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46. 
Rubinstein LV, Korn EL, Freidlin B, Hunsberger S, Ivy SP, Smith MA. Design issues of 
randomized phase II trials and a proposal for phase II screening trials. Journal of clinical oncology : 
official journal of the American Society of Clinical Oncology 2005;23:7199-206. 
47. 
Ruhle PF, Fietkau R, Gaipl US, Frey B. Development of a Modular Assay for Detailed 
Immunophenotyping of Peripheral Human Whole Blood Samples by Multicolor Flow Cytometry. Int J 
Mol Sci 2016;17. 
48. 
Feichtenbeiner A, Haas M, Buttner M, Grabenbauer GG, Fietkau R, Distel LV. Critical role of 
spatial interaction between CD8(+) and Foxp3(+) cells in human gastric cancer: the distance matters. 
Cancer immunology, immunotherapy : CII 2014;63:111-9. 
49. 
Nagl S, Haas M, Lahmer G, et al. Cell-to-cell distances between tumor-infiltrating 
inflammatory cells have the potential to distinguish functionally active from suppressed inflammatory 
cells. Oncoimmunology 2016;5:e1127494. 
50. 
Posselt R, Erlenbach-Wunsch K, Haas M, et al. Spatial distribution of FoxP3+ and CD8+ tumour 
infiltrating T cells reflects their functional activity. Oncotarget 2016. 
 
 
 

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13.0 ABBREVIATIONS 
3D-RT 
Three-dimensional radiotherapy 
5-FU 
5-fluorouracil 
AE 
Adverse Event       
ADCC 
Antibody dependent cellular cytotoxicity 
ADL 
Activities of Daily Living 
ALT 
Alanine Aminotransferase       
ANC 
Absolute Neutrophil Count      
AP 
Alkaline Phosphatase       
aPTT 
Activated Partial Thromboplastin Time     
AST 
Aspartate Aminotransferase       
BCG 
Bacillus Calmette–Guérin 
CBC 
Complete Blood Count      
CI 
Confidence Interval       
CNS 
Central Nervous System      
CPS 
Combined positive score 
CR 
Complete Response       
CrCl 
Calculated Creatinine Clearance      
CRF 
Case Report Form      
CRT 
Chemoradiation        
CT 
Computed Tomography       
CTCAE 
Common Toxicity Criteria for Adverse Events   
CTFG 
Clinical Trial Facilitation Group 
CTLA-4 
Cytotoxic T-Lymphocyte-Associated Antigen-4      
CTV 
Clinical Target Volume      
CUP 
Cancer of unknown primary 
DEGRO 
Deutsche Gesellschaft für Radioonkologie e.V. 
DKA 
Diabetic ketoacidosis 
DSMC 
Data Safety Monitoring Committee 
DVH 
Dose volume histogram 
ECI 
Event of Clinical Interest     
ECG 
Electrocardiogram        
ECOG 
Eastern Cooperative Oncology Group     
EMA 
European Medicines Agency 

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EORTC 
European Organization for Research and Treatment of Cancer 
ERC 
Ethics Review Committee      
FDA 
Food and Drug Administration     
FDAAA 
Food and Drug Administration Amendments Act   
FDAMA 
Food and Drug Administration Modernization Act 
GCP 
Good Clinical Practice      
GFR 
Glomerular Filtration Rate      
GTV 
Gross Tumor Volume      
hBsAg 
Hepatitis B surface Antigen     
HCV 
Hepatitis C Virus      
HIV 
Human Immunodeficiency Virus      
HNC 
Head and Neck Cancer     
HNSCC 
Head and Neck Squamous Cell Carcinoma   
Hr(s) 
Hour(s) 
IB 
Investigator’s Brochure       
ICH 
International Conference on Harmonization     
IEC 
Independent Ethics Committee 
IFN 
γ Interferon gamma      
Ig 
Immunglobuline 
IGRT 
Image guided radiotherapy 
IL 
Interleukin 
IMRT 
intensity-modulated radiotherapy 
INR 
International Normalized Ratio      
IRB 
Institutional Review Board      
iRECIST 
RECIST for immune-based therapeutics 
ITIM 
Immunoreceptor Tyrosine-based Inhibition Motif     
ITSM 
Immunoreceptor Tyrosine-based Switch Motif     
ITV 
Internal target volume 
ISF 
Investigator Site File 
IV/i.v. 
Intravenous        
Kg 
Kilogram        
LA 
HNSCC Locally Advanced Head and Neck Squamous Cell Carcinoma 
mAb 
Monoclonal Antibody        
mcL 
Microliters         
Mg 
Milligram         

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Mg/kg 
Milligram per Kilogram       
ml 
milliliter         
MRI 
Magnetic Resonance Imaging       
MSD 
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
MTD 
Maximum Tolerated Dose       
NA 
or N/A Not Applicable      
NCI 
National Cancer Institute       
NSAID 
Non-Steroidal Anti-inflammatory Drug       
NSCLC 
Non-Small Cell Lung Cancer      
ORR 
Objective Response Rate       
OS 
Overall Survival        
OTC 
Over-the-counter         
PD 
Progressive Disease / Pharmacodynamics      
PD-1 
Programmed Cell Death Receptor 1     
PD-L1 
Programmed Cell Death Receptor Ligand 1    
PD-L2 
Programmed Cell Death Receptor Ligand 2    
PFS 
Progression Free Survival       
PK 
Pharmacokinetic         
PO 
Oral Administration        
PR 
Partial Response        
PTV 
Planning Target Volume       
PT 
Prothrombin Time        
PTT 
Partial Thromboplastin Time       
RTOG 
Radiation Therapy Oncology Group 
QW 
Every Week        
Q2W 
Every 2 Weeks       
Q3W 
Every 3 Weeks       
RECIST 
Response Evaluation Criteria in Solid Tumors    
RNA 
Ribonucleic Acid        
RT 
Radiotherapy or Radiation Therapy      
SAE 
Serious Adverse Events       
SAP 
Statistical Analysis Plan       
SGOT 
Serum Glutamic Oxaloacetic Transaminase      
SGPT 
Serum Glutamic Pyruvic Transaminase      
SJS 
Stevens-Johnson syndrome 

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SmPC 
Summary of medicinal Product Characteristics 
SRT 
stereotactic radiotherapy 
t½ 
Terminal half-life        
TB 
Bacillus Tuberculosis 
TEN 
toxic epidermal necrolysis 
TIL 
tumor-infiltrating lymphocytes 
TSH 
Thyroid Stimulating Hormone       
ULN 
Upper Limit of Normal      
VMAT 
volumetric modulated arc therapy 
WBC 
White Blood Cell       
 
 

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14.0 APPENDICES 
14.1 ECOG Performance Status 
Table 14: ECOG 
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. 
 
14.2 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) 
 
14.3 Response Evaluation Criteria iRECIST 
Response evaluation will be performed according to iRECIST* and RECIST**. These 
iRECIST criteria are the RECIST 1.1 criteria adapted for immunotherapy.  
* As published in Lancet Oncology: 
Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, Lin NU, Litière S, 
Dancey J, Chen A, Hodi FS, Therasse P, Hoekstra OS, Shankar LK, Wolchok JD, Ballinger 

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M, Caramella C, de Vries EG; RECIST working group. iRECIST: guidelines for response 
criteria for use in trials testing immunotherapeutics. Lancet Oncol. 2017 Mar;18(3):e143-e152. 
** As published in the European Journal of Cancer: 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck 
S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij 
J. New response evaluation criteria in solid tumours: 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. 
 
 

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15.2 Investigator 
I agree to conduct this clinical trial in accordance with the design outlined in this protocol and 
to abide by all provisions of this protocol (including other manuals and documents referenced 
from this protocol). I agree to conduct the trial in accordance with generally accepted standards 
of Good Clinical Practice. I also agree to report all information or data in accordance with the 
protocol and, in particular, I agree to report any SAEs as defined in the section in the protocol. 
I also agree to handle all clinical supplies provided by the Sponsor and collect and handle all 
clinical specimens in accordance with the protocol. I understand that information that identifies 
me will be used and disclosed as described in the protocol, and that such information may be 
transferred to countries that do not have laws protecting such information. Since the 
information in this protocol and the referenced IB is confidential, I understand that its 
disclosure to any third parties, other than those involved in approval, supervision, or conduct 
of the trial is prohibited. I will ensure that the necessary precautions are taken to protect such 
information from loss, inadvertent disclosure or access by third parties. 
TYPED NAME 
 
TITLE 
 
SIGNATURE 
 
DATE SIGNED