Conditions: Head and Neck Carcinoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 22
Healthy volunteers: no

Brief summary:
Squamous cell carcinoma of the head and neck, which accounts for 90% of head and neck cancers, is the tenth most common cancer worldwide with over 650000 new cases per year. The major risk factors for HNSCC development comprise alcohol and tobacco consumption. During the last decades human papilloma virus infection (HPV) has been identified to contribute to the development of oropharyngeal HNSCC in a subgroup of patients5. Standard treatment options include surgery, (chemo)radiation and chemotherapy. Despite improvements of treatment regimens the recurrence rate of stage III/IV disease after curative therapy is about 30-40%. In locoregionally unresectable recurrent or metastatic disease palliative poly-chemotherapy is the mainstay of therapy.The median survival time of these patients is 6-8 months. Based on the results of the EXTREME study a combination regimen containing a platinum drug, 5 fluorouracil (5-FU) and weekly cetuximab has become standard of care in this setting. For patients, who progressed after platinum based therapy, treatment options are scarce. Besides platinum drugs, taxanes such as paclitaxel or docetaxel were shown to be of particular use in this setting. Apart from that there has been increasing preclinical and clinical evidence that immune-checkpoint inhibitors such as pembrolizumab might play a role in HNSCC. Thus, it is the aim of this study to test if the combination of docetaxel and pembrolizumab after platinum failure is an effective and safe regimen.

Detailed description:
not provided

Arms:
arm 1: Docetaxel 75mg/m2 plus pembrolizumab 200mg will be administered every 3 weeks intravenously for 6 cycles. Thereafter pembrolizumab 200mg every 3 weeks will be given as maintenance therapy until progression.

Interventions: intervention 1: Docetaxel intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: Docetaxel 75mg/m2; q21 intervention 2: Pembrolizumab 200mg, q21

Protocol document:
Prot_SAP_000.pdf: 
 
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SPONSOR:  Medical University of Vienna 
                      Spitalgasse 23 
                      1090 Vienna 
           Tel: +43-1-401 600 
 
TITLE: Immunomodulation of pembrolizumab plus docetaxel for the treatment of r/m 
SCCHN after platinum failure 
 
NCT02718820 
EudraCT NUMBER (Studies in Europe only): 2015-002325-18 
 
 
 
PRINCIPAL INVESTIGATOR: 
Dr. Thorsten Füreder 
Department of Internal Medicine I, Division of Oncology 
Comprehensive Cancer Center Vienna 
Medical University of Vienna  
A-1090 Vienna, Währinger Gürtel 18-20 
Tel: +43-1-40 400-75720 
Fax: +43-1-40 400-60880 
Monitor: 
Marika Rosner 
Department of Internal Medicine I, A-1090 Vienna, Währinger Gürtel 18-20 


 
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TRIAL SUMMARY 
Abbreviated Title 
PemDoc 
Trial Phase 
I/II 
Clinical Indication 
Recurrent and metastatic head and neck cancer after platinum failure 
Trial Type 
Interventional prospective, single-arm, phase II 
Route of administration 
Intravenous 
 
Trial Blinding 
Unblinded open label 
Treatment Groups  
1 
Number of trial subjects 
22 
Estimated enrollment period 
24 months 
Objectives 
 
 
 
 
Primary objective 
• To evaluate the Overall Response Rate  (CR/PR) rate in patients 
treated with pembrolizumab plus docetaxel for recurrent or metastatic 
(R/M) HNSCC after platinum-based first-line therapy 
• To evaluate the safety of pembrolizumab in combination with 
docetaxel in subjects diagnosed with R/M HNSCC 
Secondary objectives 
• To describe Best Overall Response categories (CR, PR, SD, PD) in 
patients treated with pembrolizumab in combination with docetaxel 
in subjects diagnosed with R/M HNSCC after platinum-based first-
line therapy 
• To describe individual duration of response over time  
• To evaluate changes in health-related quality-of-life assessments 
from baseline in subjects with R/M HNSCC using the EORTC QLQ 
C-30 and EORTC QLQ-H&N35.  
• To assess median Overall Survival (OS) and Progression Free 
Survival (PFS)  in this patient population 
Exploratory objectives 
• To assess PD-L1 as a predictive marker for response to 
pembrolizumab  
− 
Examination of PD-L1 expression in blood and tumor tissue, 
including infiltrating immune cells, obtained during biopsy 
of primary tumor (and recurrent tumor if available) 


 
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• 
To investigate molecular genetic pattern in tumor tissue obtained 
during biopsy of the primary tumor (and recurrent tumor if available) 
via next generation sequencing (NGS) using the Qiagen 
Comprehensive Cancer GeneRead DNAseq Targeted Panel in order 
to predict response to docetaxel/pembrolizumab. 
 
Selection criteria 
Inclusion criteria:  
• 
The patient has provided written informed consent prior to any 
study-related procedure. 
• 
The patient is at least 18 years of age 
• 
Histologically proven locally advanced unresectable, recurrent 
and/or metastatic squamous cell carcinoma of the oropharynx, 
hypopharynx, larynx or oral cavity  not amenable for salvage 
surgery 
• 
P16 mutation status has to be determined 
• 
Documented progressive disease based on investigator assessment 
according to RECIST 1.1, following receipt of a cisplatin and/or 
carboplatin based regimen independent of whether patient 
progressed during or after platinum based therapy. Platinum therapy 
might have been administered either as part of induction 
chemotherapy (12 months), chemoradiation (6 months) or as first 
line systemic palliative chemotherapy (6 months). 
• 
Measurable disease according to RECIST 1.1. 
• 
The patient has a life expectancy of at least 3 months. 
• 
Has a performance status of 0 or 1 on the ECOG Performance Scale 
• 
Female subject of childbearing potential should have a negative urine 
or serum pregnancy prior to study registration and re-tested within 72 
hours prior to receiving the first dose of study medication. If the urine 
test is positive or cannot be confirmed as negative, a serum pregnancy 
test will be required. 
• 
Female subjects of childbearing potential should be willing to use 2 
methods of birth control or be surgically sterile, or abstain from 
heterosexual activity for the course of the study through 120 days after 
the last dose of study medication. Subjects of childbearing potential 
are those who have not been surgically sterilized or have not been free 
from menses for > 1 year. 


 
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• 
Male subjects should agree to use an adequate method of 
contraception starting with the first dose of study therapy through 120 
days after the last dose of study therapy. 
• 
Demonstrate adequate organ function as defined in Table 1, all 
screening labs should be performed within 10 days of treatment 
initiation.  
 
Exclusion criteria:  
• 
Prior taxane therapy is not allowed except as part of induction 
therapy (at least 6 months before study entry) 
• 
Nasopharyngeal carcinomas or salivary glands cancers are not 
eligible 
• 
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. 
• 
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. 
 
• 
Has a known history of active TB   (Bacillus Tuberculosis) 
• 
Hypersensitivity to pembrolizumab or any of its excipients. 
• 
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 adverse events due to agents administered more 
than 4 weeks earlier. 
• 
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 adverse events due to 
a previously administered agent. 
- 
Note:  If subject received major surgery, they must have 
recovered adequately from the toxicity and/or 
complications from the intervention prior to starting 
therapy.   
• 
Has a known additional malignancy that is progressing or requires 
active treatment.  Exceptions include basal cell carcinoma of the 
skin or squamous cell carcinoma of the skin that has undergone 
potentially curative therapy or in situ cervical cancer. 


 
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• 
Has known active central nervous system (CNS) metastases and/or 
carcinomatous meningitis.  Subjects with previously treated brain 
metastases may participate provided they are stable (without 
evidence of progression by imaging for at least four weeks prior to 
the first dose of trial treatment and any neurologic symptoms have 
returned to baseline), have no evidence of new or enlarging brain 
metastases, and are not using steroids for at least 7 days prior to trial 
treatment. This exception does not include carcinomatous 
meningitis which is excluded regardless of clinical stability. 
• 
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.  
• 
Has known history of, or any evidence of active, non-infectious 
pneumonitis. 
• 
Has an active infection requiring systemic therapy. 
• 
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.   
• 
Has known psychiatric or substance abuse disorders that would 
interfere with cooperation with the requirements of the trial. 
• 
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. 
• 
Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-
PD-L2 agent. 
• 
Has a known history of Human Immunodeficiency Virus (HIV) 
(HIV 1/2 antibodies). 
• 
Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C 
(e.g., HCV RNA [qualitative] is detected). 
• 
Has received a live vaccine within 30 days of planned start of study 
therapy. 
Duration of Participation 
Each subject will participate in the trial until death, drop out, or loss-to-
follow-up from the time the subject signs the Informed Consent Form 


 
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(ICF) through the final contact. Treatment on trial will continue until 
disease progression is confirmed. 
 
 


 
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GLOSSARY OF ABBREVIATIONS 
AE adverse event  
ALT alanine aminotransferase 
aPTT activated partial thromboplastin time 
ASCT autologous stem cell transplantation  
AST aspartate aminotransferase 
BRAF v-Raf murine sarcoma viral oncogene homolog B1 
beta-HCG beta human chorionic gonadotrophin 
CHF congestive heart failure 
CNS central nervous system  
CT computed tomography 
CTLA4 cytotoxic T-lymphocyte-associated protein 4 
CR complete remission 
CRF case report form 
CrCl creatinine clearance 
CTCAE Common Terminology Criteria for Adverse Events  
ECG electrocardiogram 
ECOG Eastern Cooperative Oncology Group 
EDTA ethylenediaminetetraacetic acid 
ELISA Enzyme-linked Immunoabsorbent Assay  
EORTC European Organization for Research and Treatment of Cancer 
FAS Full analysis set 
GCP Good Clinical Practice  
HBV sAg hepatitis B virus surface antigen  
HCV RNA hepatitis C virus ribonucleic acid  
HIV human immunodeficiency virus  
HNSCC head and neck squamous cell carcinoma 
HPV human papilloma virus  
ICH International Conference on Harmonisation 
IEC Independent Ethics Committee 
INR International Normalized Ratio 
IPCG International Primary Central Nervous System Lymphoma Collaborative Group 
IRB Institutional Review Board 
ITIM immunoreceptor tyrosine inhibitory motif 


 
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ITSM immunoreceptor tyrosine-based switch motif 
mAbs monoclonal antibodies 
MRI magnetic resonance imaging  
MSD Merck Sharp & Dohme 
MTX methotrexate 
NaCl natrium chloride 
NCI National Cancer Institute  
NGS Next generation sequencing 
NSCLC and non-small cell lung carcinoma  
NYHA New York Heart Association  
PD progressive disease 
PD-1 programmed death 1 
PD-L1 programmed death ligand 1 
PR partial remission 
PT prothrombin time 
RCC renal cell carcinoma 
SAE Serious adverse event  
SD stable disease  
SmPC Summary of product characteristics ULN upper limit of normal 
SOP standard operating procedure 
sGOT serum glutamic oxaloacetic transaminase 
sGPT serum glutamic-pyruvic transaminase 
TAM tumor-associated macrophages 
TILs tumor-infiltrating lymphocytes  
WBC white blood cells 
WHO World Health Organization 
 
 


 
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TABLE OF CONTENTS 
TITLE: Immunomodulation of pembrolizumab plus docetaxel for the treatment of r/m 
SCCHN after platinum failure ................................................................................... 1 
TRIAL SUMMARY ................................................................................................................ 2 
Glossary of Abbreviations ...................................................................................................... 7 
1. 
Introduction and study rationale ............................................................................. 13 
1.1. 
Introduction ........................................................................................................... 13 
1.2. 
Programmed death receptor-1 (PD-1, CD279) background ............................. 13 
1.3. 
Study rationale....................................................................................................... 14 
1.4. 
Pembrolizumab Background ............................................................................... 15 
1.4.1. Pharmaceutical Background of Pembrolizumab ............................................... 15 
1.4.2. Preclinical and Clinical Trial Data ...................................................................... 15 
1.4.3. Rationale for Dose Selection/Regimen/Modification ......................................... 15 
1.4.4. Docetaxel dose selection ........................................................................................ 17 
2. 
Study OBJECTIVES ................................................................................................. 17 
2.1 
Primary Objectives ............................................................................................... 17 
2.2 
Secondary Objectives ............................................................................................ 18 
2.3 
Exploratory Objectives ......................................................................................... 18 
3. 
Total Number of Patients ......................................................................................... 18 
4. 
Selection Criteria ....................................................................................................... 18 
4.1. Inclusion Criteria ........................................................................................................... 18 
4.2. Exclusion Criteria .......................................................................................................... 20 
5. 
Endpoint assessment ................................................................................................. 22 
5.1. Safety ............................................................................................................................... 22 


 
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5.2. Response assessment ...................................................................................................... 22 
5.3. Response duration .......................................................................................................... 23 
5.4. EEORTC QLQ-C30 and eEORTC QLQ-H&N35 questionnaire .............................. 23 
5.5. Exploratory analyses ...................................................................................................... 25 
6. 
INVESTIGATIONAL PLAN ................................................................................... 25 
6.1. Screening and Enrolment .............................................................................................. 25 
6.2. Treatment ........................................................................................................................ 25 
6.3. Monitoring and Inspection by authorities ................................................................... 26 
6.4. Follow-up ......................................................................................................................... 26 
6.5. Withdrawal of consent ................................................................................................... 26 
6.6. Lost to follow-up ............................................................................................................. 26 
6.7. Study design schematic .................................................................................................. 28 
6.8. Pembrolizumab Dose Modification Guidelines for Drug Related Adverse Event ... 29 
6.9. Docetaxel Dose Modification Guidelines for Drug Related Adverse Events ............ 31 
6.10. Concomitant Medications and chemotherapy pre-medication ................................ 34 
6.11. Study flow chart ........................................................................................................... 35 
7. 
Ethical considerations ............................................................................................... 36 
7.1. Good clinical practice ..................................................................................................... 36 
7.2. Institutional Review Board/Independent Ethics Committee ..................................... 36 
7.3. Informed consent ............................................................................................................ 37 
8. 
STUDY MEDICATIONs .......................................................................................... 37 
8.1. Investigational Product .................................................................................................. 37 
8.2. Handling and Dispensing ............................................................................................... 37 
8.3. Product description pembrolizumab ............................................................................ 38 


 
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8.4. Pembrolizumab administration .................................................................................... 38 
8.5. Packaging and Labeling Information ........................................................................... 38 
8.6. Clinical Supplies Disclosure .......................................................................................... 39 
8.7. Storage and handling ..................................................................................................... 39 
8.8. Returns and Reconciliation ........................................................................................... 39 
8.9. Docetaxel administration ............................................................................................... 39 
8.10. Supportive Care guidelines ......................................................................................... 39 
8.11. Diet/Activity/Other Consideration .............................................................................. 43 
8.12. Subject Withdrawal/Discontinuation Criteria .......................................................... 44 
8.13. Criteria for Early Trial Termination ......................................................................... 45 
9. 
STATISTICAL CONSIDERATIONS ..................................................................... 46 
9.1. Sample Size Calculation ................................................................................................. 46 
9.2. Study population ............................................................................................................ 46 
9.2.1. Full analysis set Assessment of Efficacy .................................................................. 46 
9.2.2. Safety Analyses set .................................................................................................... 47 
9.2.3. Assessment of Safety ................................................................................................. 47 
9.2.4. Secondary Objectives ................................................................................................ 47 
9.2.5. Exploratory Objectives ............................................................................................. 47 
10. 
Adverse Event ........................................................................................................... 47 
10.1. Definition of an overdose for this protocol and reporting pf overdose to the sponsor   
and MERCK .............................................................................................................. 48 
10.2. Reporting of pregnancy and lactation to the sponsor and to MERCK ................... 49 
10.3. Immediate reporting of adverse events to the sponsor and to MERCK ................. 49 
10.3.1. Serious adverse events and Suspected unexpected serious adverse reaction 
(SUSARS) ................................................................................................................... 49 


 
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10.4. Events of clinical interest ............................................................................................. 50 
10.5. Evaluating adverse event ............................................................................................. 51 
10.6. Sponsor responsibility for reporting serious adverse events .................................... 52 
11. 
Insurance Policy ...................................................................................................... 52 
12. 
Publication ................................................................................................................. 52 
13. 
Financial considerations and research funding ...................................................... 52 
14. 
APPENDICES ........................................................................................................... 55 
15. 
REFERENCES .......................................................................................................... 56 
 
 
 
 


 
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1. INTRODUCTION AND STUDY RATIONALE 
1.1. Introduction 
Squamous cell carcinoma of the head and neck (HNSCC), which accounts for 90% of head and 
neck cancers, is the tenth most common cancer worldwide with over 650000 new cases per year1-
3. The major risk factors for HNSCC development comprise alcohol and tobacco consumption4. 
During the last decades human papilloma virus infection (HPV) has been identified to contribute 
to the development of oropharyngeal HNSCC in a subgroup of patients5. These population show a 
more favourable prognosis compared to HPV negative disease5. A multidisciplinary approach 
involving radiation oncologists, medical oncologist and head and neck surgeons is necessary for 
the optimal management of these patients. Standard treatment options include surgery, 
(chemo)radiation and chemotherapy. Despite improvements of treatment regimens the recurrence 
rate of stage III/IV disease after curative therapy is about 30-40% in the first 2 years of follow up 
and a constant rate of 2-3% per year of second primaries is observed6,7. In locoregionally 
unresectable recurrent or metastatic (R/M) disease palliative poly-chemotherapy is the mainstay of 
therapy. Although novel targeted therapies such as cetuximab in the past decade have been 
implemented in these regimens, the prognosis of patients with locoregionally advanced R/M 
disease remains poor. The median survival time of these patients is 6-8 months 8. Based on the 
results of the EXTREME study a combination regimen containing a platinum drug, 5-FU and 
weekly cetuximab has become standard of care in this setting9. For patients, who progressed after 
platinum based therapy, treatment options are scarce. Besides platinum drugs, MTX or taxanes 
such as paclitaxel or docetaxel were shown to be of particular use at this stage of disease10-14. Thus, 
it is obvious that novel treatment strategies are desperately needed.  
1.2. Programmed death receptor-1 (PD-1, CD279) 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. 
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 


 
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tyrosine-based switch motif (ITSM).  Following T-cell stimulation, PD-1 recruits the tyrosine 
phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 which are involved in 
the CD3 T-cell signaling cascade.  The mechanism by which PD-1 down modulates T-cell 
responses is similar to, but distinct from that of CTLA-4 as both molecules regulate an overlapping 
set of signaling proteins.  PD-1 was shown to be expressed on activated lymphocytes including 
peripheral CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer cells.  Expression has also 
been shown during thymic development on CD4-CD8- (double negative) T-cells as well as subsets 
of macrophages and dendritic cells.  The ligands for PD-1 (PD-L1 and PD-L2) are constitutively 
expressed or can be induced in a variety of cell types, including non-hematopoietic tissues as well 
as in various tumors.  Both ligands are type I transmembrane receptors containing both IgV- and 
IgC-like domains in the extracellular region and contain short cytoplasmic regions with no known 
signaling motifs.  Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through 
the T-cell receptor.  PD-L1 is expressed at low levels on various non-hematopoietic tissues, most 
notably on vascular endothelium, whereas PD-L2 protein is only detectably expressed on antigen-
presenting cells found in lymphoid tissue or chronic inflammatory environments.  PD-L2 is thought 
to control immune T-cell activation in lymphoid organs, whereas PD-L1 serves to dampen 
unwarranted T-cell function in peripheral tissues.  Although healthy organs express little (if any) 
PD-L1, a variety of cancers were demonstrated to express abundant levels of this T-cell inhibitor.  
PD-1 has been suggested to regulate tumor-specific T-cell expansion in subjects with melanoma.  
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. 
 
1.3. Study rationale 
During the last years there has been increasing preclinical and clinical evidence that immune-
checkpoint inhibitors might play a role in HNSCC: It has been shown that PD-L1 expression is 
very common in tonsillar crypt epithelium in the presence of HPV infection15. In the R/M setting 
it has been demonstrated that PD-L1 is highly expressed 15. Apart from that PD-L1 expression 
seems to correlate with the HPV status 16. Trials evaluating pembrolizumab in head and neck 
cancer have demonstrated clinical activity in patients with recurrent and/or metastatic disease. 
KEYNOTE 012 is a phase Ib study of pembrolizumab in patients with HPV-negative and HPV-
positive head and neck cancer. This trial enrolled an initial 60 patient cohort with R/M HNSCC for 
treatment with single agent pembrolizumab. Preliminary results of this cohort were reported at the 
Annual Meeting of the American Society of Clinical Oncology (ASCO) in 2014, showing an 
overall response rate (confirmed and unconfirmed) of 19.6% (10 partial responses [PRs], 1 
complete response [CR] out of 56 patients evaluable for response) at the time of the meeting. An 
additional 16/56 patients (28.6%) experienced stable disease (SD), with 51% of patients 
experiencing some numerical decrease in tumor burden from baseline. Seventeen total patients 
with CR, PR, or SD remain on therapy at the time of the reporting for > 6 months. There were no 
new or unexpected toxicity signals in this patient cohort, with infrequent grade 3-4 drug-related 
(DR) adverse events (AEs).  


 
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Although these data are promising, conventional chemotherapy is still the mainstay of treatment 
of R/M HNSCC patients. Besides platinum drugs, taxanes such as paclitaxel or docetaxel were 
shown to be of particular use in this setting10-13. Apart from their cytotoxic effects there is profound 
evidence that these chemotherapeutics interact with the immune system as well: A very recent 
preclinical study demonstrated that chemoradiation and taxane containing induction chemotherapy 
in stage III/IV SCCHN patients results in PD-1 up-regulation17.  On the other hand it is generally 
known that single agent taxane treatment exerts immunomodulatory effects: In preclinical models 
it has been shown that docetaxel therapy enhances immune response in combination with cancer 
vaccines18. Clinically it has been demonstrated very recently in prostate cancer patients that there 
is a major effect on regulatory T cells after docetaxel exposure providing further scientific rationale 
for the combination of taxanes either with cancer vaccines or immune checkpoint inhibitors19.    
In summary the combination of docetaxel and pembrolizumab after platinum failure seems to be 
an interesting approach as a salvage therapy in R/M HNSCC patients, might boost the immune 
response and exert superior anti-tumor activity. 
 
 
1.4. Pembrolizumab Background  
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background information 
on MK-3475. 
 
1.4.1. Pharmaceutical Background of Pembrolizumab 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-
L1 and PD-L2.  KeytrudaTM (pembrolizumab) has recently been approved in the United Stated for 
the treatment of patients with unresectable or metastatic melanoma and disease progression 
following ipilumumab and, if BRAF V600 mutation positive, a BRAF inhibitor. 
1.4.2. Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
1.4.3. Rationale for Dose Selection/Regimen/Modification 
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and clinical 
activity of single agent MK-3475.  The dose escalation portion of this trial evaluated three dose 
levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects with 
advanced solid tumors.  All three dose levels were well tolerated and no dose-limiting toxicities 
were observed.  This first in human study of MK-3475 showed evidence of target engagement and 
objective evidence of tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg 


 
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Q2W).  No MTD has been identified to date.  10.0 mg/kg Q2W, the highest dose tested in PN001, 
will be the dose and schedule utilized in Cohorts A, B, C and D of this protocol to test for initial 
tumor activity.  Recent data from other clinical studies within the MK-3475 program has shown 
that a lower dose of MK-3475 and a less frequent schedule may be sufficient for target engagement 
and clinical activity. 
 
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic clearance, 
limited volume of distribution, and a long half-life (refer to IB).  Pharmacodynamic data (IL-2 
release assay) suggested that peripheral target engagement is durable (>21 days).  This early PK 
and pharmacodynamic data provides scientific rationale for testing a Q2W and Q3W dosing 
schedule.   
 
A population pharmacokinetic analysis has been performed using serum concentration time data 
from 476 patients. Within the resulting population PK model, clearance and volume parameters of 
MK-3475 were found to be dependent on body weight. The relationship between clearance and 
body weight, with an allometric exponent of 0.59, is within the range observed for other antibodies 
and would support both body weight normalized dosing or a fixed dose across all body weights.  
MK-3475 has been found to have a wide therapeutic range based on the melanoma indication.  The 
differences in exposure for a 200 mg fixed dose regimen relative to a 2 mg/kg Q3W body weight 
based regimen are anticipated to remain well within the established exposure margins of 0.5 – 5.0 
for MK-3475 in the melanoma indication. The exposure margins are based on the notion of similar 
efficacy and safety in melanoma at 10 mg/kg Q3W vs. the proposed dose regimen of 2 mg/kg Q3W 
(i.e. 5-fold higher dose and exposure). The population PK evaluation revealed that there was no 
significant impact of tumor burden on exposure. In addition, exposure was similar between the 
NSCLC and melanoma indications. Therefore, there are no anticipated changes in exposure 
between different indication settings. 
 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in solid 
tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 2 mg/kg 
or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response relationships of 
pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg Q3W, 
3) the lack of effect of tumor burden or indication on distribution behavior of pembrolizumab (as 
assessed by the population PK model) and 4) the assumption that the dynamics of pembrolizumab 
target engagement will not vary meaningfully with tumor type. 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based on 
simulations performed using the population PK model of pembrolizumab showing that the fixed 
dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent with those 
obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient exposures in the 
exposure range established in melanoma as associated with maximal efficacy response and 3) will 
maintain individual patients exposure in the exposure range established in melanoma that are well 
tolerated and safe.  


 
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A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians and 
to reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity in the 
logistical chain at treatment facilities and reduce wastage. 
1.4.4. Docetaxel dose selection 
 
Docetaxel is a semisynthetic taxane derived from a precursor extracted from the needles of the 
European yew, Taxus baccata. It has a mechanism of action which is similar to (or may be identical 
to) paclitaxel. Docetaxel enhances microtubule assembly and inhibits the depolymerization of 
tubulin. As with paclitaxel, this can lead to bundles of microtubules in the cell, which by blocking 
cells in the M phase of the cell cycle results in the inability of the cells to divide. This contrasts 
with the action of other spindle poisons in clinical use such as colchicine or vinca-alkaloids which 
inhibit tubulin assembly in microtubules. Comparing paclitaxel and docetaxel using the "tubulin 
in vitro assay", the concentration required to provide 50% inhibition of microtubule disassembly 
(or IC50) for Docetaxel is 0.2 μm and for paclitaxel is 0.4 μm. 
 
Docetaxel will be administered at 75mg/m2 every three weeks, which is a well established and 
approved regimen in various malignancies including HNSCC20. This regimen has been tested in 
numerous clinical trials both as a monotherapy and in combination with other cytotoxic drugs and 
monoclonal antibodies, which did not result in unacceptable toxicity. Additionally, docetaxel 
75mg/m2 every three weeks is part of the currently used induction chemotherapy regimens in 
HNSCC, where it is combined with cisplatin and 5-FU21. Thus the choice of Docetaxel 75mg/m2 
Q3W seems to be an appropriate dose in combination with pembrolizumab 200mg Q3W. 
 
For further details please refer to the attached product information.  
 
  
2. STUDY OBJECTIVES 
2.1 
Primary Objectives 
• To evaluate the Overall Response Rate (CR/PR) rate in patients treated with 
pembrolizumab plus docetaxel for R/M HNSCC after platinum-based first-line therapy. 
If there are 7 or more successes (CR or PR) out of the 22 patients the study is considered 
to be a success and the null hypothesis (Clinical Benefit Rate is ≤15 %) will be rejected 
in favour of the alternative hypothesis of a higher Overall Response Rate. 
 
• To evaluate the safety of pembrolizumab in combination with docetaxel in subjects 
diagnosed with R/M HNSCC 
 


 
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2.2 
Secondary Objectives  
• To describe Best Overall Response categories (CR, PR, SD, PD) in patients treated with 
pembrolizumab in combination with docetaxel in subjects diagnosed with R/M HNSCC 
after platinum-based first-line therapy. 
• To describe individual duration of response over time 
• To evaluate changes in health-related quality-of-life assessments from baseline in subjects 
with R/M HNSCC using the EORTC QLQ C-30 and EORTC QLQ-H&N35. 
• To assess median Overall Survival (OS) and Progression Free Survival (PFS)  in this patient 
population 
  
2.3 
Exploratory Objectives 
 
• To assess PD-L1 as a predictive marker for response to pembrolizumab  
➢ Examination of PD-L1 expression in blood and tumor tissue, including infiltrating 
immune cells, obtained during biopsy of primary tumor (and recurrent tumor if 
available) 
• To investigate molecular genetic pattern in tumor tissue obtained during biopsy of the 
primary tumor (and recurrent tumor if available) via next generation sequencing (NGS) 
using the Qiagen Comprehensive Cancer GeneRead DNAseq Targeted Panel in order to 
predict response to docetaxel/pembrolizumab. 
3. TOTAL NUMBER OF PATIENTS 
 
22 evaluable patients. 
 
4. SELECTION CRITERIA 
 
4.1. Inclusion Criteria 
 
• The patient has provided written informed consent prior to any study-related procedure. 


 
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• The patient is at least 18 years of age 
• Histologically proven locally advanced unresectable, recurrent and/or metastatic squamous 
cell carcinoma of the oropharynx, hypopharynx, larynx or oral cavity  not amenable for 
salvage surgery 
• P16 mutation status has to be determined 
• Documented progressive disease based on investigator assessment according to RECIST 
1.1, following receipt of a cisplatin and/or carboplatin based regimen independent of 
whether patient progressed during or after platinum based therapy. Platinum therapy might 
have been administered either as part of induction chemotherapy (12 months), 
chemoradiation (6 months) or as first line systemic palliative chemotherapy (6 months). 
• Measurable disease according to RECIST 1.1. 
• The patient has a life expectancy of at least 3 months. 
• Has a performance status of 0 or 1 on the ECOG Performance Scale 
• Female subject of childbearing potential should have a negative urine or serum pregnancy 
prior to study registration and re-tested within 72 hours prior to receiving the first dose of 
study medication. If the urine test is positive or cannot be confirmed as negative, a serum 
pregnancy test will be required. 
• Female subjects of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of the 
study through 120 days after the last dose of study medication. Subjects of childbearing 
potential are those who have not been surgically sterilized or have not been free from 
menses for > 1 year. 
• Male subjects should agree to use an adequate method of contraception starting with the 
first dose of study therapy through 120 days after the last dose of study therapy. 
• 
Demonstrate adequate organ function as defined in Table 1, all screening labs should be 
performed within 10 days of treatment initiation.  
 
System  
 
Laboratory Value  
 
Hematological  
 
Absolute neutrophil count (ANC)  
 
Platelets  
 
 
≥1,500 /mcL  
≥100,000 / mcL  


 
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Hemoglobin  
 
 
Renal  
Creatinine  
  
  
Hepatic  
Total bilirubin  
 
 
AST (SGOT) and ALT (SGPT)  
 
 
 
Coagulation  
International Normalized Ratio (INR) or 
Prothrombin Time (PT)  
Activated Partial Thromboplastin Time 
(aPTT)  
  
 
≥9 g/dL or ≥5.6 mmol/L  
 
 
≤2xULN 
 
 
≤1.5xULN OR  
Direct bilirubin ≤ULN for subjects with total 
bilirubin levels >1.5xULN  
≤2.5xULN OR  
≤5xULN for subjects with liver metastases  
 
≤1.5xULN unless subject is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic range 
of intended use of anticoagulants  
≤1.5xULN unless subject is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic range 
of intended use of anticoagulants 
 
 
4.2. Exclusion Criteria 
 
The subject must be excluded from participating in the trial if the subject: 
• Prior taxane therapy is not allowed except as part of induction therapy (at least 6 months 
before study entry) 
• Nasopharyngeal carcinomas or salivary glands cancers are not eligible 
• 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. 
• 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.  
• Has a known history of active TB   (Bacillus Tuberculosis) 
• Hypersensitivity to pembrolizumab or any of its excipients. 
• 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 adverse events due to agents 
administered more than 4 weeks earlier. 


 
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• 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 
adverse events due to a previously administered agent. 
- 
Note:  If subject received major surgery, they must have recovered adequately from 
the toxicity and/or complications from the intervention prior to starting therapy.   
• Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin 
that has undergone potentially curative therapy or in situ cervical cancer. 
• Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  Subjects with previously treated brain metastases may participate provided they 
are stable (without evidence of progression by imaging for at least four weeks prior to the 
first dose of trial treatment and any neurologic symptoms have returned to baseline), have no 
evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days 
prior to trial treatment. This exception does not include carcinomatous meningitis which is 
excluded regardless of clinical stability. 
• 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.  
• Has known history of, or any evidence of active, non-infectious pneumonitis. 
• Has an active infection requiring systemic therapy. 
• 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.   
• Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
• 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. 
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
• Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 


 
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• Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
• Has received a live vaccine within 30 days of planned start of study therapy. 
Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines and 
are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated 
vaccines, and are not allowed. 
 
5. ENDPOINT ASSESSMENT 
 
5.1. Safety 
 
Safety analyses will be performed in all treated subjects. Descriptive analysis of safety will be 
presented using National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0 (See Appendix II). All on-study AEs, treatment-related AEs, SAEs, 
and treatment-related SAEs will be tabulated using worst grade per NCI CTCAE v 4.0 criteria by 
system organ class and preferred term. On-study laboratory parameters including haematology, 
chemistry, liver function, and renal function will be summarized using worst grade NCI CTCAE 
v 4.0 criteria. 
 
5.2. Response assessment 
 
Response will be measured according to the RECIST 1.1 criteria using a CT scan or MRI every 12 
weeks. However, RECIST 1.1 will be adapted to account for the unique tumor response 
characteristics seen with treatment of pembrolizumab. Immunotherapeutic agents such as 
pembrolizumab may produce antitumor effects by potentiating endogenous cancer-specific 
immune responses. The response patterns seen with such an approach may extend beyond the 
typical time course of responses seen with cytotoxic agents, and can manifest a clinical response 
after an initial increase in tumor burden or even the appearance of new lesions. Standard RECIST 
may not provide an accurate response assessment of immunotherapeutic agents such as 
pembrolizumab. Therefore, RECIST 1.1 will be used with the following adaptations:  
 
If radiologic imaging shows initial PD, tumor assessment should be repeated ≥4 weeks later in 
order to confirm PD with the option of continuing treatment per below while awaiting radiologic 
confirmation of progression. If repeat imaging shows a reduction in the tumor burden compared to 
the initial scan demonstrating PD, treatment may be continued / resumed. If repeat imaging 


 
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confirms progressive disease, subjects will be discontinued from study therapy. In subjects who 
have initial evidence of radiological PD, it is at the discretion of the treating physician whether to 
continue a subject on study treatment until repeat imaging is obtained. This clinical judgment 
decision should be based on the subject’s overall clinical condition, including performance status, 
clinical symptoms, and laboratory data. Subjects may receive pembrolizumab treatment while 
waiting for confirmation of PD if they are clinically stable as defined by the following criteria:  
 
• Absence of signs and symptoms indicating disease progression  
• No decline in ECOG performance status  
• Absence of rapid progression of disease  
• Absence of progressive tumor at critical anatomical sites (e.g., cord compression) requiring 
urgent alternative medical intervention  
 
When feasible, subjects should not be discontinued until progression is confirmed. This allowance 
to continue treatment despite initial radiologic progression takes into account the observation that 
some subjects can have a transient tumor flare in the first few months after the start of 
immunotherapy, but with subsequent disease response. Subjects that are deemed clinically unstable 
are not required to have repeat imaging for confirmation of progressive disease.  
5.3. Response duration 
 
Response duration (CR, PR, or SD) will be measured from the time measurement criteria for CR 
or PR are first met. Patients without evidence of progression will be censored at the last follow-up 
visit date. If a patient received a subsequent anti-tumoral therapy without prior documentation of 
disease progression, the patient will be censored at the date of starting new anti-tumoral therapy. 
 
5.4. EEORTC QLQ-C30 and eEORTC QLQ-H&N35 questionnaire 
 
The EORTC-QLQC30 is the most widely used cancer specific HRQoL instrument, which contains 
30 items and measures five functional dimensions (physical, role, emotional, cognitive and social), 
three symptom items (fatigue, nausea/vomiting, and pain), six single items (dyspnea, sleep 
disturbance, appetite loss, constipation, diarrhea, and financial impact), and a global health and 
quality of life scale 22.  
 
The EORTC QLQ-H&N35 is in use worldwide as one of the standard instruments for measuring 
quality of life in head and neck cancer subjects and consists of 7 multi-item scales measuring pain 
in the mouth, problems with swallowing, senses, speech, social eating and social contact, and 11 
single-item scales assessing problems with teeth, mouth opening, dry mouth, sticky saliva, 
coughing, feeling ill, use of analgesics, use of nutritional supplements, use of feeding tube, weight 
gain, and weight loss23. The EORTC QLQ-C30 and EORTC QLQ-H&N35 are psychometrically 


 
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and clinically validated instruments appropriate for assessing quality of life in subjects with head 
and neck cancer. These instruments were used in the EXTREME registration trial comparing 
platin-5-fluorouracil alone versus combined with cetuximab as first-line treatment in R/M HNSCC 
which led to the FDA approval of cetuximab monotherapy in subjects with R/M HNSCC refractory 
to cisplatin. 
 
 


 
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5.5. Exploratory analyses 
 
Tumor tissue assessment 
Formalin-fixed and paraffin embedded tumor tissue from the initial diagnosis or recurrent tumors 
will be collected where available. We will perform immunohistochemistry for PD-L1 and PD1 as 
described previously 24. Expression of PD-L1 (positive versus negative using a 1% cut-off) and 
the frequency of PD1+ tumor-infiltrating lymphocytes (low versus high as determined 
semiquantitatively) will be described (frequencies, percentages). Additionally circulating PD-L1 
expression will be measured in patients’ blood samples. 
 
Next generation sequencing 
On the molecular level HNSCC shows a wide spectrum of genetic aberrations: Mutations such as 
in the oncogenic EGFR-MEK, PI3K-AKT, NOTCH, PTEN, JAK-STAT or cMET pathways or in 
tumor suppressor genes have been frequently described for SCHNN25,26. However, just a few serve 
as oncogenic drivers as recently described for PI3K mutations in SCHNN25,27.  While it is well 
known that PD-L1 is regulated by interferon gamma and cytokine release, the association between 
oncogenic pathways and PD-L1 expression is still under investigation. A recent publication 
demonstrated the link between PD-L1 expression and oncogenic pathways in melanoma cell 
lines28. For HNSCC this question has not been addressed so far. Thus, next generation sequencing 
(NGS) of tumor tissues will be performed and a panel of 160 genes that are most commonly 
mutated in cancers will be investigated (Qiagen Comprehensive Cancer GeneRead DNAseq 
Targeted Panel). Tissue will be collected before treatment with pembrolizumab/docetaxel, stored 
and at the end of the study  bioinformatics will be done.  
6. INVESTIGATIONAL PLAN 
 
6.1. Screening and Enrolment 
 
The Investigator is responsible for keeping a record of all subjects who sign an Informed Consent 
Form for entry into the study. All subjects will be screened for eligibility.  Study assessments must 
take place within 28 days prior to initiation of therapy unless otherwise specified. Screening 
pregnancy tests for women of child-bearing potential must occur 24 hours from initiation of 
therapy. All eligible patients will be informed about alternative treatment options outside the trial 
although no standard is defined.  
6.2. Treatment 
 


 
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All patients will receive pembrolizumab intravenously 200mg every 3 weeks in combination with 
docetaxel 75mg/m2 every three weeks for 6 cycles followed by pembrolizumab maintenance 
200mg every 3 weeks until tumor progression, unacceptable toxicity or withdrawal of consent. 
6.3. Monitoring and Inspection by authorities 
 
Study initiation visit, monitoring visits, remote monitoring and close-out visit will be performed at 
specified time points by sponsor personnel. The investigator also agrees to allow audits, IRB/ERC 
review and regulatory authority inspection of trial-related documents and procedures and provide for 
direct access to all trial-related source data and documents. 
6.4. Follow-up 
During the treatment period all patients will attend their regular treatment visits every three weeks 
before the next application of pembrolizumab plus docetaxel. Treatment visits include clinical 
examination and blood work-up. Furthermore, all patients will be assessed for response by CT or 
MRI scans: the first one (baseline) within 4 weeks before start of therapy, then every 12 weeks or 
if clinically indicated.  
Patients who have discontinued study drug for any reason (e.g. clinical progression, withdrawal of 
consent) will perform an End of Treatment Visit after stop of therapy. The patient will then enter 
the Post-Treatment Follow-up period, which lasts either until death, loss to follow-up, or end of 
trial, whatever comes first. Post-Treatment Follow-Up Visits should be performed every 3 months.  
 
6.5. Withdrawal of consent 
 
Subjects who request to discontinue study treatment will remain in the study and must continue to 
be followed for protocol specified follow-up procedures. The only exception to this is when a 
subject specifically withdraws consent for any further contact with the PI physician or persons 
previously authorized by subject to provide this information. Subjects should notify the 
investigator of the decision to withdraw consent from future follow-up in writing, whenever 
possible. The withdrawal of consent should be explained in detail in the medical records by the 
investigator, as to whether the withdrawal is from further treatment with study drug only or also 
from study procedures and/or post treatment study follow-up, and entered on the appropriate CRF 
page. In the event that vital status (whether the subject is alive or dead) is being measured, publicly 
available information should be used to determine vital status only as appropriately directed in 
accordance with local law. 
6.6. Lost to follow-up 
 


 
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All reasonable efforts must be made to locate subjects to determine and report their ongoing status. 
This includes follow-up with persons authorized by the subject as noted above. Lost to follow-up 
is defined by the inability to reach the subject after a minimum of three documented phone calls, 
faxes, or emails as well as lack of response by subject to one registered mail letter. All attempts 
should be documented in the subject’s medical records. If it is determined that the subject has died, 
the site will use permissible local methods to obtain the date and cause of death. If investigator’s 
use of third-party representative to assist in the follow-up portion of the study has been included 
in the subject’s informed consent, then the investigator may use a Sponsor-retained third-party 
representative to assist site staff with obtaining subject’s contact information or other public vital 
status data necessary to complete the follow-up portion of the study. The site staff and 
representative will consult publicly available sources, such as public health registries and 
databases, in order to obtain updated contact information. If after all attempts, the subject remains 
lost to follow-up, then the last known alive date as determined by the investigator should be 
reported and documented in the subject’s medical records. 
 


 
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6.7. Study design schematic 
 
 
Figure 1: Study design 
 
 
Patients with R/M 
HNSCC after platinum failure 
(n=22) 
Pembrolizumab 200mg i.v. in combination 
with Docetaxel 75mg/m2 i.v. every 3 
weeks for 6 cycles followed by 
pembrolizumab maintenance 200mg i.v. 
every 3 weeks until progression or 
unacceptable toxicity 


 
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The treatment to be used in this trial is outlined below in Table 1 
Table 1: Trial Treatment 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Pembrolizumab 200 mg  
Q3W 
IV infusion 
Day 1 of each 3 week 
cycle 
Experimental 
Docetaxel 
75mg/m2 
Q3W 
IV infusion 
Day 1 of each 3 week 
cycle 
Standard of 
care 
 
 
Trial treatment should begin as close as possible to the date on which treatment is 
allocated/assigned. 
 
6.8. Pembrolizumab Dose Modification Guidelines for Drug Related Adverse Event 
 
Adverse events (both non-serious and serious) associated with docetaxel/pembrolizumab exposure 
may represent an immunologic etiology.  These adverse events may occur shortly after the first 
dose or several months after the last dose of treatment. Pembrolizumab must be withheld for drug-
related toxicities and severe or life-threatening AEs as per Table 2 below. 
Table 2: Pembrolizumab dose Modification Guidelines for Drug-Related Adverse Events 
 
General instructions: 
1. 
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. 
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks.  
3. 
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment 
should be initiated if irAEs cannot be controlled by corticosteroids. 
 
Immune-
related AEs 
Toxicity grade 
or conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies  
Monitor and follow-up  
Pneumonitis  
Grade 2 
Withhold  
• Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper 
• 
Monitor participants for signs and 
symptoms of pneumonitis 


 
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Grade 3 or 4, or 
recurrent Grade 2 
Permanently 
discontinue 
 
• 
Evaluate participants with suspected 
pneumonitis with radiographic imaging 
and initiate corticosteroid treatment 
• 
Add prophylactic antibiotics for 
opportunistic infections 
Diarrhea / 
Colitis  
Grade 2 or 3 
Withhold 
• Administer corticosteroids 
(initial dose of 1-2 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) 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. 
Grade 4 
Permanently 
discontinue 
AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2 
Withhold 
• Administer corticosteroids (initial 
dose of 0.5- 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 or 4  
Permanently 
discontinue 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
Type 1 diabetes 
mellitus 
(T1DM) or 
Hyperglycemia 
 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -
cell failure 
Withhold 
• Initiate insulin replacement 
therapy for participants with 
T1DM  
• Administer anti-hyperglycemic in 
participants with hyperglycemia  
 
• 
Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes. 
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 
discontinue1  
Hyperthyroidis
m  
Grade 2 
Continue  
• Treat with non-selective beta-
blockers (eg, propranolol) or 
thionamides as appropriate  
• 
Monitor for signs and symptoms of 
thyroid disorders.  
 
Grade 3 or 4  
Withhold or  
permanently 
discontinue1 
Hypothyroidism 
Grade 2-4 
Continue  
• 
Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyroinine) per standard of 
care 
• 
Monitor for signs and symptoms of 
thyroid disorders.  
 
Nephritis and 
Renal 
dysfunction 
Grade 2 
Withhold  
• 
Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper. 
• 
Monitor changes of renal function 
 
Grade 3 or 4  
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
• 
Based on severity of AE 
administer corticosteroids 
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 


 
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Grade 3 or 4 
Permanently 
discontinue 
 
All other 
immune-related 
AEs 
Intolerable/ 
persistent Grade 
2 
Withhold 
• 
Based on type and severity of 
AE administer corticosteroids  
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
Grade 3 
Withhold or 
discontinue based 
on the type of 
event.  Events that 
require 
discontinuation 
include and not 
limited to:  
Gullain-Barre 
Syndrome, 
encephalitis 
Grade 4 or 
recurrent Grade 3  
Permanently 
discontinue 
1. 
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.   
NOTE:  
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed 
when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).   
 
6.9. Docetaxel Dose Modification Guidelines for Drug Related Adverse Events 
 
If necessary, treatment can be delayed for toxicity for a maximum of 2 weeks. In case of treatment 
delay both drugs have to be delayed during combination therapy within cycle 1-4. Thereafter, 
docetaxel can be discontinued because of intolerable toxicity and pembrolizumab maintenance 
therapy can be initiated.  
Every effort will be made to administer the full dose regimen to maximize dose-intensity.  
If possible, toxicities should be managed symptomatically. If toxicity occurs, the appropriate 
treatment will be used to ameliorate signs and symptoms including anti-emetics for nausea and 
vomiting, anti-diarrheals for diarrhea, and antipyretics and/or antihistamines for drug fever. 
 
 


 
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Table 3: Dose levels for docetaxel dose reduction 
 
Dose Level  
DOCETAXEL  
Q3 WEEKS  
0  
75 mg/m2  
-1  
60 mg/m2  
-2  
45 mg/m2  
 
 
Hematologic Toxicity:  
• Neutropenia and/or its complications:  
Adverse event  
Action to be taken  
- Grade 4 neutropenia* for 7 days or more  
- Grade 3-4 neutropenia* with oral fever >38.5°C  
- Infection with grade 3-4 neutropenia*  
If the patient develops one of these adverse 
events, the next infusion should be given with a 
one-level dose reduction.  
 
• Thrombocytopenia:  
In case of grade ≥ 3 platelet-toxicity, delay maximum 2 weeks until platelets recover to ≥ 100 x 
109/l, then treat with a one-level dose reduction.  
 
• Allergy (anaphylactic and hypersensitivity reactions) due to Docetaxel:  
Hypersensitivity reactions that occur despite pre-medication are very likely to occur within a few 
minutes of start of the first or of the second infusion of docetaxel. Therefore, during the 1st and the 
2nd infusion, careful evaluation of general sense of well-being and blood pressure and heart rate 
monitoring will be performed for at least the first 10 minutes, so that immediate intervention is 
possible in response to symptoms of an untoward reaction.  
Facilities and equipment for resuscitation must be immediately available: antihistamine, 
corticosteroids, aminophylline, epinephrine.  
If a reaction occurs, the specific treatment that is medically indicated for a given symptom (e.g. 
epinephrine in case of anaphylactic shock, aminophylline in case of bronchospasm, etc.) will be 
instituted.  
 
• Nausea/Vomiting:  


 
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A prophylactic anti-emetic treatment should be given to the patients from the first cycle. Anti-
emetic prophylaxis with 5-HT3 Antagonists (i.e. ondansetron) should be given to all patients.  
If despite even more aggressive antiemetic medication (i.e.aprepitant), grade ≥ 3 nausea/vomiting 
still occur, reduce the dose of study drug by one dose level. If despite dose reduction, 
nausea/vomiting still occur at grade ≥ 3, the patient will go off study. 
• Liver toxicity:  
 
In case of increase of ASAT and/or ALAT to >3-5 x ULN or bilirubin to >1.5-3 ULN, delay study 
drug treatment for up to 2 weeks until ASAT and/or ALAT return to ≤ 3 x ULN and bilirubin to 
1.5≤ ULN. Then re-treat at one dose level lower. If no recovery to < 3 x ULN and bilirubin to 1.5< 
ULN within two weeks delay, patient will go off protocol therapy.  
 
• Docetaxel-induced fluid retention:  
 
In case of fluid retention (peripheral edema and/or effusions) during treatment with docetaxel, the 
signs and symptoms should be graded as mild, moderate, severe or life-threatening.  
 
NO DOSE REDUCTION IS PLANNED.  
 
The patient’s body weight will be recorded and followed as frequently as possible to document any 
weight gain which could be related to edema. 
• Alopecia and nail changes:  
 
NO DOSE REDUCTION PLANNED. 
• Stomatitis:  
 
Grade ≤ 2: no dose reduction, study chemotherapy should be withheld until resolution to grade ≤ 
1.  
If grade 3 stomatitis occurs, study drug should be withheld until resolution to grade ≤ 1. Treatment 
may then be resumed, but the dose of study drug should be reduced by one dose level for all 
subsequent doses.  
In case of grade 4 stomatitis, the patient will go off study.  
 
• Peripheral neuropathy:  
 
In case of signs or symptoms experienced by the patient, dose modification should be performed 
as follows:  
Grade ≤ 1: no change.  
Grade 2: re-treat with a one-level dose reduction (no further dose reduction is planned).  
Grade ≥ 3: patient will go off protocol therapy. 


 
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6.10. Concomitant Medications and chemotherapy pre-medication 
 
Chemotherapy pre-medication 
Prior to docetaxel/pembrolizumab therapy subjects receive pre-medication with dexamethasone 8 
mg on the day of therapy and 5-HT3 antagonists on day 1-3 according to the site standard. 
Additional glucocorticoids are prohibited (see section below). 
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. Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and Treatment 
Phase of this trial: 
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab 
• Radiation therapy 
o Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may be 
allowed at the investigator’s discretion.   
• Live vaccines within 30 days prior to the first dose of trial treatment and while participating 
in the trial.  Examples of live vaccines include, but are not limited to, the following: 
measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine.  
• Systemic glucocorticoids for other purposes as specified above or other than to modulate 
symptoms from an event of clinical interest of suspected immunologic etiology. 
 
 


 
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6.11. Study flow chart 
 
Table 4: Overview of procedures 
 
 
Baseline 
 
During treatment 
After treatment 
Investigation 
Within 4 weeks prior to 
pembrolizumab/docetaxel 
start  
On day of each 
docetaxel/ 
pembrolizumab 
administration 
or within 72 
hours before 
10 (+/-2) 
days after 
each 
cycle 
Every 12 
weeks 
End 
of 
treatment 
(within 4 weeks 
after 
last 
treatment 
administration) 
Until PD 
every 12 
weeks 
Informed 
consent 
⧫ 
  
 
  
  
  
Clinical 
examination 
⧫ 
⧫ 
⧫ 
  
⧫ 
⧫ 
Medical history, 
demographics 
⧫ 
  
 
  
  
  
ECOG status 
⧫ 
⧫ 
⧫ 
 
⧫ 
 
Adverse events 
assessment 
⧫ 
⧫ 
⧫ 
  
⧫ 
⧫ 
EORTC QLQ 
C-30 and 
EORTC QLQ-
H&N35.  
⧫ 
⧫ 
 
 
 
 
ECG 
⧫ 
  
 
  
  
  
Hematology  
⧫ 
⧫ 
⧫ 
  
⧫ 
  
Serum 
chemistry incl. 
thyroid function 
⧫ 
⧫ 
⧫ 
  
⧫ 
  
Urinalysis 
for 
proteinuria 
⧫ 
⧫ 
 
 
⧫ 
 


 
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HIV test 
⧫ 
 
 
  
 
  
Hepatitis 
serology 
⧫ 
 
 
  
 
  
Pregnancy test  
⧫ (within 24 hours before 
1stpembrolizumab 
infusion) 
 
 
  
 
  
CT/MRI scan 
⧫ 
  
 
⧫ 
  
⧫ 
Tumor 
biopsy 
for NGS and 
p16 staining 
⧫ 
 
 
 
 
 
Blood 
sample 
(15ml) 
⧫ 
 
 
⧫ 
 
 
Survival 
 
 
 
 
 
⧫ 
 
7. ETHICAL CONSIDERATIONS 
 
7.1. Good clinical practice 
 
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/E. 
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study. 
Personnel involved in conducting this study will be qualified by education, training, and experience 
to perform their respective tasks. 
7.2. Institutional Review Board/Independent Ethics Committee 
 


 
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Before study initiation, the investigator must have a written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, subject recruitment materials (eg, 
advertisements), and any other written information to be provided to subjects. The investigator 
should provide the IRB/IEC with reports, updates and other information (eg, expedited safety 
reports, amendments, and administrative letters) according to regulatory requirements or institution 
procedures. 
 
7.3. Informed consent 
Investigators will ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding participation in this clinical study. Only patients who have 
signed the informed consent formed for this trial will be enrolled. 
 
8. STUDY MEDICATIONS 
 
8.1. Investigational Product 
 
The investigator shall take responsibility for and shall take all steps to maintain appropriate records 
and ensure appropriate supply, storage, handling, distribution and usage of investigational product 
in accordance with the protocol and any applicable laws and regulations. 
Clinical Supplies will be provided by Merck as summarized in Table 5. 
Table 5: Product descriptions 
Product Name &Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
 
8.2. HANDLING AND DISPENSING 
 
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by MSD. If concerns 
regarding the quality or appearance of the study drug arise, the study drug should not be dispensed 


 
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and contact MSD immediately. Investigational product documentation must be maintained that 
includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (eg, required diluents, administration sets). Infusion-
related supplies (eg, IV bags, in-line filters, 0.9% NaCl solution) will not be supplied by MSD and 
should be purchased locally if permitted by local regulations. For non-investigational product, if 
marketed product is utilized, it should be stored in accordance with the package insert, summary 
of product characteristics (SmPC), or similar. Please refer to the current version of the Investigator 
Brochure and/or pharmacy reference sheets for complete storage, handling, dispensing, and 
infusion information for pembrolizumab. 
 
8.3. Product description pembrolizumab 
 
For details regarding drug storage, preparation, administration, and use time please refer to the 
pembrolizumab Investigator Brochure and/or pharmacy reference sheets. 
8.4. Pembrolizumab administration 
 
MK-3475 will be administered as a 30 minute IV infusion. 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). Further details on preparation and administration of 
pembrolizumab (MK-3475) are provided in the Pharmacy Manual.   
The pharmacists will prepare the MK-3475 medication for administration. The Procedures Manual 
contains specific instructions for MK-3475 dose calculation, reconstitution, preparation of the 
infusion fluid, and administration. This document is available for reference by the pharmacist and 
study personnel. 
8.5. Packaging and Labeling Information 
 
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements. 
 
 
 
 


 
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8.6. 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. 
 
8.7. Storage and handling 
Clinical supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label.   
Receipt and dispensing of trial medication must be recorded by an authorized person at the trial 
site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
 
8.8. Returns and Reconciliation 
 
The investigator is responsible for keeping accurate records of the clinical supplies received from 
Merck or designee, the amount dispensed to and returned by the subjects and the amount remaining 
at the conclusion of the trial.  
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s responsibility 
to arrange for disposal of all empty containers, provided that procedures for proper disposal have 
been established according to applicable federal, state, local and institutional guidelines and 
procedures, and provided that appropriate records of disposal are kept. 
8.9. Docetaxel administration 
 
Docetaxel will be provided by the AKH hospital pharmacy as routine ready to use infusion 
bag and will be administered as a 60 minute IV infusion prior to pembrolizumab. Patients 
will receive docetaxel intravenous infusions via infusion pump. 
8.10. Supportive Care guidelines 
 


 
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Subjects should receive appropriate supportive care measures as deemed necessary by the treating 
investigator.  Suggested supportive care measures for the management of adverse events with 
potential immunologic etiology are outlined below and in greater detail in the ECI guidance 
document. Where appropriate, these guidelines include the use of oral or intravenous treatment 
with corticosteroids as well as additional anti-inflammatory agents if symptoms do not improve 
with administration of corticosteroids.   Note that several courses of steroid tapering may be 
necessary as symptoms may worsen when the steroid dose is decreased. For each disorder, attempts 
should be made to rule out other causes such as metastatic disease or bacterial or viral infection, 
which might require additional supportive care. Thetreatment guidelines are intended to be applied 
when the investigator determines the events to be related to pembrolizumab.  
Note: if after the evaluation the event is determined not to be related, the investigator is instructed 
to follow the ECI reporting guidance but does not need to follow the treatment guidance (as 
outlined in the ECI guidance document). Refer to Section 6.8 for dose modification.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event. Suggested conditional procedures, as appropriate, 
can be found in the ECI guidance document. 
 
• Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids. When symptoms improve 
to Grade 1 or less, steroid taper should be started and continued over no less than 4 
weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  Administer 
additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of prolonged 
steroid administration. 
 
 
• Diarrhea/Colitis: 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus).   
 
o All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.  For Grade 2 or higher diarrhea, 
consider GI consultation and endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids.  


 
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o For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous 
steroids followed by high dose oral steroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
 
 
• Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ 
Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis 
(DKA) 
 
o For T1DM or Grade 3-4 Hyperglycemia 
▪ Insulin replacement therapy is recommended for Type I diabetes mellitus 
and for Grade 3-4 hyperglycemia associated with metabolic acidosis or 
ketonuria.  
▪ Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide.  
 
• Hypophysitis: 
 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 
1 or less, steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is 
tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by 
oral corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered. 
 
 
• Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated 
based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. 
 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
▪ In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 
▪ In hypothyroidism, 
thyroid 
hormone 
replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
▪ Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered. 


 
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• Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly). 
▪ Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks. 
 
• Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4weeks. 
 
• Management of Infusion Reactions: Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of completion 
of infusion.  
 
 
Table 6 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab (MK-3475). 
 
Table 6 Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for 
< =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
Subject may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
pembrolizumab (MK-3475) with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
 
Acetaminophen 500-1000 mg po 
(or equivalent dose of antipyretic). 


 
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NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g., from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose. 
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be 
permanently discontinued from further trial 
treatment administration. 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly responsive 
to symptomatic medication and/or 
brief interruption of infusion); 
recurrence of symptoms following 
initial improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or ventilatory 
support indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from 
further trial treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration. 
 
 
8.11. Diet/Activity/Other Consideration 
• Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE such as 
diarrhea, nausea or vomiting. 
• Contraception 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.  Non-pregnant, non-
breast-feeding women may be enrolled if they are willing to use 2 methods of birth control or are 
considered highly unlikely to conceive.  Highly unlikely to conceive is defined as 1) surgically 
sterilized, or 2) postmenopausal (a woman who is ≥45 years of age and has not had menses for 
greater than 1 year will be considered postmenopausal), or 3) not heterosexually active for the 
duration of the study.  The two birth control methods can be either two barrier methods or a barrier 
method plus a hormonal method to prevent pregnancy. Subjects should start using birth control 
from study Visit 1 throughout the study period up to 120 days after the last dose of study therapy.  


 
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The following are considered adequate barrier methods of contraception: diaphragm, condom (by 
the partner), copper intrauterine device, sponge, or spermicide.  Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or intramuscular 
agents). 
Subjects should be informed that taking the study medication may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in the 
study they must adhereto the contraception requirement (described above) for the duration ofthe 
study and during the follow-up period defined in section 7.2.2-Reporting of Pregnancy and 
Lactation to the Sponsor and to Merck.  If there is any question that a subject will not reliably 
comply with the requirements for contraception, that subject should not be entered into the study. 
• Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the subject 
will immediately be removed from the study.  The site will contact the subject at least monthly and 
document the subject’s status until the pregnancy has been completed or terminated.  The outcome 
of the pregnancy will be reported to the Sponsor and to Merck without delay and within 24 hours 
to the Sponsor and within 2 working days to Merck if the outcome is a serious adverse experience 
(e.g., death, abortion, congenital anomaly, or other disabling or life-threatening complication to 
the mother or newborn).   
The study investigator will make every effort to obtain permission to follow the outcome of the 
pregnancy and report the condition of the fetus or newborn to the Sponsor.   If a male subject 
impregnates his female partner the study personnel at the site must be informed immediately and 
the pregnancy reported to the Sponsor and to Merck and followed as described above and in 
Section 7.2.2. 
• 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. 
 
8.12. 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. 


 
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A subject must be discontinued from the trial for any of the following reasons: 
• The subject or legal representative (such as a parent or legal guardian) withdraws consent. 
• Confirmed radiographic disease progression 
Note: For unconfirmed radiographic disease progression, please see Section 5.2.2 
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 
7.1.2.7.1 
• 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 24 months of uninterrupted treatment with pembrolizumab or 35 
administrations of study medication, whichever is later. 
Note: 24 months of study medication is calculated from the date of first dose. Subjects who 
stop pembrolizumab after 24 months may be eligible for up to one year of additional study 
treatment if they progress after stopping study treatment provided they meet the 
requirements detailed in Section 7.1.5.5 
• Administrative reasons 
 
8.13. 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 


 
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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  
 
 
9. STATISTICAL CONSIDERATIONS 
9.1. Sample Size Calculation 
 
The primary objective of this Phase II study is to evaluate the proportion of patients responding to 
pembrolizumab plus docetaxel. An exact binominal test with a nominal 0.050 one-sided 
significance level will have 84% power to detect the difference between the null hypothesis 
proportion, π0 of 0.15 and the alternative proportion, πA of 0.40 when the sample size is 22. This 
corresponds to a rejection of the Null hypothesis, if 7 or more successes are observed in 22 treated 
patients. 
Continuous variables will be summarized using descriptive statistics and Kaplan Meier curves will 
be calculated to estimate OS and PFS. The Overall Response Rate (CR/PR together) will be 
described by absolute frequencies and percentages. The corresponding one-sided exact 95 % 
confidence interval will by calculated. 
9.2. Study population 
 
9.2.1. Full analysis set Assessment of Efficacy 
 
All registered patients who started treatment will be included in the full analysis set (FAS) when 
assessing efficacy. For assessing patients´ response or progression of disease all patients with at 
least one tumor assessment (CT or MRI) after start of treatment are included.  Patients lost to 
follow-up before their first imaging assessment will be replaced by another eligible patient. 
The Overall Response Rate (CR/PR together) will be described by absolute frequencies and 
percentages. The corresponding one-sided exact 95 % confidence interval will by calculated. 
If there are 7 or more successes (CR or PR) out of the 22 patients the study is considered to be a 
success and the null hypothesis (Clinical Benefit Rate is ≤15 %) will be rejected in favour of the 
alternative hypothesis of a higher Overall Response Rate. 
 


 
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9.2.2. Safety Analyses set 
 
All registered patients receiving at least one treatment dose are included in the safety analyses set. 
 
9.2.3. Assessment of Safety 
 
A complete patient Adverse Event listing, including details (intensity, relation to drug, etc.) for all 
patients enrolled in this trial will be given. Adverse Event (including abnormal laboratory values) 
intensity and relationship to trial drug will be presented as summary tables. Serious Adverse Events 
(grade 3-4), will be summarised in a brief case history. 
 
9.2.4. Secondary Objectives 
 
The Best OR categories will be described by frequencies and percentages. Individual patients 
response over time of will be reported as case studies. Kaplan Meier curves will be calculated to 
estimate OS. Patients lost to follow up will be censored at the date of last known survival status. 
Changes in quality of life measurements will be reported by frequencies and percentages. 
9.2.5. Exploratory Objectives 
 
Exploratory endpoints will be analysed in a descriptive way only. Categorical data will be 
described by frequencies and percentages. Continuous data are summarized by mean and standard 
deviation in case of normal distribution and by median, minimum and maximum otherwise. Repeat 
measurements will be graphically shown by line plots for every patient. 
 
 
10. Adverse Event 
 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-


 
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specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Merck’s product, is also an adverse event. 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time. 
Merck product includes any pharmaceutical product, biological product, device, diagnostic 
agent or protocol-specified procedure, whether investigational (including placebo or active 
comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by Merck for human use. 
Adverse events may occur during the course of the use of Merck product in clinical trials or 
within the follow-up period specified by the protocol, or prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal. 
Adverse events may also occur in screened subjects during any pre-allocation baseline 
period as a result of a protocol-specified intervention, including washout or discontinuation 
of usual therapy, diet, placebo treatment or a procedure. 
Progression of the cancer under study is not considered an adverse event unless it is 
considered to be drug related by the investigator. 
All adverse events will be recorded from the time the consent form is signed through 30 days 
following cessation of treatment and at each examination on the Adverse Event case report 
forms/worksheets. The reporting timeframe for adverse events meeting any serious criteria 
is described below. 
10.1. Definition of an overdose for this protocol and reporting pf overdose to the sponsor   
and MERCK 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 mg 
or greater (≥5 times the indicated dose).  No specific information is available on the treatment of 
overdose of pembrolizumab. Appropriate supportive treatment should be provided if clinically 
indicated. In the event of overdose, the subject should be observed closely for signs of toxicity.  
Appropriate supportive treatment should be provided if clinically indicated. 
 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are met. 


 
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If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional overdose 
without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 24 hours to the 
Sponsor and within 2 working days hours to Merck Global Safety. (Attn: Worldwide Product 
Safety; FAX 215 993-1220) 
10.2. Reporting of pregnancy and lactation to the sponsor and to MERCK 
 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject (spontaneously 
reported to them), including the pregnancy of a male subject's female partner that occurs during 
the trial or within 120 days of completing the trial completing the trial, or 30 days following 
cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier.  All 
subjects and female partners of male subjects who become pregnant must be followed to the 
completion/termination of the pregnancy.  Pregnancy outcomes of spontaneous abortion, missed 
abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage and 
stillbirth must be reported as serious events (Important Medical Events).  If the pregnancy 
continues to term, the outcome (health of infant) must also be reported. 
Such events must be reported within 24 hours to the Sponsor and within 2 working days to Merck 
Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
10.3. Immediate reporting of adverse events to the sponsor and to MERCK 
10.3.1. Serious adverse events and Suspected unexpected serious adverse reaction (SUSARS) 
 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck’s 
product that: 
- 
Results in death; 
- 
Is life threatening; 
- 
Results in persistent or significant disability/incapacity; 
- 
Results in or prolongs an existing inpatient hospitalization; 
- 
Is a congenital anomaly/birth defect; 
- 
Is a new cancer (that is not a condition of the study); 


 
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- 
Is associated with an overdose; 
- 
Is an other important medical event  
 
Any serious adverse event, or follow up to a serious adverse event, including death due to any 
cause other than progression of the cancer under study that occurs to any subject from the time the 
consent is signed through 90 days following cessation of treatment, or the initiation of new anti-
cancer therapy, whichever is earlier, whether or not related to Merck product, must be reported 
within 24 hours to the Sponsor and within 2 working days to Merck Global Safety.  
Pembrolizumab SUSARs represent Serious Adverse Events related to pembrolizumab (=Adverse 
Reactions), considered “unexpected” with regard to the valid investigator brochure for pembrolizumab. 
SUSARS and non-serious Events of Clinical Interest will be forwarded to Merck Global Safety 
and will be handled in the same manner as SAEs.  
The sponsor is solely responsible for sending the reports on SAEs and SUSARs to all participating 
investigators, to Regulatory agencies and Ethics Committees concerned in accordance with 
international and local laws and regulations as well as ICH/GCP guidelines. 
Additionally, any serious adverse event, considered by an investigator who is a qualified physician 
to be related to Merck product that is brought to the attention of the investigator at any time outside 
of the time period specified in the previous paragraph also must be reported immediately to the 
Sponsor and to Merck. 
 
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:  +1-215-993-1220 
 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators. Investigators will cross reference this submission according to local regulations to the 
Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission.  
Additionally investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) at the time of submission to FDA. 
All subjects with serious adverse events must be followed up for outcome. 
 
10.4. Events of clinical interest 


 
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Selected non-serious and serious adverse events are also known as Events of Clinical Interest (ECI) 
and must be recorded as such on the Adverse Event case report forms/worksheets and reported 
within 24 hours to the Sponsor and within 2 working days to Merck Global Safety. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) Events of clinical interest for this trial include: 
1.  an overdose of Merck product, as defined in Section Definition of an Overdose for This Protocol 
and Reporting of Overdose to the Sponsor, that is not associated with clinical symptoms or 
abnormal laboratory results.  
2.  an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of normal 
and an elevated total bilirubin lab value that is greater than or equal to 2X the upper limit of normal 
and, at the same time, an alkaline phosphatase lab value that is less than 2X the upper limit of 
normal, as determined by way of protocol-specified laboratory testing or unscheduled laboratory 
testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an additional 
evaluation for an underlying etiology.  The trial site guidance for assessment and follow up of 
these criteria can be found in the Investigator Trial File Binder (or equivalent). 
1. Additional adverse events: 
 
A separate guidance document has been provided entitled “Event of Clinical Interest Guidance 
Document” (previously entitled, “Event of Clinical Interest and Immune-Related Adverse 
Event Guidance Document”).  This document provides guidance regarding identification, 
evaluation and management of ECIs and irAEs.   
 
ECIs (both non-serious and serious adverse events) identified in this guidance document from 
the date of first dose through 90 days following cessation of treatment, or 30 days after the 
initiation of a new anticancer therapy, whichever is earlier, need to be reported within 24 hours 
to the Sponsor and within 2 working days to Merck Global Safety. (Attn: Worldwide Product 
Safety; FAX 215 993-1220), regardless of attribution to study treatment, consistent with 
standard SAE reporting guidelines. 
 
Subjects should be assessed for possible ECIs prior to each dose.  Lab results should be 
evaluated and subjects should be asked for signs and symptoms suggestive of an immune-
related event.  Subjects who develop an ECI thought to be immune-related should have 
additional testing to rule out other etiologic causes.  If lab results or symptoms indicate a 
possible immune-related ECI, then additional testing should be performed to rule out other 
etiologic causes.  If no other cause is found, then it is assumed to be immune-related. 
10.5. Evaluating adverse event 
 


 
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An investigator who is a qualified physician will evaluate all adverse events according to the NCI 
Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event which 
changes CTCAE grade over the course of a given episode will have each change of grade recorded 
on the adverse event case report forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 
 
10.6. Sponsor responsibility for reporting serious adverse events 
 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations. 
11. Insurance Policy  
In accordance with the provisions of the law and ICH GCP, the sponsor has an insurance policy 
intended to guarantee against possible damages resulting from research. The studies and/or 
experiments performed on behalf of the Medical University of Vienna  are specifically and 
expressly guaranteed. It is advisable to underline that non compliance with the research legal 
conditions are clauses of guarantee exclusion. 
12.  Publication 
This trial is intended for publication, even if terminated prematurely. Publication may include any 
or all of the following: posting of a synopsis online, abstract and/or presentation at a scientific 
conference, or publication of a full manuscript. Any publications of the results, either in part or in 
total by investigators or their representatives will require pre-submission review by the Sponsor 
and Merck.  
 
 
13. Financial considerations and research funding 
This trial is supported by a research grant by Merck.  Merck does not pay incentives to enroll 
subjects in this trial. The investigators have no conflict of interest to declare. 


 
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Table 7:  Evaluating Adverse Events 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
V4.0 
CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. 
 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization [including hospitalization for an elective procedure] for a preexisting 
condition which has not worsened does not constitute a serious adverse event.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or 
 
Is a new cancer; (that is not a condition of the study) or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event. An overdose that is not 
associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action taken  
Did the adverse event cause the Merck product to be discontinued? 
Relationship to 
test drug  
Did the Merck product cause the adverse event? The determination of the likelihood that the Merck product caused the adverse event will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information.  
The following components are to be used to assess the relationship between the Merck product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Merck product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to the Merck product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
 
Time Course 
Did the AE follow in a reasonable temporal sequence from administration of the Merck product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)? 
 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors 


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


 
 
 
 
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14. APPENDICES 
 
• ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, 
J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The 
Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern 
Cooperative Oncology Group, Robert Comis M.D., Group Chair. 
 
 
• 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) 
 
• Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors 
RECIST version 1.1 will be used in this study for assessment of tumor response. While either 
CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this 
study. 
 
 
 
 


 
 
 
 
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15. REFERENCES 
 
References:  
1. 
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Leemans CR, Tiwari R, Nauta JJ, van der Waal I, Snow GB. Recurrence at the primary 
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Sturgis EM, Miller RH. Second primary malignancies in the head and neck cancer 
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Frampton JE. Cetuximab: a review of its use in squamous cell carcinoma of the head 
and neck. Drugs 2010;70:1987-2010. 
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Vermorken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab 
in head and neck cancer. The New England journal of medicine 2008;359:1116-27. 
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Hitt R, Irigoyen A, Cortes-Funes H, et al. Phase II study of the combination of 
cetuximab and weekly paclitaxel in the first-line treatment of patients with recurrent and/or 
metastatic squamous cell carcinoma of head and neck. Ann Oncol 2012;23:1016-22. 
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Knoedler M, Gauler TC, Gruenwald V, et al. Phase II study of cetuximab in combination 
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Internistische Onkologie. Oncology 2013;84:284-9. 
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Forastiere AA, Shank D, Neuberg D, Taylor SGt, DeConti RC, Adams G. Final report 
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Guardiola E, Peyrade F, Chaigneau L, et al. Results of a randomised phase II study 
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Lyford-Pike S, Peng S, Young GD, et al. Evidence for a role of the PD-1:PD-L1 
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16. 
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Parikh F, Duluc D, Imai N, et al. Chemoradiotherapy-induced upregulation of PD-1 
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Garnett CT, Schlom J, Hodge JW. Combination of docetaxel and recombinant vaccine 
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on the number and function of regulatory T cells. Oncoimmunology 2013;2:e27025. 
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Jimeno A, Bauman JE, Weissman C, et al. A randomized, phase 2 trial of docetaxel with 
or without PX-866, an irreversible oral phosphatidylinositol 3-kinase inhibitor, in patients with 
relapsed or metastatic head and neck squamous cell cancer. Oral oncology 2015;51:383-8. 
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Amendment 1 to the protocol V3.0 
 
Exploratory analysis of cytokine profile in HNSCC patients treated with docetaxel and 
pembrolizumab 
It has been published recently, that serum cytokine levels are altered in HNSCC patients and 
correlate with disease progression1.  Apart from that, it there is growing evidence that not only 
cytokines such as interferon gamma but also soluble PD-L1 levels are of prognostic and 
predictive value in patients treated with CPI2,3. 
Based on this recent evidence we propose a retrospective exploratory analysis of the serum 
samples collected within the Pem-Doc study prior to publication in order to better understand 
the treatment responses. 
In particular we plan to measure the serum levels of interferon gamma; Interleukin 6, interleukin 
17A, soluble PD-L1, major-histocompatibility-complex (MHC) class I-related chain genes A 
and B employing a ProcartaPlex 6-plex immunoassay. Soluble serum parameters will be 
quantified at baseline and at the initial restaging for patients with disease control and non-
responders. Potential differences between paired data will be calculated using Wilcoxon signed-
rank tests. 
Since this is a retrospective exploratory analysis of stored serum samples there will be no 
additional risks for the remaining patients.  
Next generation sequencing 
As already described in the protocol next generation sequencing will be performed. However, 
the Oncomine Comprehensive Assay v3 (Thermo Fisher Scientific, Waltham, MA, USA) 
instead of the Qiagen Comprehensive Cancer GeneRead DNAseq Targeted Panel will be used, 
since this assay is the one currently employed (for routine purposes as well) at the Department 
of Pathology due to superior performance. 
 
1. 
Bussu F, Graziani C, Gallus R, et al. IFN-γ and other serum cytokines in head and neck 
squamous cell carcinomas. Acta otorhinolaryngologica Italica : organo ufficiale della Societa 
italiana di otorinolaringologia e chirurgia cervico-facciale 2018;38:94-102. 
2. 
Khan M, Zhao Z, Arooj S, Fu Y, Liao G. Soluble PD-1: Predictive, Prognostic, and 
Therapeutic Value for Cancer Immunotherapy. Frontiers in immunology 2020;11:587460. 
3. 
Hirashima T, Kanai T, Suzuki H, et al. The Levels of Interferon-gamma Release as a 
Biomarker for Non-small-cell Lung Cancer Patients Receiving Immune Checkpoint Inhibitors. 
Anticancer research 2019;39:6231-40.