Phase II Basket Trial Evaluating the Efficacy of a Combination of Pembrolizumab and Vorinostat in Patients With Recurrent and/or Metastatic Squamous Cell Carcinoma
Phase: PHASE2
Conditions: Squamous Cell Lung Cancer, Vulvar Cancer, Penile Cancer, Cervix Cancer, Head and Neck Squamous Cell Carcinoma, Anal Cancer
Sponsor: UNICANCER

 
 
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CONFIDENTIEL 
 
UNICANCER Group Tumor: 
Personalized Medicine 
 
Protocol n°: UC-GMP-1908 
 
EudraCT n°: 2019-003839-33 
 
Phase II basket trial evaluating the efficacy of a combination of pembrolizumab 
and vorinostat in patients with recurrent and/or metastatic squamous cell 
carcinoma 
 
Abbreviated title: PEVOsq  
 
Version n°1.1 – 14 April 2020 
 
PROTOCOL 
VERSION N° - DATE  
CPP approval 
ANSM 
authorisation 
INITIAL 
1.1 - 14 April 2020 
18-05-2020 
15-05-2020 
 
COORDINATING 
INVESTIGATOR 
Prof. Christophe LE TOURNEAU 
Institut Curie 
Department of Drug Development and Innovation (D3i) 
26 rue d’Ulm -75005 PARIS 
Phone: +33 (0)1 44 32 46 75 
Email: christophe.letourneau@curie.fr 
SPONSOR 
UNICANCER 
101, rue de Tolbiac 
75654 Paris Cedex 13 (France) 
Phone: + 33 (0)1 44 23 04 04 – Fax: + 33 (0)1 44 23 55 69 
 

 
 
UNICANCER Personalized Medicine Group  
Protocol n°: UC-GMP-1908 
EudraCT n°: 2019-003839-33 
 
 
 
 
 
 
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CONFIDENTIEL 
 
CONTACT DETAILS  
PROTOCOL N°: UC-GMP-1908 
 
Trial Title:  
Phase II basket trial evaluating the efficacy of a combination of pembrolizumab and 
vorinostat in patients with recurrent and/or metastatic squamous cell carcinoma 
 
WRITING COMMITTEE 
Christophe Le Tourneau, Maud Kamal, Lilian Amrein, Marta Jimenez, 
Thomas Filleron 
 
CONTACT DETAILS AND USEFUL INFORMATION 
Prof. Christophe LE 
TOURNEAU 
Coordinating Investigator 
Institut Curie 
Department of Drug Development and Innovation (D3i) 
26 rue d’Ulm -75005 PARIS 
Phone: +33 (0)1 44 32 46 75 
Email: christophe.letourneau@curie.fr 
Mr. Thomas FILLERON 
Statistician 
Institut Claudius Regaud, IUCT-O 
Department of biostatistics 
1 avenue Irène Joliot-Curie 
31059 TOULOUSE Cedex 9 
Phone: +33 (0)5 31 15 58 65 
Email: filleron.thomas@iuct-oncopole.fr 
Ms. Maud KAMAL 
Ancillary/translational 
coordinator 
Institut Curie 
Department of Drug Development and Innovation (D3i) 
26 rue d’Ulm -75005 PARIS 
Phone: +33 (0)1 44 32 44 20 
Email: maud.kamal@curie.fr 
 
Mr. François LEGRAND 
Project Manager 
 
R&D UNICANCER 
101 rue de Tolbiac – 75654 PARIS Cedex 13 
Phone: + 33 (0)1 73 79 73 02 
Fax: + 33 (0)1 44 23 55 69 
Email: f-legrand@unicancer.fr 
Pharmacovigilance 
Notification 
R&D UNICANCER Pharmacovigilance Unit 
101 rue de Tolbiac – 75654 PARIS Cedex 13 
Phone: + 33 (0)1 44 23 04 16 
Fax: + 33 (0)1 44 23 55 70 
Email: pv-rd@unicancer.fr 
 
 
 
 
 
 

 
UNICANCER Personalized Medicine Group  
Protocol n°: UC-GMP-1908 
EudraCT n°: 2019-003839-33 
 
 
 
 
 
 
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CONFIDENTIEL 
APPROVAL AND SIGNATURE  
FOR PROTOCOL N°: UC-GMP-1908 
 
Trial Title: Basket phase II trial evaluating the efficacy of a combination of pembrolizumab and 
vorinostat in patients with recurrent and/or metastatic squamous cell carcinoma 
 
Title 
Name 
Address 
Date 
(dd-mm-yyyy) 
Signature 
Director of 
Clinical 
Operations 
Beata  
Juzyna 
R&D UNICANCER 
101 rue de Tolbiac 
75654 Paris cedex 13, France 
Tel: +33 (0)1 71 93 61 60 
Fax: +33 (0)1 44 23 55 69 
Email: b-juzyna@unicancer.fr 
26/05/2020 
Project 
Manager 
François 
Legrand 
R&D UNICANCER 
101 rue de Tolbiac 
75654 Paris cedex 13, France 
Phone: + 33 (0)1 73 79 73 02 
Fax: + 33 (0)1 44 23 55 69 
Email: f-legrand@unicancer.fr 
20/05/2020 
Coordinating 
Investigator 
Christophe  
Le Tourneau 
Institut Curie 
26 rue d’Ulm - 75005 PARIS 
Phone: +33 (0)1 44 32 46 75 
Email: christophe.letourneau@curie.fr 
20-05-2020 
 
Biostatistician
Thomas  
Filleron 
Institut Claudius Regaud, IUCT-O 
TOULOUSE 
Phone: +33 (0)5 31 15 58 65 
Email: filleron.Thomas@iuct-oncopole.fr 
2020/05/20 
 
 

 
 
UNICANCER Personalized Medicine Group  
Protocol n°: UC-GMP-1908 
EudraCT n°: 2019-003839-33 
 
 
 
 
 
 
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TABLE OF CONTENT 
LIST OF ABBREVIATIONS 
8 
STATEMENT OF COMPLIANCE 
10 
PROTOCOL SUMMARY 
11 
Synopsis ........................................................................................................................................................... 11 
Schedule of visits and activities (SOA) ............................................................................................................. 21 
1. 
INTRODUCTION 
23 
1.1. 
Background information ......................................................................................................................... 23 
 
Disease epidemiology 
23 
 
Prognosis 
23 
 
Investigational medicinal products (IMP) 
24 
1.2. 
Trial rationale .......................................................................................................................................... 24 
 
Immunotherapy for treating SCC 
25 
 
Immune checkpoint inhibitors combined with HDAC inhibitors for treating SCC 
26 
 
Pembrolizumab combined with vorinostat for treating SCC 
26 
1.3. 
Justification for the therapeutic regimens and treatment durations ....................................................... 27 
1.4. 
Potential risks and benefits .................................................................................................................... 28 
 
Known potential risks 
28 
 
Known potential benefits 
29 
1.5. 
Trial population ....................................................................................................................................... 29 
2. 
TRIAL OBJECTIVES 
30 
2.1. 
Primary objective .................................................................................................................................... 30 
2.2. 
Secondary objectives ............................................................................................................................. 30 
2.3. 
Translational objectives .......................................................................................................................... 30 
3. 
TRIAL DESIGN AND ENDPOINTS 
31 
3.1. 
Description of the trial Design ................................................................................................................ 31 
3.2. 
Trial Endpoints ........................................................................................................................................ 31 
 
Primary endpoint 
31 
 
Secondary endpoint(s) 
31 
3.3. 
Translational endpoints .......................................................................................................................... 32 
3.4. 
Progression of the trial ........................................................................................................................... 32 
3.5. 
Inclusion procedure ................................................................................................................................ 33 
3.6. 
Premature Trial Terminations and Suspension ...................................................................................... 33 

 
 
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3.7. 
Patient’s trial withdrawal and discontinuation ......................................................................................... 33 
4. 
PATIENT SELECTION 
34 
4.1. 
Diagnosis and inclusion criteria .............................................................................................................. 34 
4.2. 
Non-inclusion criteria .............................................................................................................................. 35 
5. 
TRIAL TREATMENTS/INTERVENTIONS 
37 
5.1. 
Description of trial treatments/interventions ........................................................................................... 37 
 
Pembrolizumab 
37 
 
Vorinostat 
37 
5.2. 
Acquisition, reception, and storage ........................................................................................................ 37 
5.3. 
Trial treatments accountability, return and destruction .......................................................................... 38 
5.4. 
Formulation, appearance, packaging, and labelling ............................................................................... 38 
 
Pembrolizumab 
38 
 
Vorinostat 
38 
5.5. 
Preparation ............................................................................................................................................. 39 
 
Pembrolizumab 
39 
 
Vorinostat 
39 
5.6. 
Dose adaptation ..................................................................................................................................... 39 
 
Pembrolizumab 
39 
 
Vorinostat 
39 
5.7. 
Discontinuation of treatments: ................................................................................................................ 40 
5.8. 
Concomitant medications and therapies ................................................................................................ 41 
 
Authorized concomitant treatments 
41 
 
Prohibited concomitant treatments 
41 
 
Rescue medications and therapies/Treatment at disease progression 
42 
 
Contraception during the trial 
42 
6. 
EVALUATION OF TREATMENT ACTIVITY AND SAFETY 
45 
6.1. 
Activity evaluation ................................................................................................................................... 45 
 
Tumor imaging during the study 
45 
 
End of treatment and follow-up tumor imaging 
46 
 
RECIST v1.1 assessment of disease 
46 
 
iRECIST assessment of disease 
47 
 
Blinded independent central review committee (BICR): 
47 
6.2. 
Safety evaluation .................................................................................................................................... 47 
 
Physical examination 
48 
 
Vital signs 
48 
 
Clinical laboratory tests 
48 

 
 
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7. 
DESCRIPTION OF VISITS AND INVESTIGATIONS 
49 
7.1. 
Baseline visit ........................................................................................................................................... 49 
7.2. 
Visits and assessment during treatment period ..................................................................................... 50 
7.3. 
End-of-treatment visit ............................................................................................................................. 51 
7.4. 
Follow-up ................................................................................................................................................ 52 
7.5. 
Provisions in case of treatment or trial interruption ................................................................................ 53 
8. 
REPORTING OF ADVERSE EVENTS 
54 
8.1. 
Adverse event: general definition ........................................................................................................... 54 
8.2. 
Serious adverse event: general definition .............................................................................................. 54 
8.3. 
Measures to be taken in case of a serious adverse event ..................................................................... 55 
8.4. 
Events of Clinical Interest (ECIs) ............................................................................................................ 57 
9. 
TRANSLATIONAL STUDIES 
58 
10. DESCRIPTION OF STATISTICAL METHODS 
59 
10.1. Statistical hypothesis and sample size determination ............................................................................ 59 
10.2. Trial populations to be analyzed ............................................................................................................. 59 
10.3. Planned statistical analysis .................................................................................................................... 60 
 Modifications of SAP and initial statistical analysis strategy 
60 
11. OVERSIGHT COMMITTEES 
61 
11.1. Independent data monitoring committee ................................................................................................ 61 
11.2. Steering Executive Committee ............................................................................................................... 61 
12. QUALITY ASSURANCE 
63 
12.1. Data collection ........................................................................................................................................ 63 
12.2. Access to data ........................................................................................................................................ 64 
12.3. Trial monitoring ....................................................................................................................................... 64 
12.4. Audits and inspections ........................................................................................................................... 65 
13. ETHICAL AND REGULATORY CONSIDERATIONS 
66 
13.1. General requirements ............................................................................................................................. 66 
13.2. Patient identification ............................................................................................................................... 66 
13.3. Patient information and consent ............................................................................................................. 66 
13.4. Insurance compensation ........................................................................................................................ 67 
13.5. Investigator responsibilities .................................................................................................................... 67 
13.6. Federation of the Patient Committees for Clinical Research in Cancerology ........................................ 68 
13.7. Human biological samples collection ..................................................................................................... 68 

 
 
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 Storage and use of disease assessment samples (blood, biopsy, tumor specimen, etc.) 
68 
 Collecting additional biological samples for research purpose 
69 
14. DATA PROCESSING AND CONSERVATION OF DOCUMENTS AND DATA 
OF THE RESEARCH 
70 
14.1. Data processing ...................................................................................................................................... 70 
 Under the responsibility of the sponsor 
70 
 In the investigational center, when computerized medical records are used 
70 
14.2. Retention of documents by investigator sites ......................................................................................... 70 
15. DATA OWNERSHIP AND CONFIDENTIALITY 
72 
16. PUBLICATION RULES 
72 
17. REFERENCES 
74 
18. APPENDICES 77 
 
Performance status evaluation – WHO scale ......................................................................... 78 
 
World Medical Association - Declaration of Helsinki .............................................................. 79 
 
ICH Harmonised Tripartite Guideline for Good Clinical Practice (ICH-GCP) ......................... 80 
 
List of medications with (a) defined risk, (b) possible, and (c) conditional risk of Torsade de 
Pointes 
81 
 
Corticosteroid Dose Equivalents ............................................................................................ 82 
 
A brief summary of tumor classification RECIST v1.1............................................................ 83 
 
Description of the iRECIST Process for Assessment of Disease Progression ...................... 86 
 
Toxicity criteria (NCI-CTCAE) ................................................................................................. 91 
 
Dose modification and toxicity management guidelines for immune-related AEs associated 
with pembrolizumab .......................................................................................................................................... 92 
 
Dose modification and toxicity management of infusion-reactions related to pembrolizumab
 
95 
 
Dose modification and toxicity management of drug reactions related to vorinostat ............. 97 
 
Translational studies ............................................................................................................... 98 
 
 

 
 
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Protocol n°: UC-GMP-1908 
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L I S T  O F  A B B R E V I A T I O N S  
 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
ANSM 
Agence Nationale De Sécurité Du Médicament Et Des Produits De Santé 
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase  
HCG 
Beta Human Chorionic Gonadotropin 
BCG 
Bacillus Calmette–Guérin 
BP 
Blood Pressure 
CI 
Confidence Interval 
CNS 
Central Nervous System 
CPP 
Comité De Protection Des Personnes 
CR 
Complete Response 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organization 
CTCAE 
Common Terminology Criteria For Adverse Events 
CT-Scan 
Computed Tomography Scanner 
DCF 
Data Correction Form 
DMR 
Differentially Methylated Regions 
DOR 
Duration Of Response 
DSMB 
Data And Safety Monitoring Board 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
FDA 
Food And Drug Administration 
FFPE 
Formalin-Fixed, Paraffin-Embedded 
g 
Gram 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyl Transferase 
HBsAg 
Hepatitis B Surface Antigen 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HDAC 
Histone Deacetylase 
HIV 
Human Immunodeficiency Virus 
HLA 
Human Leukocyte Antigen 
H&N 
Head and Neck 
HNSCC 
Head and neck squamous cell carcinoma 
HPV 
Human Papilloma Virus 
IB 
Investigator Brochure 
IBBL 
Integrated BioBank of Luxembourg 
IC 
Insitut Curie 
ICF 
Inform Consent Form 
ICH 
International Conference On Harmonization 
IDMC 
Independent Data Monitoring Committee 

 
 
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Protocol n°: UC-GMP-1908 
EudraCT n°: 2019-003839-33 
 
 
 
 
 
 
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IEO 
Istituto Europeo di Oncologia 
IHC 
Immuno Histo Chemestry  
IMF 
Investigator Master File 
IMF-P 
Investigator Master File-Pharmacy 
INN 
International Non-Proprietary Name 
INR 
International Normalized Ratio 
iORR 
Immune Objective Response Rate 
iPFS 
Immune Progression Free Survival 
IP 
Investigational Products 
irAEs 
Immune-Related Adverse Events 
iRECIST 
Immune-Specific Response Evaluation Criteria In Solid Tumors 
IV 
Intravenous 
L 
Liter 
mg 
Milligram(S) 
min 
Minute(S) 
mL 
Milliliter(S) 
MSI-H 
Microsatellite instability -high 
NCI 
National Cancer Institute 
NSCLC 
Non-small cell lung cancer 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PBMC 
Peripheral Blood Mononuclear Cells 
PD 
Progressive Disease 
PD-1 
Programmed Cell Death-1 
PD-L1 
Programmed Cell Death-Ligand 1 
PR 
Partial Response 
PFS 
Progression-Free Survival 
PT 
Prothrombin Time 
PUVA 
Psoralen Plus Ultraviolet A Radiation 
Q3W 
Every 3 Weeks 
RBC 
Red Blood Cell 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RNA 
Ribonucleic Acid 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SCCa 
Squamous Cell Carcinoma Antigen 
SCC 
Squamous cell carcinoma 
SD 
Stable Disease  
SmPC 
Summary Of Products Characteristics 
SOA 
Schedule Of Visits And Activities 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TME 
Tumor Microenvironment 
TMF 
Trial Master File 
TSH 
Thyroid Stimualting Hormone 
ULN 
Upper Limit Normal 
ULN 
Upper Limit Of Normal 
VKA 
Vitamin K Antagonist 
WBC 
White Blood Cells 

 
 
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S T A T E M E N T  O F  C O M P L I A N C E  
 
UNICANCER, the trial sponsor, certifies that the trial PEVOsq will be conducted in compliance with 
the protocol described in this document, and in accordance with the French national regulatory 
requirements: 
 
Declaration of Helsinki, as modified in 2008. 
 
Loi n°2012-300 du 5 mars 2012 relative aux recherches impliquant la personne humaine, as 
modified in 2016. 
 
Regulation (EU) 2016/679 on the protection of natural persons with regard to the processing 
of personal data and on the free movement of such data (General Data Protection 
Regulation). 
 
Amended Loi Informatique et Libertés n° 78-17 du 6 janvier 1978, relative à la protection des 
personnes physiques à l'égard des traitements de données à caractère personnel. 
 
Amended Loi n° 2004-800 du 6 août 2004, relative à la bioéthique. 
 
Décision du 24 novembre 2006 fixant les règles de bonnes pratiques cliniques pour les 
recherches biomédicales portant sur des médicaments à usage humain. 
 
Arrêté du 24 mai 2006 relatif au contenu et aux modalités de présentation d’un protocole de 
recherche biomédicale portant sur un médicament à usage humain. 
 
Good Manufacturing Practices, in particular, Annex 13 on investigational medicinal products. 
 
 
 

 
 
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Protocol n°: UC-GMP-1908 
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P R O T O C O L  S U M M A R Y  
SYNOPSIS 
A) TRIAL IDENTIFICATION 
SPONSOR – PROTOCOL CODE NUMBER: UC-GMP-1908 
VERSION (NUMBER & DATE): v1.1, 14 April 2020 
TRIAL TITLE: Phase II basket trial evaluating the efficacy of a combination of pembrolizumab and 
vorinostat in patients with recurrent and/or metastatic squamous cell carcinoma 
PHASE: II 
TRIAL TITLE FOR LAY PEOPLE: Efficacy of immunotherapy in combination with a drug in patients with 
advanced mucosal cancer of different locations that has progress. 
ABBREVIATED TITLE: PEVOsq: PEmbrolizumab and VOrinostat in patients with recurrent and/or 
metastatic SQuamous cell carcinoma 
COORDINATING INVESTIGATOR: Christophe Le Tourneau, Institut Curie, Paris, France 
STATISTICIAN : Thomas Filleron, Institut Claudius Regaud, IUCT-O, Toulouse, France 
NUMBER OF CENTERS: around 15 
NUMBER OF PATIENTS: 111 
 
B) SPONSOR IDENTIFICATION 
NAME:  
UNICANCER 
101, rue de Tolbiac 
75654 Paris Cedex 13 
France 
CONTACT PERSON: 
MR FRANCOIS LEGRAND 
PROJECT MANAGER 
R&D UNICANCER 
Tel: +33 (0) 1 73 79 73 02 
email: f-legrand@unicancer.fr 
 
C) TRIAL GENERAL INFORMATION 
INDICATION: 
Patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck, cervix, 
lung, anus, vulva, and penis. 

 
 
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TRIAL DESCRIPTION/DESIGN: 
Open-label, non-randomized, multi-center, basket phase II trial, evaluating the efficacy 
pembrolizumab in combination with vorinostat in adult patients with recurrent and/or metastatic 
squamous cell carcinoma of different locations. 
PRIMARY OBJECTIVE: 
To evaluate the antitumor activity of pembrolizumab in combination with vorinostat in patients with 
recurrent and/or metastatic squamous cell carcinoma of the head and neck, cervix, lung, anus, 
vulva, and penis, using the ORR during treatment (investigator assessment). 
SECONDARY OBJECTIVES: 
 
To determine, in each cohort, the anti-tumor activity in term of: 
 Centrally confirmed objective response rate (ORR), as per RECIST v1.1. 
 Centrally confirmed immune objective response rate (iORR), as per iRECIST. 
 Duration of response (DOR). 
 Progression-free survival (PFS), as per RECIST. 
 Immune-progression-free survival (iPFS), as per iRECIST. 
 Overall survival (OS). 
 
To evaluate the safety and tolerability of pembrolizumab in combination with vorinostat 
according to NCI CTCAE v5.0: 
 In each cohort. 
 In the overall study population. 
TRANSLATIONAL OBJECTIVES: 
The translational studies associated with this clinical study aim to assess the following: 
 
Link between the tumor molecular profile and immune parameters. 
 
Link between immune-related biomarkers and drug combination efficacy. 
 
Post-treatment modification of immune-related and molecular epigenetic biomarkers. 
 
Predictive value of tumor microenvironment and epigenetic parameters. 
 
Predictive value of circulating biomarkers. 
DIAGNOSIS AND INCLUSION CRITERIA: 
1. Aged ≥18 years old. 
2. Patients with Eastern Cooperative Oncology Group (ECOG) performance status ≤1. 
3. Patients must have histologically confirmed recurrent and/or metastatic squamous cell 
carcinoma of the head and neck, cervix, lung, anus, vulva, or penis. 
4. Patients must have radiologically confirmed progressive recurrent and/or metastatic disease.  
5. Patients naive or previously treated for recurrent and/or metastatic disease. 
6. Disease amenable to biopsy for study purpose. 
7. Measurable disease according to RECIST v1.1. 

 
 
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8. Adequate renal function: serum creatinine ≤1.5 x upper limit of normal (ULN) (OR creatinine 
clearance [Cockcroft and Gault] ≥30 mL/min for participant with creatinine levels >1.5 × ULN) 
within 14 days prior inclusion. 
9. Adequate liver function: aspartate aminotransferase (AST) and alanine aminotransferase 
(ALT) levels ≤3 × ULN (≤5 ULN when documented liver metastases) and total bilirubin level 
≤1.5 × ULN, within 14 days prior inclusion. 
10. Adequate bone marrow function: absolute neutrophil count (ANC) ≥1,000/mm³, platelet count 
≥100,000/mm³, and hemoglobin ≥9 g/dL, within 14 days prior inclusion. 
11. Adequate coagulation: prothrombin time (PT)/international normalized ratio (INR) ≤1.5 × ULN 
within 14 days prior inclusion If participant is receiving anticoagulant therapy  then the PT or 
activated partial thromboplastin time (aPTT) should be within the therapeutic range of 
intended use of anticoagulant. 
12. Female of child-bearing potential must have a negative serum pregnancy test within 72 h 
before starting study treatment.  
13. Female of childbearing potential, must use "highly effective" methods of contraception for the 
study duration and for 4 months following the last dose of pembrolizumab and 6 months 
following the last dose of vorinostat. 
14. Male participants must agree to use an effective contraceptive for the duration of the trial and 
for at least 4 months after the last the last dose of pembrolizumab and 6 months following the 
last dose of vorinostat (to allow for effective elimination of the study drugs). Also, they should 
refrain from donating sperm during this period. 
15. Patients must be willing and able to comply with the protocol for the duration of the study 
including scheduled visits, treatment plan, and laboratory tests.  
16. Patients must be willing and able to comply with other study procedures, including a baseline 
tumor biopsy and a series of blood samples throughout the study. 
17. Patients able to swallow oral medications. 
18. Patients must be affiliated to a Social Security System (or equivalent). 
19. Patients must have signed a written informed consent prior to any trial-specific procedures. 
When the patient is physically unable to give their written consent, a trusted person of their 
choice, independent from the investigator or the sponsor, can confirm in writing the patient’s 
consent. 
NON-INCLUSION CRITERIA: 
1. Prior treatment with anti-PD-1/PD-L1 agents or histone deacetylases (HDAC) inhibitors. 
2. Patients with central nervous system involvement that has not been controlled for >3 
months. 
3. Patients with no other site for biopsy than bone lesions. 
4. Patients with other concurrent severe and/or uncontrolled medical disease which could 
compromise participation in the study, including uncontrolled diabetes, cardiac disease, 
uncontrolled hypertension, congestive cardiac failure, ventricular arrhythmias, active 
ischemic heart disease, myocardial infection within one year, chronic liver or renal disease, 
active gastrointestinal tract ulceration, severely impaired lung function. 

 
 
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5. Known history of human immunodeficiency virus (HIV), Hepatitis B virus (HBV; defined as 
Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (HCV; 
defined as HCV RNA detected) virus infection. 
6. History of autoimmune disease with the exception of:  
 
(1) Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid 
replacement hormone,  
 
(2) Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen, 
 
(3) Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis would be 
excluded) provided that they meet the following conditions: (i) Rash must cover less 
than 10% of body surface area; (ii) Disease is well controlled at baseline and only 
requiring low potency topical steroids; (iii) No acute exacerbations of underlying 
condition within the previous 12 months (not requiring psoralen plus ultraviolet A 
radiation [PUVA], methotrexate, retinoid, biologic agents, oral calcineurin inhibitors, 
high-potency or oral steroids). 
7. History of allogeneic organ or bone marrow transplantation. 
8. History of non-infectious pneumonitis that required steroids or has current pneumonitis. 
9. Has an active infection requiring systemic therapy. 
10. Has received a live vaccine within 30 days prior to the first dose of study drug.  Examples 
of live vaccines include, but are not limited to, the following:  measles, mumps, rubella, 
varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and 
typhoid vaccine.  Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live 
attenuated vaccines and are not allowed. 
11. Known prior severe hypersensitivity to investigational products or its excipients,  
12.  Has received prior systemic anti-cancer therapy including investigational agents within 4 
weeks [could consider shorter interval for kinase inhibitors or other short half-life drugs] 
prior to first dose of study treatments. 
Note: Participants must have recovered from all AEs due to previous therapies to ≤Grade 
1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible. 
13. Has received prior radiotherapy within 2 weeks of start of study treatment. Participants must 
have recovered from all radiation-related toxicities, not require corticosteroids, and not have 
had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks 
of radiotherapy) to non-CNS disease. 
14. Major surgery within 28 days prior to the first dose of study treatments.  
Note: Local surgery of isolated lesions for palliative intent is acceptable. 
15. Current or prior use of immunosuppressive medication within 7 days before the first dose 
of pembrolizumab. The following are exceptions to this criterion: 
 
Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular 
injection), 

 
 
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 
Systemic corticosteroids at physiologic doses ≤10 mg/day of prednisone or its 
equivalent, 
 
Steroids as premedication for hypersensitivity reactions (e.g., CT scan 
premedication). 
16. Patients using drugs that could have pharmacokinetics interaction with investigational 
drugs. This includes, but is not limited to, valproic acid, coumarin-derivative anticoagulants, 
drugs that disrupt electrolyte levels, drugs that may prolong QT. 
17. Pregnant women or women who are breast-feeding. 
18. Patients enrolled in another therapeutic study within 30 days prior to inclusion and during 
the treatment period. Patients can participate in an independent approved non-
interventional studies. 
19. Patients unwilling or unable to comply with the medical follow-up required by the trial 
because of geographic, familial, social, or psychological reasons. 
20. Persons deprived of their liberty or under protective custody or guardianship. 
PRIMARY ENDPOINT: 
Investigators will assess the ORR. The ORR is defined in each cohort as the percentage of 
evaluable patients for ORR, designate as the proportion of patients with best response of complete 
response (CR) or a partial response (PR) during treatment according to RECIST v1.1. 
SECONDARY ENDPOINTS: 
 
Anti-tumor activity endpoints will be evaluated in each cohort:  
 ORR defined as the proportion of patients with best response of CR or PR during 
treatment, as assessed by a central radiological panel according to RECIST v1.1. 
 iORR defined as the proportion of patients with best response of CR or PR during 
treatment, as assessed by a central radiological panel according to immune-specific 
response criteria (iRECIST). 
 DOR will be evaluated in patients with either a complete response (CR) or partial response 
(PR). DOR is defined as the time from the first assessment of a CR or PR until the date 
of the first occurrence of progressive disease (PD) or death from any cause (if death 
occurred within predefined period), whichever occurs first. 
 PFS is defined per RECIST1.1 as the time from inclusion until disease progression (per 
RECIST v1.1) or death from any cause, whichever occurs first. At the time of analysis, a 
patient alive and without disease progression will be censored at the date of the last tumor 
assessment. Patients alive without disease progression who started a new anticancer 
therapy will be censored at the date of the last tumor assessment prior to the start of the 
new anticancer therapy. 
 iPFS is defined per iRECIST as the time from inclusion until confirmed disease 
progression (per iRECIST), or death from any cause, whichever occurs first. At the time 
of analysis, a patient alive and without progression will be censored at the date of the last 
tumor assessment. Patients alive without disease progression who started a new anti-
cancer therapy will be censored at the date of the last tumor assessment prior to the start 
of the new anticancer therapy. 

 
 
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 OS is defined as the time from inclusion until death from any cause. Patients who are alive 
at last follow-up news will be censored at this date. 
 
The safety will be evaluated according to the incidence of adverse events (AEs) graded by 
NCI-CTCAE v5.0: 
 In each cohort. 
 In the overall study population. 
TRANSLATIONAL ENDPOINTS: 
 
To assess the link between the tumor molecular profile including epigenetics features and 
immune parameters of the tumor microenvironment (TME) and in blood samples. 
 
To assess the link between immune-related biomarkers in the TME and in blood samples 
(including but not limited to tumor tissue PD-L1 expression by IHC, RNA gene expression 
profiling, and DNA mutation analysis), and measures of efficacy. 
 
To explore the modification of immune-related and molecular epigenetic biomarkers following 
treatment. 
 
To analyze the impact of TME and epigenetics parameters on sensitivity/response to 
treatment. 
 
To assess the predictive value of circulating biomarkers on sensitivity or resistance to 
treatment. 
 
D) INVESTIGATIONAL MEDICINAL PRODUCTS 
PRODUCT NAMES AND ADMINISTRATION: 
Drug name (INN) 
Registered 
name 
Pharmaceutical 
form 
Administration 
route 
Posology 
Pembrolizumab 
Keytruda 
100 mg/vial (liquid) 
Intra-venous (IV) 
200 mg every 
3 weeks  
Vorinostat 
Zolinza® 
100 mg/capsule 
Per os 
400 mg once 
daily 
 
THERAPEUTIC REGIMENS: 
Patients will take vorinostat orally at 400 mg once daily with food.  
Pembrolizumab will be administered intravenously at 200 mg every 3 weeks up to 35 
administrations (approximately 2 years). 
Treatment will be administered until disease progression, unacceptable toxicity, or patient’s 
decision, and up to 35 administrations for pembrolizumab. 
Continuation of pembrolizumab beyond 35 cycles may be allowed under certain conditions and 
must be agreed with the sponsor before continuing the treatment. 

 
 
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TRIAL FLOWCHART: 
Study Design: A fresh tumor biopsy is mandatory prior to treatment (baseline). Optional biopsies 
might be collected within the week before the first disease assessment and at disease progression. 
Imaging will be performed every 6 weeks. Blood sampling for research will be performed at baseline 
before pembrolizumab plus vorinostat treatment, at Day 1 of cycle 3 and cycle 5, and at disease 
progression. 
C1-Cx: The duration of each treatment cycles is 3 weeks. 
TREATMENT DURATION: 
Patients will be treated until disease progression (or for up to 35 cycles for pembrolizumab) or 
unacceptable toxicity or patient decision. 
Continuation of pembrolizumab beyond 35 cycles may be allowed under certain conditions and 
must be agreed with the sponsor before continuing the treatment. 
 
E) STATISTICAL ANALYSIS PLAN 
REQUIRED NUMBER OF PATIENTS TO BE SCREENED/INCLUDED: 111 
The primary aim of the study is to assess the antitumor activity of the combination of 
pembrolizumab and vorinostat in patients with selected recurrent and/or metastatic solid tumors. 
ORR reported in the literature with pembrolizumab or nivolumab in phase III clinical trials ranged 
from 6% to 24% depending on the tumor type. 

 
 
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The primary endpoint is the rate of patient presenting an objective response (defined as the 
proportion of patients with best response of a complete response (CR) or a partial response (PR) 
according to RECIST v1.1) while on study protocol. 
The required number of evaluable patients for each cohort was determined using an A’Hern design 
(A'Hern 2001) based on different hypotheses. Design parameters and decision rules for each 
cohort are summarized in the following table: 
Cohort 
p0 
p1 
Alpha 
Power 
Nb of 
evaluable / 
included 
patients 
Sufficiently active 
Head and Neck 
10% 
35% 
5% 
85% 
19 / 21 
≥5 CR/PR 
Cervix 
5% 
30% 
5% 
90% 
16 / 18 
≥3 CR/PR 
Lung 
15% 
40% 
5% 
85% 
23 / 25 
≥7 CR/PR 
Anus 
15% 
40% 
5% 
85% 
23 / 25 
≥7 CR/PR 
Penis 
5% 
30% 
10% 
85% 
10 /11 
≥2 CR/PR 
Vulva 
5% 
30% 
10% 
85% 
10 / 11 
≥2 CR/PR 
 
p0: maximal unacceptable rate of patient presenting an objective response for whom the 
experimental treatment will be considered as insufficiently active. 
 
p1: minimal acceptable rate of patient presenting an objective response for whom the 
experimental treatment will be considered as sufficiently active. 
To compensate for drop out, we plan to include an additional 10% of patients in each cohort; 
therefore a total of 111 patients are required for this study. 
 
  
Cohort 
Nb of evaluable patients 
Insufficiently active 
Sufficiently active 
Penis, vulva 
10 
<2 CR/PR 
≥2 CR/PR 
Cervix 
16 
<3 CR/PR  
≥3 CR/PR  
Head & Neck 
19 
<5 CR/PR 
≥5 CR/PR 
Lung, Anus 
23 
<7 CR/PR 
≥7 CR/PR 
STATISTICAL ANALYSIS: 
Demographic and clinical data 
Demographic and clinical characteristics (including HPV status) will be presented in the overall 
population and per cohort using usual statistics. Quantitative data will be summarized as median, 
min, max, and number of missing data. Qualitative variables will be described as number, 
percentage, and number of missing data. 
Population definition 
The following populations will be considered for analyses: 

 
 
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 
Per-protocol: all eligible patients with at least one valid post-baseline disease assessment (or 
with disease progression) and have received at least one dose of the study treatments 
(pembrolizumab or vorinostat). 
 
Safety population: all patients who initiated allocated treatment (at least one dose of the study 
treatments). 
Primary endpoint 
The primary endpoint will be assessed in the per protocol population and will be reported per 
cohort. The primary endpoint is the rate of evaluable patients for response presenting an objective 
response assessed by the investigators according to RECISTv1.1. It will be presented as number, 
percentage, and 95% confidence interval (CI): by the binomial exact distribution. 
Secondary endpoints 
The secondary efficacy endpoints will be assessed in the per protocol population and will be 
reported per cohort. 
ORR, iORR, and DOR will be presented using frequency, percentage frequencies, percentages, 
and the 95% CI (Binomial exact distribution). 
A radiological panel will centrally assess the ORR, iORR, and iPFS.  
Survival rates (PFS, iPFS OS) will be estimated at different time points using the Kaplan-Meier 
method. Median survival times will be estimated and reported with the corresponding 95% CI. 
Number of pembrolizumab injections and dose intensity of vorinostat will also be recorded. 
Incidence rates of adverse events and serious adverse events will be presented using frequencies 
and percentages by system organ class and MedDRA preferred term. Pharmacovigilance will be 
handled by UNICANCER. 
 
F) SAMPLES COLLECTED FOR TRANSLATIONAL RESEARCH 
SAMPLE TYPES:   
SAMPLE QUANTITIES: 
TIMEPOINTS: 
Blood samples 
Mandatory 
2 x 10 mL  
PACgene CCF tubes 
Baseline,  
C3D1, C5D1, Progression 
Mandatory 
3 x 8.5 mL CPT tubes 
Baseline,  
C3D1, C5D1, Progression 
Mandatory 
1 x 4 mL EDTA Tubes 
Baseline, 
Tumor Samples 
Mandatory 
Up 4 cores:  
2 FFPE, 2 frozen 
Baseline 
Optional 
Up 4 cores:  
2 FFPE, 2 frozen 
C3D1,  Progression 
 

 
 
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G) TRIAL DURATIONS 
INCLUSION PERIOD: 18 months 
TRIAL TREATMENT PERIOD:  Until disease progression (or up to 35 cycles for pembrolizumab) or 
unacceptable toxicity or patient‘s decision. Approximately 6 months 
POST-TREATMENT FOLLOW-UP: 1 year 
DURATION UNTIL PRIMARY ENDPOINT EVALUATION: 18 + 24 = 42 months  
OVERALL TRIAL DURATION (INCLUDING FOLLOW-UP): 18+24+12 =  54 months approximately 

 
 
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SCHEDULE OF VISITS AND ACTIVITIES (SOA) 
VISITS 
Baseline 
Treatment phase 
End of study 
treatment visit 10 Follow-up 11 
Visit Dates 
Day -28 to 0 
Day 1 
Day 22 Day 43 Day 64 Every 21 days 
CYCLES (every 3 weeks) 
 
C1 
C2 
C3 
C4 
C5 and after 
Patient history 
 
 
 
 
 
 
 
 
Inclusion/non-inclusion criteria 
D-28 
 
 
 
 
 
 
 
Signed informed consent form 
D-28 
 
 
 
 
 
 
 
Demography 
D-28 
 
 
 
 
 
 
 
Medical history and prior cancer treatment 
D-28 
 
 
 
 
 
 
 
History of HIV, Hepatitis B and C 
D-28 
 
 
 
 
 
 
 
Physical examination 
 
 
 
 
 
 
 
 
Clinical examination 1 
D-14 
 
D1 
 
D1 
D1 
 
 
Weight, ECOG  
D-14 
D1 
D1 
D1 
D1 
D1 
X 
 
Adverse events 
D-28 
D1 
D1 
D1 
D1 
D1 
X 
X 
Post study anticancer treatment 
 
 
 
 
 
 
 
X 12 
Paraclinical examination 
 
 
 
 
 
 
 
 
Tumor measurements as per RECIST1.1 and 
iRECIST (CT-scan or MRI) 2, 22 
D-7 
 
D1(-7d) 
 
D1(-7d) 2 
X 
X 3 
12 lead electrocardiogram 
D-14 
 
 
 
 
 
 
 
Biological tests 
 
 
 
 
 
 
 
 
Hematology 4  
D-14 
D1(+/-3d) D1(+/-3d) D1(+/-3d) D1(+/-3d) 
D1(+/-3d) 
X 
 
Biochemistry 5 
D-14 
D1(+/-3d) D1(+/-3d) D1(+/-3d) D1(+/-3d) 
D1(+/-3d) 
X 
 
Thyroid function test 6 
D-14 
D1(+/-3d) 
 
D1(+/-3d) 
 
D1(+/-3d) 6 
 
 
Squamous cell carcinoma antigen (SCCa) 6 
D-14 
 
 
 D1(+/-7d) 
 
D1(+/-7d) 6 
X 
 
Serum pregnancy test 7 
D-3 (72 h) 
 
D1(+/-3d) D1(+/-3d) D1(+/-3d) 
D1(+/-3d) 
X 
 
Treatments 
 
 
 
 
 
 
 
 
Pembrolizumab 8 
 
D1 
D1 
D1 
D1 
D1 
 
 
Vorinostat 9 
 
Every day 
 
 

 
 
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VISITS 
Baseline 
Treatment phase 
End of study 
treatment visit 10 Follow-up 11 
Visit Dates 
Day -28 to 0 
Day 1 
Day 22 Day 43 Day 64 Every 21 days 
CYCLES (every 3 weeks) 
 
C1 
C2 
C3 
C4 
C5 and after 
Translational research (mandatory) 
 
 
 
 
 
 
 
 
Blood samples (30 to 40 mL each) 
D-14 
 
 
D1(+/-7d) 
 
D1(+/-7d) 13 
At progression 
 
Mandatory tumor biopsy 
D-14 14 
 
 
 
 
 
 
 
Translational research (optional) 
 
 
 
 
 
 
 
 
Optional tumor biopsy 
 
 
 
D1(+/-7d) 14 
 
 
At progression 14 
 
Notes: 
1. Includes pulse rate, systolic and diastolic blood pressure, and body temperature. 
2. CT scan or MRI of the chest, abdomen, and pelvis should be performed for tumor assessment according to RECIST/ iRECIST. Imaging disease assessments should be 
obtained every 6 weeks (within 7 days prior to CxD1), or sooner if clinically indicated, during the first 12 months of treatment phase, and every 12 weeks (within 7 days prior 
to treatment) thereafter. They should be repeated 4 weeks after assessment of a PR or CR as per RECIST and after assessment of iUPD as per iRECIST guidelines. Tumor 
assessments must be performed regardless of changes to the study treatment administration schedule (e.g., dose delay). 
3. Tumor evaluations are to be continued during the post-treatment follow-up period if withdrawal was not related to disease progression. Evaluations should be continued and 
documented every 6 weeks (or every 12 weeks after the first 12 months of treatment phase) until disease progression or initiation of an antineoplastic treatment. 
4. Hemoglobin, red blood cell count, white blood cell count (WBC), absolute neutrophil count (ANC), lymphocyte count, and platelet count. 
5. Includes blood ionogram (Na, K, Ca, Mg, P, Cl, CO2, total protein, albumin), renal function (blood urea, creatinine), hepatic function (direct bilirubin, alkaline phosphatase, 
ALT, AST, GGT), coagulation profile (PT/INR, aPTT) – Baseline only, fasting plasma glucose, creatinine phosphokinase. 
6. Thyroid function test include TSH, free T3, free T4, and SCCa should be performed every 2 cycles starting with C1D1. 
7. Serum pregnancy test (pre-menopausal patients only) within 72 h prior to starting study treatment, and at each 21-day cycle. 
8. Pembrolizumab will be administered IV, 200 mg, at day 1 of a 3-week cycle, and up to 35 administrations (approximately 2 years).  
9. Vorinostat will be taken orally, 400 mg, once daily (starting on day 1), until disease progression or unacceptable toxicity. Dose adaptation are described in section 5.6 
10. Patients who discontinue study drug will return to the clinic for a treatment discontinuation visit 1 week after the last dose of all study drugs.  
11. Patients should be followed up every 3 months (maximum of 1 year) until death, withdrawal of consent, or lost to follow-up. 
12. Information on the first systemic anti-cancer therapy initiated after the first disease progression will be collected at the same time as survival assessments. 
13. To be collected at C5D1 only 
14. When possible, up to 4 cores (2 frozen, 2 FFPE) will be collected at each time points. Biopsies must be done on the same site as the baseline sample. If the sample volume 
is not sufficient to obtain four biopsy cores, priority will be given according to the following algorithm: 
 
 
 
Priority order for biopsy cores collection depending on the tumor location/volume 
Number of cores collected 
Cores’ preparation 
1 (favorable situation) 
4 
2 Frozen, 2 FFPE  
2 
3 
2 Frozen, 1 FFPE 
3 
2 
1 Frozen, 1 FFPE 
4 (unfavorable situation) 
1 
1 Frozen 

 
 
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1 .  I N T R O D U C T I O N  
1.1. Background information 
 Disease epidemiology 
Squamous cell carcinomas (SCC) can originate from various location within the body. In humans, 
they are among the most frequently occurring solid cancers (Dotto and Rustgi 2016). Indeed, 
worldwide in 2018, there were 2.1 million new cases of lung cancers (Bray, Ferlay et al. 2018). Of 
these, 85% are NSCLCs of which 30% are SCC (Heist, Mino-Kenudson et al. 2012, Derman, 
Mileham et al. 2015). H&N SCC are also fairly common, with 600,000 new cases of H&N SCC 
declared globally each year (Mangano, Mangano et al. 2015, Marur and Forastiere 2016). In contrast 
to lung SCC and H&N SCC, other SCCs are quite rare. Penile SCC is extremely rare with an 
incidence between 0.1-0.9 cases per 100,000 men, in Europe (Novara, Galfano et al. 2007). As is 
vulvar SCC, with an age-specific incidence rate of 0.4 per 100,000 women in their 30’s increasing to 
20 per 100,000 in women older than 70 years old (Gadducci, Tana et al. 2012). Anal SCC has a 
global annual incidence of about 1-3 cases per 100,000 individuals, with yearly about 48,000 new 
cases diagnosed worldwide (Bray, Ferlay et al. 2018, Morton, Melnitchouk et al. 2018, Eng, Messick 
et al. 2019). Finally, cervical SCC represents about 80% of cervical cancers (Li, Liu et al. 2016). 
Numerous environmental factors including UV exposure, cigarette smoking, alcohol consumption, 
and infections favor the development of SCCs (Dotto and Rustgi 2016). Infectious agents such as 
the human papilloma virus (HPV) infections are implicated in most cervical SCCs and anal SCCs, a 
significant number of vulvar and penis SCC, and to a lesser extend HNSCC (Osborne, Maykel et al. 
2014, Dotto and Rustgi 2016, Brianti, De Flammineis et al. 2017, Brotherton, Budd et al. 2020). In 
contrast, mycobacterium tuberculosis infection, but not HPV, is associated with lung SCC (Dotto and 
Rustgi 2016). However, one of the main environmental factor for developing lung SCC, as well as 
H&N SCC, is cigarette smoking (Dotto and Rustgi 2016). 
 Prognosis 
The prognosis of patients with SCC varies largely according to the location. In patients with local or 
regional H&N SCC disease recurrences occurs in about 30% of patients (Cooper, Pajak et al. 2004). 
In addition, about 25% will develop distant metastases. The 5-year survival rate is 40%. Concerning 
lung SCC, it is difficult to diagnose at an early stage, and is less sensitive to radiotherapy and 
chemotherapy (Wang, Wang et al. 2019). Consequently, the 5-year survival rate remains low despite 
surgery, radiotherapy, and chemotherapy. In patients with penal SCC, lymph node involvement in 
the groin is the most important prognostic factor for survival (Novara, Galfano et al. 2007). Thus, the 
5-year cancer specific survival for men with SCC of the penis is between 75-93% for those with 
node-negative disease that diminishes with lymph node involvement. Similarly, lymph node status is 
the most important prognostic factor for women with vulvar SCC (Gadducci, Tana et al. 2012). The 
5-year survival rate is between 70-98% for vulvar SCC patients with negative nodes compared to 
only 12-41% with metastatic nodes. In Europe, the 5-year survival rate of patients with anal SCC 
varies between 44-66% depending on the region (Glynne-Jones, Nilsson et al. 2014). A study that 
assessed survival in 198 cervical SCC patients reported a median OS of 61.3 months and a 5-year 
OS rate of 56.6% (Li, Liu et al. 2016). The study also showed that the presence of lymph node 
metastasis is a negative prognostic factor for survival in cervical SCC patients.  

 
 
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 Investigational medicinal products (IMP) 
1.1.3.1. Pembrolizumab 
Pembrolizumab is a highly selective humanized monoclonal antibody (mAb) that bind to the cell 
surface receptor programmed cell death protein 1 (PD-1) (du Rusquec, de Calbiac et al. 2019). This 
binding antagonizes the interaction between PD-1 and its ligands, PD-L1 and PD-L2: interrupting 
the down-modulation of T-cell immune response. Pembrolizumab is a human immunoglobulin 
G4/kappa isotype with a stabilizing sequence alteration in the Fc region.  
Pembrolizumab is approved for treating melanoma, non-small cell lung cancer (NSCLC), Hodgkin 
lymphoma, urothelial carcinoma, H&N SCC, and renal cell carcinoma (du Rusquec, de Calbiac et al. 
2019). Pembrolizumab is predominantly used for patients with metastatic disease or in cases were 
available treatments have failed. For treating renal cell carcinoma, it is approved in combination with 
other treatments. In NSCLC and H&N SCC is can be used as monotherapy or in combination. In the 
other cancer mention, pembrolizumab is only approved as monotherapy. 
Refer to the current version of the pembrolizumab investigator brochure (IB) for a complete summary 
of non-clinical and clinical data including safety, efficacy, and pharmacokinetics data. 
1.1.3.2. Vorinostat 
Vorinostat is a synthetic hydroxamic acid derivative that inhibits histone deacetylase (HDAC). by 
binding to the catalytic domain of the HDAC (Laengle, Kabiljo et al. 2020).  
Small molecule inhibitors of HDAC are a new class of antineoplastic agents. They have 
antiproliferative effects, such as inducing cell differentiation, cell-cycle growth arrest, and apoptosis 
(Duvic and Vu 2007). HDAC inhibitors, such as vorinostat, act mainly by preventing deacetylation 
resulting in the accumulation of both hyperacetylated histones and transcription factors. Vorinostat 
direct effect the regulation of numerous genes, ultimately resulting in a decrease in the proliferation 
of malignant cells. Vorinostat is approved for the treatment of cutaneous manifestations in patients 
with cutaneous T-cell lymphoma who have progressive, persistent, or recurrent disease on or 
following two systemic therapies. 
Refer to the current version of the vorinostat SmPC for a complete summary of non-clinical and 
clinical data including safety, efficacy, and pharmacokinetics data. 
1.2. Trial rationale 
Traditionally, cancer treatments have been approved according to their location. However, now with 
a deeper understanding of the genetic and molecular mechanism of cancer, this paradigm is being 
questioned. Indeed, the FDA has recently approved pembrolizumab for tumours with high 
microsatellite instability (MSI) and larotrectinib for neurotrophic receptor tyrosine kinase (NRTK) 
fusion tumours. These agnostic therapies target underlying biological mechanism common to 
several tumours. Indeed, SCCs have traditional been treated according to their location, despite 
sharing genetic, genomic, and epigenetic modifications. Consequently, new agnostic therapies have 
and are being developed to target these common modifications. 

 
 
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 Immunotherapy for treating SCC 
Immunotherapy has already proven to be an effective treatment for patients with advanced SCC 
(see Table 1). Indeed, several clinical trials have assessed immunotherapies, pembrolizumab and 
nivolumab, in several SCCs including H&N, anal, cervical, vulvar, and lung SCC. These 
immunotherapies show activity in several SCCs, with ORR ranging from 0 to 32%. 
There is no strong evidence yet, that HPV status is correlated to anti-tumor activities of 
immunotherapies. In the study KEYNOTE-055, ORR observed in H&N patients treated with 
pembrolizumab is similar in both HPV populations (HPV+:n=37, 16% ; HPV– n=131, 15%). 
Contradictorily, in the study KEYNOTE-012, ORR observed in H&N patient treated with 
pembrolizumab is more important in the HPV+ subgroup (HPV+ n=28, 32% ;HPV- n=104, 14%). 
 
Table 1 - Immune checkpoint inhibitors evaluated for treating squamous cell carcinomas (SCC) 
Trial name 
Type of 
SCC 
Immune 
checkpoint 
inhibitor 
Lines of 
prior 
treatment 
Patient 
selection 
N 
Phase 
ORR 
(%) 
References 
Keynote-
040 
H&N 
pembrolizumab 
1-3 
- 
247 
III 
15 
(Cohen, 
Soulieres et 
al. 2019) 
Checkmate 
141 
H&N 
nivolumab 
Any 
- 
240 
III 
13 
(Ferris, 
Blumenschein 
et al. 2016) 
Keynote-
055 
H&N 
pembrolizumab 
Any 
- 
HPV+ 
HPV- 
CPS>1 
CPS<1 
CPS>50 
CPS<50 
171 
37 
131 
140 
26 
48 
118 
II 
16 
16 
15 
18 
12 
27 
13 
(Bauml, 
Seiwert et al. 
2017) 
Keynote-
012 
(Expansion 
cohorts) 
H&N 
pembrolizumab 
Any 
- 
CPS>1 
CPS<1 
HPV+ 
HPV- 
TPS<1% 
TPS>1% 
132 
107 
25 
28 
104 
43 
89 
I 
18 
22 
4 
32 
14 
16 
19 
(Chow, 
Haddad et al. 
2016) 
Keynote-
012 
H&N 
pembrolizumab 
Any 
PD-
L1>1% 
HPV+ 
HPV- 
45 
16 
29 
I 
18 
25 
14 
(Seiwert, 
Burtness et 
al. 2016) 
NCI9673 
Anal 
nivolumab 
>2 
- 
37 
II 
24 
(Morris, 
Salem et al. 
2017) 
Keynote-
028 
Anal 
pembrolizumab 
Any 
PD-L1>1 
25 
I 
16 
(Ott, Bang et 
al. 2019) 

 
 
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Trial name 
Type of 
SCC 
Immune 
checkpoint 
inhibitor 
Lines of 
prior 
treatment 
Patient 
selection 
N 
Phase 
ORR 
(%) 
References 
Keynote-
028 
Cervical 
pembrolizumab 
Any 
PD-L1>1 
24 
I 
17 
(Frenel, Le 
Tourneau et 
al. 2017) 
Checkmate 
358 
Cervical 
nivolumab 
1-3 
- 
19 
I/II 
26 
(Naumann, 
Hollebecque 
et al. 2019) 
Keynote-
028 
Vulvar 
pembrolizumab 
Any 
PD-L1>1 
18 
I 
6 
(Ott, Bang et 
al. 2019) 
Checkmate 
358 
Vulvar 
nivolumab 
1-3 
- 
5 
I/II 
0 
(Naumann, 
Hollebecque 
et al. 2019) 
Checkmate 
017 
Lung 
nivolumab 
Any 
- 
135 
III 
20 
(Brahmer, 
Reckamp et 
al. 2015) 
 
 
 Immune checkpoint inhibitors combined with HDAC inhibitors for treating SCC 
We have seen that immunotherapies as monotherapy have shown anti-cancer activity in several 
SCCs. However, several studies have shown that HDAC inhibitors potentiate immunotherapy 
(Mazzone, Zwergel et al. 2017). Indeed, a recent preclinical study reported enhanced efficacy in 
combining an immune checkpoint inhibitor with an HDAC inhibitor (belinostat) in murine 
hepatocellular carcinoma models (Llopiz, Ruiz et al. 2019). Similar results were reported in lung and 
renal cell carcinomas murine tumour models. Indeed, entinostat a HDAC inhibitor potentiated PD-1 
inhibit in these models (Orillion, Hashimoto et al. 2017). Therefore, preclinical studies provide 
rationale for combining an HDAC inhibitor with an immune checkpoint inhibitor. 
 
This combination is currently being assessed in several ongoing early phase trials. These include 
pembrolizumab combined with vorinostat in advanced renal or urothelial cell carcinoma patients 
(NCT02619253), pembrolizumab combined with entinostat in metastatic uveal melanoma patients 
(NCT02697630) (Jespersen, Olofsson Bagge et al. 2019), nivolumab combined with azacitidine and 
entinostat in non-small cell lung cancer patients (NCT01928576), and aldesleukin (interleukin-2) 
combined with entinostat in metastatic kidney cancer patients (NCT01038778). 
 Pembrolizumab combined with vorinostat for treating SCC 
In this study, we would like to assess vorinostat combined with pembrolizumab for treating SCCs at 
various locations. This combination (vorinostat and pembrolizumab) has already been evaluated in 
SCCs and results have recently been published (Gray, Saltos et al. 2019, Rodriguez, Wu et al. 2020). 
Firstly, the results of a phase I/Ib study assessing pembrolizumab combined with vorinostat for 
treating patients with advanced/metastatic NSCLC have recently been published (Gray, Saltos et al. 
2019). In the 24 patients evaluable for efficacy: 3 patients with PR, 11 with SD, and 10 with PD. The 
disease control rate (patients with PR and SD) was 58%. In addition, in the study population (n=33), 
median OS was 18.2 months and median PFS was 15.3 months.  

 
 
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Secondly, Rodriguez et.al. assessed the pembrolizumab-vorinostat combination in patients with 
recurrent metastatic head and neck SCC and salivary gland cancers(Rodriguez, Wu et al. 2020). 
The study enrolled 25 patients with H&N SCC. After a median follow-up of 12.6 months, the median 
OS was 12.6 months and the median PFS was 4.5 months. Of the 25 patients, 8 patients had a PR, 
4 a SD, and 10 a PD. The median duration of response was 6.2 months and the ORR was 32%.  
Therefore, we designed the PEVOsq trial to evaluate the efficacy of pembrolizumab combined with 
vorinostat in patients with recurrent and/or metastatic SCC in various anatomical locations. 
Furthermore, we planned to collect and analyze biological samples to identify potential biomarkers 
of efficacy and resistance. 
1.3. Justification for the therapeutic regimens and treatment durations 
Pembrolizumab efficacy is driven by the reactivation of adaptive immune response by blocking PD-
1 expressed on T cells and not through the direct binding to cancer cells. Once the PD-1 on T cells 
are saturated through binding with pembrolizumab, efficacy is not expected to increase with further 
exposure. It has been shown that exposure at 2 mg/kg every 3 weeks (Q3W) is similar to that at 200 
mg Q3W (Freshwater, Kondic et al. 2017). In addition, PK results in participants with various 
tumours: melanoma, NSCLC, HNSCC, and MSI-H show no meaningful difference in PK of 
pembrolizumab. Therefore, a pembrolizumab dosage of 200 mg Q3W is considered appropriate for 
treating multiple indications. 
The HDAC inhibition in PBMC following vorinostat administered ration at 400 mg dose level lasted 
at least 10 hours. The pharmacokinetics PK of vorinostat after multiple dose administrations is 
qualitatively similar to that observed after a single dose. When vorinostat was taken at 400 mg once 
daily with food for 28twenty-eight consecutive days, concentration time profiles were qualitatively 
similar on days 1 and 28, indicating no obvious changes in drug absorption or elimination.  
Vorinostat reaches its maximum serum concentration within 15 min to 6 h after intake. The drug is 
rapidly eliminated with a half-life of between 60-100 min (Bubna 2015). In addition, vorinostat is not 
metabolized, nor does it inhibit, cytochrome P-450 isoenzyme. Phase I and II studies have shown 
that 400 mg of vorinostat, once daily, is effective with acceptable toxicity in patients with various 
cancers. Refer to the current version of the vorinostat SmPC for additional information. 
In the trial assessing the combination for treating H&N SCC patients, pembrolizumab (200 mg) was 
administered every 21 days, and vorinostat (400mg) taken 5 days on and 2 days off during each 21-
day cycle (Rodriguez, Wu et al. 2020). However, the dose-escalation study assessing the 
combination gave pembrolizumab (200 mg) Q3W and oral vorinostat daily at either 200 mg (dose 
level 1) and 400 mg (dose level 2) (Gray, Saltos et al. 2019). No dose-limiting toxicities were 
observed and the recommended phase II dosage of pembrolizumab was 200 mg Q3W with daily 
vorinostat (400 mg) during every 21-day cycle. This dosage was reportedly well tolerated. Therefore, 
the dosage schedule that will be used in this trial is intravenous pembrolizumab, 200 mg Q3W 
combined with oral vorinostat, 400 mg once daily. 

 
 
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1.4. Potential risks and benefits 
 Known potential risks 
1.4.1.1. Pembrolizumab 
The safety profile of pembrolizumab is based on the cumulative safety dataset which is a pools safety 
data summary of adverse events (AE) from several clinical studies. 
The most frequently reported (≥10%) AE are fatigue, nausea, diarrhea, decreased appetite, cough, 
pruritus, constipation, dyspnea, arthralgia, rash, vomiting, pyrexia, anemia, headache, asthenia, 
back pain, and abdominal pain. The most frequently reported (≥1%) serious adverse events (SAE) 
are pneumonia, pneumonitis, pleural effusion, dyspnea, pyrexia, pulmonary embolism, anemia, and 
colitis. The most frequently reported (≥10%) drug-related AE are fatigue, pruritus, rash, diarrhea, 
and nausea. In addition, the most frequent (≥0.5%) drug-related SAEs reported were pneumonitis, 
colitis, and diarrhea. 
Pneumonitis is the most common event leading to discontinuation of pembrolizumab therapy. The 
frequency of drug-related deaths remains very low, pneumonitis being most common event leading 
to death. Immune-mediated adverse events and infusion-related reactions maybe associated with 
Pembrolizumab use. 
Refer to the current version of the pembrolizumab investigator brochure (IB) for a complete summary 
of non-clinical and clinical safety data. 
1.4.1.2. Vorinostat 
The maximum tolerated dose for continuous daily dosing without a rest period is 400 mg daily. Most 
dose limiting toxicities occurred within the first month of treatment with oral vorinostat, and resolved 
quickly once treatment is interrupted. 
The most frequently reported (≥10%) AE for patients treated with vorinostat, either as monotherapy 
or in combination, are nausea, diarrhea, fatigue, vomiting, thrombocytopenia, anemia, decreased 
appetite, constipation, neutropenia, dyspnea, pyrexia, cough, weight decreased, asthenia, blood 
creatinine increased, anorexia, hyperglycemia, leukopenia, headache, dizziness, dysguesia, 
alopecia, abdominal pain, hypokalemia, and back pain. In addition, the most frequently (≥1%) drug-
related SAE are thrombocytopenia, diarrhea, dehydration, vomiting, febrile neutropenia, anemia, 
nausea, and pneumonia. Fatigue is the most common event leading to treatment discontinuation.  
Refer to the current version of the vorinostat SmPC for a complete summary of non-clinical and 
clinical safety data. 
1.4.1.3. Safety profile of the pembrolizumab combined with vorinostat 
In the phase I/Ib study assessing the pembrolizumab-vorinostat combination for treating patients 
with advanced/metastatic NSCLC safety was assessed in 33 patients (Gray, Saltos et al. 2019). No 
dose-limiting toxicities nor treatment-related deaths were reported. The most common AEs noted 
were fatigue (33% of patients), nausea (27%), and vomiting (27%). The only immune-related AE 
reported in ≥5% of patients was hypothyroidism: reported in 15% of patients. Although, irAEs of 
increases in liver enzyme levels (ASAT/ALAT), arthralgia, colitis, diarrhea, and myalgia were all 
reported in about 3% of patients. In addition, in the study assessed the combination in patients with 

 
 
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recurrent metastatic H&N SCC and salivary gland cancer 1 of 3 patients with H&N SCC reported 
fatigue of grade 3: considered as a dose-limiting toxicity during the safety run-in period (Rodriguez, 
Wu et al. 2020). Furthermore, AEs (all grades) were reported in 14 patients (56%) and those of grade 
≥3 in 9 patients (36%). Pembrolizumab combined with vorinostat was reported to be well-tolerated 
(Gray, Saltos et al. 2019). 
 
 Known potential benefits 
As discussed above, two clinical trials have assessed the efficacy and safety of pembrolizumab 
combined with vorinostat in patients with H&N SCC and in NSCLC. Gray et al. assessed the 
combination in NSCLC patients in a phase I/Ib study (Gray, Saltos et al. 2019). The disease control 
rate (patients with PR and SD) was 58%. In addition, median OS was 18.2 months and median PFS 
was 15.3 months. The single-institution, phase II study assessed the combination in patients with 
H&N SCC and salivary gland cancer (Rodriguez, Wu et al. 2020). In H&N SCC patients (n=25), 8 
patients had a PR, 4 a SD, and 10 had disease progression: DCR was 48%. In addition, median OS 
was 12.6 months and median PFS was 4.5 months. 
Based on these data, we envisage that the combination of pembrolizumab plus vorinostat will be 
effective to treat patients with advanced SCCs of different locations. 
 
1.5. Trial population 
The trial population will be composed of men and women, aged ≥18 years, with a histologically 
confirmed progressive late-stage squamous cell carcinoma of the head and neck, cervix, lung, anus, 
vulva, or penis. 
Squamous cell cancers located in the vulva, penis, cervix or anus have no standard of care 
established in the recurrent and/or the metastatic setting. Hence the combination of pembrolizumab 
and vorinostat can be proposed as a 1st line strategy in this setting. 
For head and neck cancer, EMA has recently approved pembrolizumab in 1st line in metastatic 
setting, but approval is pending in France. For those patients, the study combination provides an 
anticipated access to immune checkpoint inhibitor. 
For lung cancer, pembrolizumab is already the standard of care in 1st line metastatic setting with or 
without chemotherapy. Proposing a combination could bring an additional benefit, which will be 
evaluated in the PEVOsq trial.  
Patient treatment-naive in recurrent and/or metastatic setting can be therefore included in study and 
treated by the combination of pembrolizumab and vorinostat. 

 
 
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2 .  T R I A L  O B J E C T I V E S  
2.1. Primary objective 
The primary objective of this trial is to evaluate the antitumor activity of pembrolizumab in 
combination with vorinostat in patients with recurrent and/or metastatic squamous cell carcinoma of 
the head and neck, cervix, lung, anus, vulva, and penis, using the ORR during treatment (investigator 
assessment). 
2.2. Secondary objectives 
The secondary objectives of this clinical study are: 
 
To determine, in each cohort, the anti-tumor activity in term of: 
 Centrally confirmed objective response rate (ORR), as per RECIST v1.1. 
 Centrally confirmed immune objective response rate (iORR), as per iRECIST. 
 Duration of response (DOR). 
 Progression-free survival (PFS), as per RECIST. 
 Immune-progression-free survival (iPFS), as per iRECIST. 
 Overall survival (OS). 
 
To evaluate the safety and tolerability of pembrolizumab in combination with vorinostat 
according to NCI CTCAE v5.0: 
 In each cohort. 
 In the overall study population. 
2.3. Translational objectives 
The translational studies associated with this clinical study aim to assess the following: 
 
Link between the tumor molecular profile and immune parameters. 
 
Link between immune-related biomarkers and drug combination efficacy. 
 
Post-treatment modification of immune-related and molecular epigenetic biomarkers. 
 
Predictive value of tumor microenvironment and epigenetic parameters. 
 
Predictive value of circulating biomarkers. 

 
 
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3 .  T R I A L  D E S I G N  A N D  E N D P O I N T S  
3.1. Description of the trial Design 
This is an open-label, non-randomized, multi-center, basket phase II trial evaluating the efficacy of 
pembrolizumab in combination with vorinostat in adult patients with recurrent and/or metastatic 
squamous cell carcinoma of different locations. 
 
Figure 1 - Study design 
 
3.2. Trial Endpoints 
 Primary endpoint 
Investigators will assess the ORR. The ORR is defined in each cohort as the percentage of evaluable 
patients for ORR, designate as the proportion of patients with best response of complete response 
(CR) or a partial response (PR) during treatment according to RECIST v1.1. (Appendix 6). 
 Secondary endpoint(s) 
 
Anti-tumor activity endpoints will be evaluated in each cohort:  
 ORR defined as the proportion of patients with best response of CR or PR during treatment, 
as assessed by a central radiological panel according to RECIST v1.1 (Appendix 6). 

 
 
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 iORR defined as the proportion of patients with best response of CR or PR during treatment, 
as assessed by a central radiological panel according to immune-specific response criteria 
(iRECIST, Appendix 7). 
 DOR will be evaluated in patients with either a complete response (CR) or partial response 
(PR). DOR is defined as the time from the first assessment of a CR or PR until the date of 
the first occurrence of progressive disease (PD) or death from any cause (if death occurred 
within predefined period), whichever occurs first. 
 PFS is defined per RECIST1.1 as the time from inclusion until disease progression (per 
RECIST v1.1) or death from any cause, whichever occurs first. At the time of analysis, a 
patient alive and without disease progression will be censored at the date of the last tumor 
assessment. Patients alive without disease progression who started a new anticancer 
therapy will be censored at the date of the last tumor assessment prior to the start of the 
new anticancer therapy. 
 iPFS is defined per iRECIST as the time from inclusion until confirmed disease progression 
(per iRECIST), or death from any cause, whichever occurs first. At the time of analysis, a 
patient alive and without progression will be censored at the date of the last tumor 
assessment. Patients alive without disease progression who started a new anti-cancer 
therapy will be censored at the date of the last tumor assessment prior to the start of the 
new anticancer therapy. 
 OS is defined as the time from inclusion until death from any cause. Patients who are alive 
at last follow-up news will be censored at this date. 
 
The safety will be evaluated according to the incidence of adverse events (AEs) graded by NCI-
CTCAE v5.0 (Appendix 8): 
 In each cohort. 
 In the overall study population. 
3.3. Translational endpoints 
 
To assess the link between the tumor molecular profile including epigenetics features and 
immune parameters of the tumor microenvironment (TME) and in blood samples. 
 
To assess the link between immune-related biomarkers in the TME and in blood samples 
(including but not limited to tumor tissue PD-L1 expression by IHC, RNA gene expression 
profiling, and DNA mutation analysis), and measures of efficacy. 
 
To explore the modification of immune-related and molecular epigenetic biomarkers following 
treatment. 
 
To analyze the impact of TME and epigenetics parameters on sensitivity/response to treatment. 
 
To assess the predictive value of circulating biomarkers on sensitivity or resistance to treatment. 
3.4. Progression of the trial 
Patients participating in the trial will comply with the protocol for approximately 2 years after they are 
included, including 1 year of follow-up after treatment termination. 
The end of the study corresponds to the last visit of the last patient (i.e. last follow-up visit). 

 
 
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The investigation/examination schedule is defined by the trial schedule of activities in Section 
“Schedule of visits and activities” of the protocol summary. 
3.5. Inclusion procedure 
After the eligibility criteria have been fulfilled and the patient consent has been obtained, the patient 
will be registered in the study using the registration form on R&D UNICANCER’s online electronic 
case report form (eCRF) website (Ennov Clinical® software): 
https://ecrf.icm.unicancer.fr/CSOnline/ 
Once the patient has been registered, automatic e-mails confirming registration will be sent to the: 
 
sponsor 
 
investigator 
 
data manager 
 
pharmacist 
The eCRF registration procedure will be explained to the center staff during the study initiation visit. 
The corresponding documents, with explanation of the procedure, will be given to the principal 
investigator of each center and filed in the Site Master File (SMF). 
3.6. Premature Trial Terminations and Suspension 
The trial can be suspended or stopped by the sponsor after meeting with the coordinating 
investigator or following a request by the respective regulatory authority and/or the responsible 
Ethics Committee for the following reasons: 
 
High frequency and/or unexpected severity of toxicity 
 
Insufficient patient enrolment 
 
Insufficient quality of data collection 
3.7. Patient’s trial withdrawal and discontinuation  
Patient withdrawal concerns patients who stop treatment and all other protocol-defined procedures. 
Please note that treatment discontinuation without consent withdrawal from a patient is not 
considered as a trial withdrawal. For treatment discontinuation only, please refer to Section 5.7. 
This can occur under the following circumstances: 
 
Patient withdraws consent  
 
The principal investigator may terminate a patient’s participants from the trial, if this is in the 
interest of the patient. 
Trial patients may withdraw their consent at any time without justification, irrespective of the 
reason(s). In the case of trial withdrawal the investigator should attempt to obtain as much 
information as possible. This information should be noted in the patient’s medical file. The patient’s 
withdrawal of consent does not impact the patient’s right to receive the standard of care medical 
treatment. 

 
 
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4 .  P A T I E N T  S E L E C T I O N  
4.1. Diagnosis and inclusion criteria 
The following criteria must be verified before inclusion. In order to participate in the study all patients 
must meet all of the following inclusion criteria: 
1. Aged ≥18 years old. 
2. Patients with Eastern Cooperative Oncology Group (ECOG) performance status ≤1 
(Appendix 1). 
3. Patients must have histologically confirmed recurrent and/or metastatic squamous cell 
carcinoma of the head and neck, cervix, lung, anus, vulva, or penis. 
4. Patients must have radiologically confirmed progressive recurrent and/or metastatic disease.  
5. Patients naive or previously treated for their recurrent and/or metastatic disease. 
6. Disease amenable to biopsy for study purpose. 
7. Measurable disease according to RECIST v1.1. 
8. Adequate renal function: serum creatinine ≤1.5 x upper limit of normal (ULN) (OR creatinine 
clearance [Cockcroft and Gault] ≥30 mL/min for participant with creatinine levels >1.5 × ULN) 
within 14 days prior inclusion. 
9. Adequate liver function: aspartate aminotransferase (AST) and alanine aminotransferase 
(ALT) levels ≤3 × ULN (≤5 ULN when documented liver metastases) and total bilirubin level 
≤1.5 × ULN, within 14 days prior inclusion. 
10. Adequate bone marrow function: absolute neutrophil count (ANC) ≥1,000/mm³, platelet count 
≥100,000/mm³, and hemoglobin ≥9 g/dL, within 14 days prior inclusion. 
11. Adequate coagulation: prothrombin time (PT)/international normalized ratio (INR) ≤1.5 × ULN 
within 14 days prior inclusion If participant is receiving anticoagulant therapy  then the PT or 
activated partial thromboplastin time (aPTT) should be within the therapeutic range of 
intended use of anticoagulant. 
12. Female of child-bearing potential must have a negative serum pregnancy test within 72 h 
before starting study treatment.  
13. Female of childbearing potential, must use "highly effective" methods of contraception for the 
study duration and for 4 months following the last dose of pembrolizumab and 6 months 
following the last dose of vorinostat. 
14. Male participants must agree to use an effective contraceptive for the duration of the trial and 
for at least 4 months after the last the last dose of pembrolizumab and 6 months following 
the last dose of vorinostat (to allow for effective elimination of the study drugs). Also, they 
should refrain from donating sperm during this period. 
15. Patients must be willing and able to comply with the protocol for the duration of the study 
including scheduled visits, treatment plan, and laboratory tests.  
16. Patients must be willing and able to comply with other study procedures, including a baseline 
tumor biopsy and a series of blood samples throughout the study. 
17. Patients able to swallow oral medications. 

 
 
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18. Patients must be affiliated to a Social Security System (or equivalent). 
19. Patients must have signed a written informed consent prior to any trial-specific procedures. 
When the patient is physically unable to give their written consent, a trusted person of their 
choice, independent from the investigator or the sponsor, can confirm in writing the patient’s 
consent. 
4.2. Non-inclusion criteria 
Patients are not eligible to participate in the trial if they comply with any of the following criteria: 
1. Prior treatment with anti-PD-1/PD-L1 agents or histone deacetylases (HDAC) inhibitors. 
2. Patients with central nervous system involvement that has not been controlled for >3 months. 
3. Patients with no other site for biopsy than bone lesions. 
4. Patients with other concurrent severe and/or uncontrolled medical disease which could 
compromise participation in the study, including uncontrolled diabetes, cardiac disease, 
uncontrolled hypertension, congestive cardiac failure, ventricular arrhythmias, active 
ischemic heart disease, myocardial infection within one year, chronic liver or renal disease, 
active gastrointestinal tract ulceration, severely impaired lung function. 
5. Known history of human immunodeficiency virus (HIV), Hepatitis B virus (HBV; defined as 
Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (HCV; defined 
as HCV RNA detected) virus infection. 
6. History of autoimmune disease with the exception of:  
 
(1) Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid 
replacement hormone,  
 
(2) Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen, 
 
(3) Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis would be 
excluded) provided that they meet the following conditions: (i) Rash must cover less 
than 10% of body surface area; (ii) Disease is well controlled at baseline and only 
requiring low potency topical steroids; (iii) No acute exacerbations of underlying 
condition within the previous 12 months (not requiring psoralen plus ultraviolet A 
radiation [PUVA], methotrexate, retinoid, biologic agents, oral calcineurin inhibitors, 
high-potency or oral steroids). 
7. History of allogeneic organ or bone marrow transplantation. 
8. History of non-infectious pneumonitis that required steroids or has current pneumonitis. 
9. Has an active infection requiring systemic therapy. 
10. Has received a live vaccine within 30 days prior to the first dose of study drug.  Examples of 
live vaccines include, but are not limited to, the following:  measles, mumps, rubella, 
varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and 
typhoid vaccine.  Seasonal influenza vaccines for injection are generally killed virus vaccines 
and are allowed; however, intranasal influenza vaccines (e.g, FluMist®) are live attenuated 
vaccines and are not allowed. 

 
 
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11. Known prior severe hypersensitivity to investigational products or its excipients,  
12.  Has received prior systemic anti-cancer therapy including investigational agents within 4 
weeks [could consider shorter interval for kinase inhibitors or other short half-life drugs] prior 
to first dose of study treatments. 
Note: Participants must have recovered from all AEs due to previous therapies to ≤Grade 1 
or baseline. Participants with ≤Grade 2 neuropathy may be eligible. 
13. Has received prior radiotherapy within 2 weeks of start of study treatment. Participants must 
have recovered from all radiation-related toxicities, not require corticosteroids, and not have 
had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks 
of radiotherapy) to non-CNS disease. 
14. Major surgery within 28 days prior to the first dose of study treatments.  
Note: Local surgery of isolated lesions for palliative intent is acceptable. 
15. Current or prior use of immunosuppressive medication within 7 days before the first dose of 
pembrolizumab. The following are exceptions to this criterion: 
 
Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular 
injection), 
 
Systemic corticosteroids at physiologic doses ≤10 mg/day of prednisone or its 
equivalent (see Appendix 5), 
 
Steroids as premedication for hypersensitivity reactions (e.g., CT scan 
premedication). 
16. Patients using drugs that could have pharmacokinetics interaction with investigational drugs. 
This includes, but is not limited to, valproic acid, coumarin-derivative anticoagulants, drugs 
that disrupt electrolyte levels, drugs that may prolong QT (see Appendix 4). 
17. Pregnant women or women who are breast-feeding. 
18. Patients enrolled in another therapeutic study within 30 days prior to inclusion and during the 
treatment period. Patients can participate in an independent approved non-interventional 
studies. 
19. Patients unwilling or unable to comply with the medical follow-up required by the trial because 
of geographic, familial, social, or psychological reasons. 
20. Persons deprived of their liberty or under protective custody or guardianship. 

 
 
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5 .  T R I A L  T R E A T M E N T S / I N T E R V E N T I O N S  
5.1. Description of trial treatments/interventions 
Patients having signed the informed consent form and successfully registered in the study (i.e. 
included) will receive concomitant pembrolizumab and vorinostat within 7 days of registration. 
 Pembrolizumab 
Patients will be administrated pembrolizumab by intravenous injection of 200 mg on day1 of each 
21-day cycles. Sites should make every effort to target infusion timing to be as close to 30 min as 
possible. However, given the variability of infusion pumps from site to site, a window of -5 min and 
+10 min is permitted (i.e., infusion time is 30 min: -5 min/+10 min). 
Refer to Section 5.5.1 for specific instructions for the preparation of the pembrolizumab infusion fluid. 
Pembrolizumab will be given up to 35 administrations (approximately 2 years).  
Continuation of pembrolizumab beyond 35 cycles may be allowed under certain conditions and must 
be agreed with the sponsor before continuing the treatment.  
 Vorinostat 
From day 1 of the Cycle 1, patients will take vorinostat orally once daily at a dose of 400 mg . 
Vorinostat should be taken approximately within 30 min of a meal. Patients should be instructed to 
drink at least 2 liters/day of fluids for adequate hydration. 
Patients are eligible for repeated treatment cycles in the absence of disease progression and undue 
adverse events. 
5.2. Acquisition, reception, and storage 
The investigational products pembrolizumab and vorinostat provided by Merck Sharp and Dohme 
(MSD) will be distributed to the pharmacy at the investigational center via a dedicated courier in 
accordance with the current Good Distribution Practices guidelines.  
The pharmacist of the trial site will receive numbered treatment and will acknowledge receipt of all 
deliveries by sending the necessary completed documents to the distributor.  
The pharmacist is responsible for a safe and proper handling and storage of the investigational 
medicinal products at the investigational center. The investigational products must be stored in a 
locked facility with restricted access to the pharmacist and authorized personnel, and under 
environmental conditions consistent with the drug manufacturer recommendations (IB). 
 
Pembrolizumab must be stored under refrigerated conditions (2°C to 8°C). 
 
Vorinostat must be stored at 20-25°C, excursions permitted between 15°C and 30°C. 
Up to date temperature logs must be maintained by the pharmacist/investigator to document 
adequate storage during the trial. These logs must be available at the site during monitoring visits, 
and in the event of an audit or inspection. 
If the storage conditions as indicated above are exceeded (e.g. temperature excursion) the 
pharmacist/investigator must place the corresponding treatments in quarantine and immediate notify 

 
 
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the sponsor who will indicate the procedure to follow. Under no circumstances should these 
treatments be delivered to trial patients without prior authorization by the sponsor. 
5.3. Trial treatments accountability, return and destruction 
The investigator/pharmacist must ensure that the investigational product is administrated only to 
patients enrolled in this trial. The investigational product must not to be used outside the context of 
the trial protocol.  
The pharmacist or authorized staff must document the receipt, dispensation, and return or 
destruction of all investigational products received during this trial. Records on investigational 
products delivery to the center, the inventory at the center, the use by each patient, and the return 
to the sponsor or destruction by the site must be implemented and maintained by the pharmacist or 
another appropriately trained individual at the investigational center. The following minimum 
information must be present: all relevant dates (delivery dates, dispensation, returns, and 
destruction), quantities, and investigational product batch numbers. Accountability forms will be 
provided by the sponsor to ensure trial treatment accountability.  
The pharmacist will implement an accounting of medicinal products dispensed, used, unused, 
returned by the patients. The accountability of the products returned by patients will be systematically 
done by the pharmacist of the site. These records will be made available to the clinical research 
associate (CRA) mandated by the sponsor. 
For vorinostat capsules, treatment observance will be recorded in the eCRF, and the patients will be 
asked to complete a personal booklet. 
5.4. Formulation, appearance, packaging, and labelling 
 Pembrolizumab 
Pembrolizumab for intra-venous infusion is supplied as a clear to opalescent liquid solution in type I 
glass vials intended for single use only. Each vial contain 100 mg of pembrolizumab. It is 
manufactured using the fully formulated pembrolizumab with L-histidine as a buffering agent, 
polysorbate 80 as a surfactant, and sucrose as a stabilizer/tonicity modifier. Pembrolizumab vial 
should be stored under refrigerated conditions (2°C to 8°C). 
 Vorinostat 
Vorinostat is supplied for oral administration in white opaque gelatin capsules (size 3) with “568” over 
“100 mg” printed within the radial bar in black ink on the capsule body. Each capsule contains 100 
mg of vorinostat and the following inactive ingredients: microcrystalline cellulose, sodium 
croscarmellose, and magnesium stearate. The capsules are supplied in HDPE high-density 
polyethylene (HDPE) bottles. Each bottle contains 120 capsules. Please refer to either the product 
labeling or the shipping documentation to check the shelf life of vorinostat. Vorinostat capsules 
should be stored at room temperature (do not store bellow 15°C and above 30°C). 
 

 
 
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5.5. Preparation 
 Pembrolizumab 
Pembrolizumab can be diluted with normal saline or 5% dextrose in the concentration range of 1 to 
10 mg/mL in intra-venous containers made of PVC or non-PVC material. Reconstituted vials should 
be used immediately to prepare the infusion solution in the intra-venous bag, and the infusion 
solution should be administered immediately. If the diluted pembrolizumab solution is not used 
immediately, it may be stored for no more than 24 h at 2°C to 8°C. This 24-h hold time from 
reconstitution may include up to 6 hours at room temperature (at or below 25°C). Any additional hold 
time must be at 2°C to 8°C. If refrigerated, the vials and/or intravenous bags must be allowed to 
come to room temperature prior to use. 
 Vorinostat 
Vorinostat capsules should not be opened or crushed. Direct contact of the powder in vorinostat 
capsules with the skin or mucous membranes should be avoided. If such contact occurs, wash 
thoroughly as outlined in the references. Personnel should avoid exposure to crushed and/or broken 
capsules. 
5.6. Dose adaptation 
 Pembrolizumab 
AEs associated with pembrolizumab exposure may represent an immunologic etiology. These 
immune-related AEs (irAEs) may occur shortly after the first dose or several months after the last 
dose of pembrolizumab treatment and may affect more than on body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications.  Based on 
existing clinical study data, most irAEs were reversible and could be managed with interruptions of 
pembrolizumab, administration of corticosteroids and/or other supportive care. For suspected irAEs, 
ensure adequate evaluation to confirm etiology or exclude other causes. Additional procedures or 
tests such as bronchoscopy, endoscopy, skin biopsy may be included as part of the evaluation. 
Based on the severity of irAEs, withhold or permanently discontinue pembrolizumab and administer 
corticosteroids. Dose modification and toxicity management guidelines for irAEs associated with 
pembrolizumab are provided in Appendix 9 and Appendix 10. 
 Vorinostat  
Vorinostat dose modification guidelines are outlined Appendix 11 and should be used for the 
management of treatment-related toxicities. Patients should be carefully instructed when any dose 
interruption occurs. 
If a patient is intolerant to vorinostat, the dose may be reduced to 300 mg orally once daily with food. 
The dose may be further reduced to 300 mg once daily with food for 5 consecutive days each week, 
as necessary. 
In patients with mild to moderate hepatic impairment (bilirubin 1 to 3 x ULN or AST greater than 
ULN), the starting dose can be of 300 mg orally once daily with food. As a general rule, if a dose 
reduction is necessary, the dose should be reduced stepwise as described in Table 2 and the subject 
should be monitored for 10 to 14 days at each dose level.  If toxicity recurs during this monitoring 

 
 
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time, the drug may need to be interrupted and/or the dose further decreased with continued 
monitoring for an additional 10-14 days at each dose level, and so on.  
The dose should not be re-escalated to an earlier dose level on improvement of an AE. 
Table 2 - Summary table for vorinostat dose reductions 
Suggested Dose Reduction Steps for 400 mg  
Starting Dose  
Starting Dose  
400 mg once daily 
Dose Level -1 
300 mg once daily 
Dose Level -2 
300 mg 5 days on/2 days off 
 
Suggested Dose Reduction Steps for 300 mg  
Starting Dose  
Starting Dose  
300 mg once daily 
Dose Level -1 
300 mg 5 days on/2 days off 
 
The management of toxicities may require a dose interruption until recovery. If recovery is not 
observed after a 2-week interruption period, resumption should be discussed with the sponsor before 
reinitiating treatment. Clinical benefit and management options will be discussed with the physician. 
5.7. Discontinuation of treatments:  
Patients can discontinue the trial treatments for the following reasons: 
 
The participant or participant’s legally acceptable representative requests to discontinue study 
treatment but accept to continue with protocol. 
 
Confirmed radiographic disease progression. 
 
Any progression or recurrence of any malignancy, or any occurrence of another malignancy 
that requires active treatment. 
 
Limiting toxicity. 
 
The participant has a confirmed positive serum pregnancy test. 
 
Recurrent grade 2 pneumonitis. 
 
The participant has a medical condition or personal circumstance which, in the opinion of the 
investigator and/or sponsor, placed the participant at unnecessary risk from continued 
administration of study treatment. 
After discontinuing all trial treatments, further treatment is left to the physician’s discretion. 

 
 
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Patients who discontinue all trial treatments will continue with the trial and the protocol-defined 
procedures and follow-up, unless they specifically withdraw their consent and indicate that they do 
not want to perform any further trial-related visits or assessments (for patient withdrawals see 
Section 3.7). 
5.8. Concomitant medications and therapies 
All medications (including herbal preparations) and therapies taken by the patients or administered 
to the patients from the onset of trial and given in addition to the investigational products during the 
trial are considered as concomitant medications. Any concomitant medication(s) during the trial 
should be carefully documented in the hospital patient records and made available to the sponsor 
CRA during the monitoring visits.  
 Authorized concomitant treatments 
The following treatments/therapies are authorized during the trial: 
 
Systemic corticosteroids may be used to treat immune-mediated adverse reactions 
concomitant with pembrolizumab. Other indications are limited to those described in Section 
5.8.1 
 
Concomitant medications or treatments (e.g., acetaminophen or dexchlorpheniramine) deemed 
necessary to provide adequate prophylactic or supportive care, except for those medications 
identified as “prohibited,” as listed in Section 5.8.2 can be administered as prescribed by the 
Investigator. 
 
Best supportive care (including antibiotics, nutritional support, correction of metabolic disorders, 
optimal symptom control, and pain management [including palliative radiotherapy to non-target 
lesions, antiemetic, etc.]) should be used, when necessary, for all patients. 
 
Inactivated viruses, such as those in the influenza vaccine. 
Note: intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not 
allowed. 
 
Drugs that disrupt electrolyte levels (i.e. loop/thiazide diuretics, laxative, enemas, amphotericin 
B, high dose corticosteroids) need to be used with caution and closely monitored. 
 Prohibited concomitant treatments 
The following treatments/therapies are prohibited during the trial: 
 
Other antitumor treatments, including chemotherapies, hormonal therapies, biological response 
modifiers, and targeted therapies. 
 
Other investigational therapeutic agents. 
 
Immunosuppressive drugs. 
 
Systemic glucocorticoids at a dose greater than prednisone 10 mg/day or equivalent (Appendix 
5). The use of physiologic doses of corticosteroids may be approved after consultation with the 
Sponsor, except in case of an urgent indication (see Section 5.8.1) or as antiemetics. Their use 
will require the highest precaution in patients with diabetes. 

 
 
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 
It is advised not to use the association of vitamin K antagonist (VKA) with chemotherapy. It is 
preferable to use heparin and therapeutic anticoagulation with low-molecular weight heparin. If 
VKA cannot be avoided, the rate of prothrombin must be checked more frequently and INR 
monitored. 
 
Drugs that may prolong QT (i.e., amiodarone, procainamide, sotalol, venlafaxine, amitriptyline, 
sunitinib, methadone, chloroquine, clarithromycin, haloperidol, fluconazole, moxifloxacin, 
domperidone, ondansetron, etc.), see Appendix 4. 
 
Pimozide (Orap®) and cisapride (Prepulsid®) are strictly contraindicated: they are associated 
with a major risk of ventricular rhythm disorder. 
 
Radiation therapy. 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 study treatment and while participating in 
the study. Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, varicella/zoster, yellow fever, rabies, Bacillus Calmette–Guérin (BCG) vaccin, 
and typhoid vaccine. 
 
Vorinostat should not be administered concomitantly with other HDAC inhibitors (e.g., valproic 
acid) as class-specific adverse reactions may be additive (ex: Grade 4 thrombocytopenia with 
associated gastrointestinal bleeding and anemia). 
 Rescue medications and therapies/Treatment at disease progression 
At disease progression the treatment will be at the investigator’s discretion. 
 Contraception during the trial 
5.8.4.1. Definitions 
Females of childbearing potential are those who are not surgically sterile (i.e., bilateral tubal ligation, 
bilateral oophorectomy, or complete hysterectomy) or post-menopausal (for the definition of post-
menopausal see below). 
Post-menopausal status is defined as: 
 
Women will be considered post-menopausal if they have been amenorrhea for 12 months 
without an alternative medical cause. The following age-specific requirements apply:  
o Women <50 years of age would be considered post-menopausal if they have been 
amenorrhea for 12 months or more following cessation of exogenous hormonal 
treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in 
the post-menopausal range for the institution or underwent surgical sterilization (bilateral 
oophorectomy or hysterectomy).  
o Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrhea for 12 months or more following cessation of all exogenous hormonal 
treatments, had radiation-induced menopause with last menses >1 year ago, had 
chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical 
sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy). 

 
 
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5.8.4.2. Acceptable contraception during the trial 
 
Female patients of child-bearing potential 
Females of childbearing potential who are sexually active with a non-sterilized male partner must 
use one or more highly effective method of contraception (See Table 3 below) during the trial and 
for 4 months  after the last the last dose of pembrolizumab and 6 months following the last dose of 
vorinostat. Non-sterilized male partners of a female patient must use male condom plus spermicide 
throughout this period. Cessation of birth control after this point should be discussed with a 
responsible physician. Female patients should also refrain from breastfeeding throughout this period. 
Table 3 Highly effective methods of contraception (<1% failure rate) 
Barrier/Intrauterine methods 
Hormonal methods 
Copper T intrauterine device 
Levonorgestrel-releasing 
intrauterine system (e.g., Mirena®)a 
 
Etonogestrel implants: e.g., Implanon or Norplan 
Intravaginal device: e.g., ethinylestradiol and etonogestrel 
Medroxyprogesterone injection: e.g., Depo-Provera 
Normal and low dose combined oral contraceptive pill 
Norelgestromin/ethinylestradiol transdermal system 
Cerazette (desogestrel) 
a This is also considered as a hormonal method. 
 
Male patients with a female partner of childbearing potential 
Male participants with female partners of childbearing potential are eligible to participate if they agree 
to one of the following during the trial and for 4 months after the last the last dose of pembrolizumab 
and 6 months following the last dose of vorinostat, defined time frame in section 4:  
o Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent 
o Use a male condom plus partner use of a contraceptive method with a failure rate of <1% 
per year as described in Table 4 when having penile-vaginal intercourse with a woman 
of childbearing potential who is not currently pregnant. 
Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-
vaginal intercourse or use a male condom during each episode of penile penetration 
Table 4 - Highly effective methods of contraception in male (<1% failure rate) 
Highly Effective Methods That Have Low User Dependency  
Failure rate of <1% per year when used consistently and correctly. 
● Vasectomized partner  

 
 
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A vasectomized partner is a highly effective contraception method provided that the 
partner is the sole male sexual partner of the WOCBP and the absence of sperm has been 
confirmed. If not, an additional highly effective method of contraception should be used.  
● Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
treatment. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant.  
Notes: 
Use should be consistent with local regulations regarding the use of contraceptive 
methods for participants of clinical studies. 
 
a) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) 
guidelines, acceptable contraceptive implants are limited to those which inhibit ovulation. 
b) If hormonal contraception efficacy is potentially decreased due to interaction with study 
treatment, condoms must be used in addition to the hormonal contraception during the 
treatment period and for at least [X days, corresponding to time needed to eliminate study 
treatment plus 30 days for study treatments with genotoxic potential]  after the last dose of 
study treatment.   
 

 
 
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6 .  E V A L U A T I O N  O F  T R E A T M E N T  A C T I V I T Y  A N D  S A F E T Y  
6.1. Activity evaluation 
 Tumor imaging during the study  
As far as possible, radiological assessments have to be repeated in the same technical conditions 
(same machine, parameters …) and reviewed by the same radiologist. 
The first on-study imaging assessment should be performed within 7 days from the date of study 
registration (i.e., inclusion). Subsequent tumor imaging and clinical assessments should be 
performed every 6 weeks (within 7 days prior CxD1) from the initiation of treatment for the first 12 
months of treatment or until first disease progression (whichever comes first), and then every 12 
weeks until disease progression, when applicable. 
The scheduled dates for tumour evaluations are not modified by dose delays. The assessment dates 
are relative to the treatment initiation date.  
Imaging should continue to be performed until disease progression is identified by the investigator. 
Objective response should be confirmed by a repeat imaging assessment. Tumor imaging to confirm 
PR or CR should be performed at least 4 weeks after the first indication of a response is observed, 
as required with RECIST v1.1 (see Appendix 6). Participants will then return to regular scheduled 
imaging every 6 weeks, starting with the next scheduled imaging time point. Participants who receive 
additional imaging for confirmation do not need to undergo the next scheduled tumor imaging if it is 
less than 4 weeks later; tumor imaging may resume at the subsequent scheduled imaging time point.  
When the Investigator identifies radiographic progression per RECIST v1.1, efforts should be made 
to verify radiologic PD. Treatment should continue until PD has been verified.  Regardless of whether 
PD is verified, if the Investigator considers the participant has progressed, but elects to implement 
RECIST, the Investigator may assess for confirmation of progression by iRECIST (Appendix 7) at 
subsequent time points.  

 
 
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Figure 2 - Imaging and treatment for clinically stable participants after first radiologic evidence of PD 
assessed by the investigator 
 
 End of treatment and follow-up tumor imaging  
In participants who discontinue all study treatments, tumor imaging should be performed at the time 
of treatment discontinuation (within 1 week). If previous imaging was obtained within 4 weeks prior 
to the date of discontinuation, then imaging at treatment discontinuation is not mandatory. In 
participants who discontinue study treatment due to documented disease progression and the 
Investigator elects not to implement iRECIST, this is the final required tumor imaging. 
In participants who discontinue study treatment without documented disease progression, every 
effort should be made to continue monitoring their disease status by tumor imaging using the same 
imaging schedule used while on treatment (every 6 weeks in the first year and then every 12 weeks 
thereafter) to monitor disease status until the start of a new anticancer treatment, disease 
progression, pregnancy, death, withdrawal of consent, or the end of the study, whichever occurs 
first. 
If pembrolizumab is permanently discontinued and vorinostat is continued, tumor imaging should be 
performed with the same imaging schedule. However, iRECIST assessment of the disease will not 
be necessary in this situation. 
 RECIST v1.1 assessment of disease 
The primary objective is to evaluate the efficacy of the combined therapy (pembrolizumab and 
vorinostat) according to the ORR. The ORR is defined as the proportion of patients with best 
response of either a CR or PR during treatment. Treatment efficacy will be evaluated by the 
investigator by measuring changes in tumor size using contrast-enhanced CT-scan or MRI.  

 
 
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RECIST v1.1 (Appendix 6) will be used to assess tumor response, date of disease progression, and 
as a basis for all protocol guidelines related to disease status (e.g., discontinuation of study 
treatment). .  
 iRECIST assessment of disease 
iRECIST is based on RECIST v1.1, but adapted to account for the unique tumor response seen with 
immunotherapeutic drugs. When clinically stable, participants should not be discontinued until 
disease progression is confirmed by the investigator, working with local radiology, according to the 
rules below. This means that treatment can be continued despite an initial radiological PD. This takes 
into account that certain participants will have a transient tumor flare in the first few months after the 
start of immunotherapy that does not reflect true tumor progression. Indeed, subsequent disease 
response have been reported after this initial pseudo-progression. 
A description of the adaptations and iRECIST process is provided in Appendix 7, with additional 
detail in the iRECIST publication [Seymour et al, 2017].  
iRECIST will be used by the investigator to assess tumor response and progression, and make 
treatment decisions.   
 Blinded independent central review committee (BICR): 
An independent radiological review is planned at the end of the study. The BICR committee will 
review all the radiological tumor assessments according to modified RECIST v1.1 and iRECIST.  
As a consequence, investigators must systematic upload a DICOM format record of the tumor 
assessment to the web platform subcontracted by Unicancer for each baseline and subsequent 
radiological tumor assessment (CT scan or MRI or other method) for all enrolled patients. 
6.2. Safety evaluation  
Safety will be assessed based on adverse event (AE) occurrence, the use of concomitant treatments, 
and changes occurring during treatment including those observed: during physical examinations, in 
vital signs (blood pressure, pulse, body temperature), and with biological and clinical examinations 
(biochemistry, hematology). Safety will be evaluated using the National Cancer Institute - common 
terminology criteria for adverse events (NCI-CTCAE) v5.0 (Appendix 8).  
In case of emergency, the patient, a patient’s relative, or the patient’s general practitioner will be 
required to contact the investigator about AE that have occurred. The possible treatment interruption 
or dose adaptation (decrease) for the investigational product will be considered, as well as, adequate 
concomitant treatment if necessary. 
It is anticipated that around 10% of patients treated with immune checkpoint inhibitors will develop 
severe, sometimes life-threatening dysimmune toxicities.  
It is therefore necessary that the investigators rely on a previously identified local network of organ 
specialists and on detailed practical guidelines to anticipate, manage, and monitor appropriately 
immune related –Adverse Event (irAEs). 

 
 
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 Physical examination 
Physical examinations will be performed according to the assessment schedule. Full physical 
examinations will include assessments of the head, eyes, ears, nose, and throat, as well as the 
respiratory, 
cardiovascular, 
gastrointestinal, 
urogenital, 
musculoskeletal, 
neurological, 
dermatological, hematologic/lymphatic, and endocrine systems. Height will be measured at baseline 
only. Targeted physical examinations are to be utilised by the investigator on the basis of clinical 
observations and symptomatology.  
Situations in which physical examination results should be reported as AEs are described in Section 
8. 
 Vital signs 
Vital signs (blood pressure [BP], pulse and temperature) and body weight will be evaluated according 
to the assessment schedules at each visit. 
 Clinical laboratory tests 
Blood samples for clinical chemistry, haematology will be collected at the times indicated in the 
assessment schedules and as clinically indicated.  
Clinical laboratory safety tests, including serum pregnancy tests, will be performed in a local licensed 
clinical laboratory. Abnormal clinically significant laboratory results should be repeated as soon as 
possible (preferably within 24 to 48 h). 
Additional safety samples may be collected if clinically indicated at the discretion of the Investigator. 
The date, time of collection, and results (values, units, and reference ranges) will be recorded in the 
eCRF. 
The laboratory variables to be measured are presented in Table 5. 
Table 5 - Laboratory variables 
Test Category 
Test Name 
Haematology 
Hemoglobin, red blood cell count (RBC), white blood count (WBC), 
absolute neutrophil count (ANC), lymphocyte count, and platelet count. 
Coagulation profile 
Activated partial thromboplastin time (aPTT), international normalised ratio 
(INR), PT/INR 
Clinical biochemistry - 
Blood ionogram (Na, K, Ca, Mg, P, Cl, CO2, total protein, albumin),  
- 
Renal function (blood urea, creatinine),  
- 
Hepatic function (direct bilirubin, alkaline phosphatase, ALT, AST, GGT), 
- 
Thyroid hormone (TSH, free T3, free T4), 
- 
Fasting plasma glucose, creatine phosphokinase,  
- 
Squamous cell carcinoma antigen (SCCa). 

 
 
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7 .  D E S C R I P T I O N  O F  V I S I T S  A N D  I N V E S T I G A T I O N S  
Patients will be monitored from the date of their screening visit until 1 year after the end of treatment 
or the date of death, withdrawal of consent, loss to follow-up, or end of study, whichever occurs first. 
A table summarizing the follow-up examination/visit schedule is provided in the section “Schedule of 
visits and activities” of the protocol summary. 
7.1. Baseline visit 
An informed consent form (ICF) must be signed before the evaluations required for inclusion and 
any study specific procedure are performed. 
After signing the study ICF, baseline assessments will be done within 1 to 28 days prior to inclusion 
depending on assessments. 
A procedure or evaluation already performed within the standard of care and which is in accordance 
with the protocol requirements does not need to be repeated unless clinically justified.  
For laboratory evaluations used to determine eligibility, a repeated evaluation within the screening 
window is permitted for baseline results out of the defined range. 
 
Patient history: within 28 days of inclusion 
 
Demographic data 
 
Medical history and characteristics/prior therapy, (including HPV status, if available). 
 
Physical examination: within 14 days of inclusion 
 Patient’s weight. 
 Complete clinical examination. 
 ECOG performance status (Appendix 1). 
 Vital signs (pulse rate, systolic and diastolic blood pressure, and body temperature). 
 Ongoing adverse events using the NCI-CTCAE v5.0 (Appendix 8). 
 
Paraclinical examination: within 7 days of inclusion 
 Radiologic assessment (RECIST [Appendix 6]): CT scan. 
 Electrocardiogram (12-lead ECG). 
 
Biological tests: within 14 days of inclusion (except pregnancy test) 
 Hematology: hemoglobin, red blood cell count, white blood cell count (WBC), absolute 
neutrophil count (ANC), lymphocyte count, and platelet count. 
 Blood ionogram: Na, K, Ca, Mg, P, Cl, CO2, total protein, albumin. 
 Renal function: blood urea, creatinine. 
 Hepatic function: direct bilirubin, alkaline phosphatase, ALT, AST, GGT. 
 Thyroid hormone: TSH, free T3, free T4. 
 Coagulation profile: PT/INR, aPTT. 
 Squamous cell carcinoma antigen (SCCa). 

 
 
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 Fasting plasma glucose, creatine phosphokinase. 
 Serum pregnancy test (βHCG) within 3 days (72 h) of inclusion 
 
Translational research: within 14 days of inclusion (refer to section 9 for detailed sampling 
and approach):  
 Blood sample : 
o 2 x 10 mL PACgene CCF tubes for plasma + buffy coat. 
o 1 x 4 ml EDTA tubes for constitutional DNA and HLA sequencing. 
o 2 x 8.5 mL CPT tubes for phenotyping of PBMC. 
 Tumor biopsy: 2 frozen, 2 FFPE 
If the tumor sample volume is not sufficient to obtain four biopsy cores, priority will be given 
according to the algorithm detailed in Table 6 
 
Table 6 - Priority order for biopsy cores 
Priority order for biopsy cores collection 
depending on the tumor location/volume 
Number of cores 
collected 
Cores’ preparation 
1 
(favorable situation) 
4 
2 Frozen, 2 FFPE 
2 
3 
2 Frozen, 1 FFPE 
3 
2 
1 Frozen, 1 FFPE 
4 
(unfavorable situation) 
1 
1 Frozen 
7.2. Visits and assessment during treatment period 
During the treatment period, patients will have a trial visit on the first day of each treatment cycle, 
every 21 days. In addition, patients will have a scheduled visit on prior to D1 cycle 3 for an optional 
tumor biopsy. However, depending on treatment tolerance, additional visits and examinations may 
be scheduled. All examinations revealing a toxicity related to one of the trial treatment must be 
periodically repeated until toxicity disappearance (or until it is deemed irreversible). 
 
Physical examination: every cycle 
 Complete clinical examination (every 2 cycles). 
 Patient’s weight. 
 ECOG performance status (Appendix 1). 
 Vital signs (pulse rate, systolic and diastolic blood pressure, and temperature). 
 Concomitant medications. 
 Ongoing toxicities or adverse event using the NCI-CTCAE v5.0 (Appendix 8). 
 
Paraclinical examination: every 2 cycles 

 
 
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 Radiologic assessment (RECIST v1.1 [Appendix 6] and iRECIST [Appendix 5]) on D1 
cycle 3 then on D1 of every 2 cycles (cycle 5, 7, 9…) during the first 12 months of 
treatment phase, and every 12 weeks thereafter: CT scan. 
 
Biological tests: every cycle +/- 3 days 
 Hematology: hemoglobin, red blood cell count, WBC, ANC, lymphocyte count, and 
platelet count. 
 Blood ionogram: Na, K, Ca, Mg, P, Cl, CO2, total protein, albumin. 
 Renal function: blood urea, creatinine. 
 Hepatic function: direct bilirubin, alkaline phosphatase, ALT, AST, GGT. 
 Fasting plasma glucose, creatine phosphokinase.  
 Squamous cell carcinoma antigen (SCCa) (every 2 cycles). 
 Pregnancy test (if applicable): serum pregnancy test (starting from C2D1). 
 
Other biological tests: every two cycles, starting from C1D1 +/- 3 days 
 Thyroid hormone: TSH, free T3, free T4. 
 
Translational research  
 Mandatory blood sample (on D1 of C3 and D1 of C5). 
o 2 x 10 mL PACgene CCF tubes for plasma + buffy coat. 
o 2 x 8.5 mL CPT tubes for phenotyping of PBMC. 
 Optional tumor biopsy (on D1 of C3): when possible, 2 frozen and 2 FFPE. 
If the tumor sample volume is not sufficient to obtain four biopsy cores, priority will be 
given according to the algorithm detailed in Table 6 
7.3. End-of-treatment visit 
Patients will perform an end-of-treatment visit 1 week after the discontinuation of all investigational 
products (pembrolizumab AND vorinostat), either due to disease progression or to other reasons 
indicated in Section 5.7 .This visit will include the following: 
 
Physical examination: 
 Patient’s weight. 
 ECOG performance status (Appendix 1). 
 Vital signs (pulse rate, systolic and diastolic blood pressure, and temperature). 
 Concomitant medications. 
 Ongoing toxicities or adverse event using the NCI-CTCAE v5.0 (Appendix 8). 
 
Paraclinical examination: 

 
 
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 Radiologic assessment (RECIST v1.1 [Appendix 6] and iRECIST [Appendix 7]): CT scan. 
Tumor imaging should not be repeated if it was obtained less than 4 weeks from 
withdrawal of therapy. 
 
Biological tests: 
 Hematology: Hemoglobin, red blood cell count, WBC, ANC, lymphocyte count, and 
platelet count. 
 Blood ionogram: Na, K, Ca, Mg, P, Cl, CO2, total protein, albumin. 
 Renal function: blood urea, creatinine. 
 Hepatic function: direct bilirubin, alkaline phosphatase, ALT, AST, GGT. 
 Thyroid hormone: TSH, free T3, free T4. 
 Fasting plasma glucose, creatine phosphokinase. 
 Squamous cell carcinoma antigen (SCCa). 
 Pregnancy test (if applicable): serum pregnancy test. 
 
Translational research: 
 Blood sample at progression 
o 2 x 10 mL PACgene CCF tubes for plasma +buffy coat 
o 2 x 8.5 mL CPT tubes for phenotyping of PBMC  
 Optional tumor biopsy at progression: when possible, 2 frozen and 2 FFPE. 
If the tumor sample volume is not sufficient to obtain four biopsy cores, priority will be 
given according to the algorithm detailed in Table 6 
7.4. Follow-up 
Patients will perform follow-up visits every 3 months after the end-of-treatment visit for 1 year. This 
visit will include the following: 
 Disease and survival status: information may be collected during visits or telephone calls. 
 Collection of persistent or long term occurring toxicities. 
Ongoing toxicities or AEs must be monitored until resolution or returned to baseline level. 
o All AEs from the time of treatment inclusion through 30 days following cessation of 
study treatment must be reported by the investigator.  
o All AEs meeting serious criteria, from the time of treatment allocation/randomization 
through 90 days following cessation of study treatment, or 30 days following cessation 
of study treatment if the participant initiates new anticancer therapy, whichever is 
earlier must be reported by the investigator.  
 First new antineoplastic therapy after study treatments termination. 
 Tumor assessment (if applicable) : 

 
 
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In participants who discontinue study treatment without documented disease progression, 
every effort should be made to continue monitoring their disease status by tumor imaging 
using the same imaging schedule used while on treatment (every 6 weeks in year 1 or every 
12 weeks after year 1) to monitor disease status until the start of a new anticancer treatment, 
disease progression, pregnancy, death, withdrawal of consent, or the end of the study, 
whichever occurs first.  
7.5. Provisions in case of treatment or trial interruption 
In case of treatment or study discontinuation, the patient will have to be followed as indicated in 
Sections 3.6, 3.7, and 5.7. However, further treatment will be at the investigator’s discretion as per 
standard of care. 

 
 
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8 .  R E P O R T I N G  O F  A D V E R S E  E V E N T S  
8.1. Adverse event: general definition 
An adverse event (AE) is defined as any untoward medical occurrence, in a patient or clinical trial 
subject treated by a medicinal product and which does not necessarily have a causal relationship 
with this treatment. 
8.2. Serious adverse event: general definition  
A serious adverse event (SAE) is defined as any untoward medical occurrence that at any 
dose: 
 
Results in death. 
 
Is life-threatening. 
 
Requires hospitalization or prolongation of existing hospitalization. 
 
Results in persistent or significant disability/incapacity. 
 
Is a congenital anomaly/birth defect. 
 
Is medically relevant in the context of the pathology and the clinical trial. 
These characteristics/consequences are to be considered at the time of the event. For example, 
regarding a life-threatening event, this refers to an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event which hypothetically might have caused death if it 
was more severe. 
The terms disability and incapacity correspond to any clinically relevant physical or psychological 
handicap, transient or permanent, which impact the patient’s physical condition/activity and/or the 
quality of life. 
Medical and scientific judgment should be exercised in deciding whether other situations should be 
considered serious, such as important medical events that might not be immediately life-threatening 
or result in death or hospitalization, but might jeopardize the patient or might require intervention to 
prevent one of the other outcomes listed in the definition above (for example: overdose [see section 
8.4], second cancer, etc.).  
The investigator will assess whether a reasonable causal relationship exists between the event and 
the treatment/therapy. If the sponsor disagrees with the investigator’s causality assessment, the 
opinion of both the investigator and the sponsor will be reported.  
The following events are considered as SAEs but should not be managed according to the section 
8.2.7. These events do not require immediate reporting and should be reported only in the case 
report form: 
 
Hospitalization occurring in the context of tumor progression of disease under trial, 
 
Progression of disease under trial, 
 
Events related to progression of disease under trial. 
The following events leading to a hospitalization or a prolongation of hospitalization are not 
considered as Serious Adverse Events: 

 
 
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 
Hospitalization already scheduled before the start of the trial, 
 
Hospitalization required as part of the protocol (biopsy, chemotherapy, etc. 
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is defined as any serious adverse 
reaction, the nature, severity or outcome is not consistent with the applicable drug information (e.g. 
IB for an unapproved investigational product or package insert for an approved product).  
The assessment of expected/unexpected character of the event is the responsibility of the 
sponsor. 
 
New event: is defined as any new event relating to the conduct of the trial or the development 
of the investigational medicinal product where that new event is likely to affect the safety of the 
subjects.  
 
Severity criterion: the severity criterion must not be confused with the seriousness criterion 
which is the guide for defining the reporting requirements. 
The intensity (severity) of events will be estimated using the extract of NCI-CTCAE v5.0 classification 
(Appendix 8). The intensity of adverse events not listed in this classification will be assessed 
according to the following qualifiers: 
 
Grade 1 (mild): asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
 
Grade 2 (moderate): minimal local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL. 
 
Grade 3: severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL. 
 
Grade 4: Life-threatening consequences; urgent intervention indicated. 
 
Grade 5: Death related to the event. 
8.3. Measures to be taken in case of a serious adverse event  
The investigator ensures that adequate medical care is provided to the patient.  
The investigator must immediately following knowledge of the event, notifies the R&D UNICANCER 
pharmacovigilance unit of any SAE or any new event defined here above, whether or not related to 
the research, which occurs during the ‘trial reporting period’. This reporting period: 
 
Starts at the date of the signature of the informed consent form. 
 
Covers the entire period during which the patient is receiving the investigational treatment or is 
subject to specific procedures related to the trial. 
 
Covers a period of 90 days after the last administration of the investigational product. 
Any later SAE, i.e. occurring after a period of 90 days, which is considered to be related to the 
experimental treatment(s) or to the research (other treatment used, diagnostic procedures and 
examinations carried out during the research) must be reported without any limitation in terms of 
deadline. 

 
 
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Notification must be carried out immediately by fax to the R&D UNICANCER pharmacovigilance unit 
by sending the form “notification of a SAE”, located in the Investigator Master File, completed as 
precisely as possible, dated and signed by the physician-investigator: 
R&D UNICANCER  
Pharmacovigilance unit, France 
Phone: +33 (0)1 44 23 04 16 – Fax: +33 (0)1 44 23 55 70 
Email: pv-rd@unicancer.fr 
Abnormal laboratory results should be reported as SAE if they possibly put at risk the patient or 
they require medical intervention to prevent an outcome corresponding to one of severity criteria. 
Second cancer, whether or not related to the research, must be reported to the R&D UNICANCER 
pharmacovigilance unit without any limitation in terms of deadline.  
The investigator shall send additional information to the R&D UNICANCER pharmacovigilance 
unit using a SAE declaration form (by ticking the Follow-up X box to specify that it is a follow-up and 
not an initial report) as soon as he is aware of the event. The investigator must also submit the last 
follow-up at the resolution or stabilization of the SAE. 
The investigator is responsible for appropriate medical follow-up of patients until the resolution or 
stabilization of the event or until the death of the patient. This can sometimes mean that the follow-
up continues after the patient has left the trial. 
The investigator must keep the documents concerning the suspected SAE in order to supplement 
the information previously submitted if necessary. 
Requests for clarification and additional information may be sent to the investigator by the R&D 
UNICANCER pharmacovigilance unit or CRA sponsor of the trial to document and treat the case.  
The physician-investigator should also attach to the form «notification of a SAE», whenever possible: 
 
a copy of the hospital report or extended hospitalization report, 
 
a copy of all results of additional investigations carried out, including also relevant negative 
results, and enclosing the normal laboratory values, 
 
a copy of the autopsy report if necessary, 
 
any other document deemed to be useful and pertinent. 
All these documents must be anonymized. 
In the event of pregnancies: 
Pregnancy is not considered as an SAE but must be reported with the same modalities as an SAE, 
using a Pregnancy Notification Form. Pregnancy will be subject to a specific follow-up until the end 
of pregnancy. While pregnancy is not considered as a SAE, any anomaly detected in the fetus or 
child, any elective termination of a pregnancy for medical reasons, or spontaneous abortion will be 
reported as an SAE, using the same procedure as an SAE. 

 
 
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Any pregnancy in a female partner of a male subject occurring during the treatment period or within 
f4 months following the last dose of pembrolizumab or 6 months following the last dose of vorinostat, 
must be reported using the same procedure as an SAE. 
Overdose 
Definition: Administration of a quantity of a medicinal product given per administration or cumulatively 
which is above the maximum recommended dose according to the authorised product information. 
Vorinostat: All overdose of Vorinostat must be reported to the sponsor. The notification will be done 
by using the SAE notification form according to the section 8.3 of this protocol.  
Pembrolizumab: see section 8.4 
8.4. Events of Clinical Interest (ECIs) 
ECIs must be reported to the sponsor immediately as per the SAE notification instructions described 
in Section 8.3, even if not fulfilling a seriousness criterion. 
Events of clinical interest for this study include:  
 
An overdose of pembrolizumab that is not associated with clinical symptoms or abnormal 
laboratory results. For purposes of this study, 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. In the event of overdose, the 
participant 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, the adverse event(s) must be reported as a serious adverse event, even 
if no other seriousness criteria are met. 
 
An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of normal 
and an elevated total bilirubin lab value that is greater than or equal to 2X the upper limit of 
normal and, at the same time, an alkaline phosphatase lab value that is less than 2X the upper 
limit of normal, as determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing.*  
Note: These criteria are based upon available regulatory guidance documents. The purpose of 
the criteria is to specify a threshold of abnormal hepatic tests that may require an additional 
evaluation for an underlying etiology. 

 
 
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9 .  T R A N S L A T I O N A L  S T U D I E S  
All patients enrolled in this study will participate in the translational study. Collection of all blood and 
baseline tumor samples are mandatory. Collection of on-treatment or at progression tumor samples 
are optional and patient must signed a separate ICF. The collection and use of the patient’s biological 
samples will not modify or influence the diagnosis, medical care, and treatment administered to the 
patient. 
The biological samples expected in this research are described in section 13.7.2. 
All the samples will be transported and centralized at Integrated BioBank of Luxembourg (IBBL), 
under the responsibility of Dr Kristin Kornerup, located at the following address: 
IBBL, INTEGRATED BIOBANK OF LUXEMBOURG 
1, rue Louis Rech, L-3555 Dudelange 
Luxembourg 
The tissue and blood samples collected will be used to identify biomarkers that may be predictive of 
response or toxicity to the proposed treatments and/or prognostic for squamous cell carcinoma of 
the head and neck, cervix, lung, anal, vulva, and penile. The collected tumor tissue and blood 
samples may also be used to develop and validate diagnostic assays and allow the generation of 
statistically meaningful biomarker data. A detailed description of the translational studies is provided 
in Appendix 12. 

 
 
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1 0 .  D E S C R I P T I O N  O F  S T A T I S T I C A L  M E T H O D S  
10.1. Statistical hypothesis and sample size determination 
The primary aim of the study is to assess the antitumor activity of the combination of pembrolizumab 
and vorinostat in patients with selected recurrent and/or metastatic solid tumors. 
ORR reported in the literature with pembrolizumab or nivolumab in phase III clinical trials ranged 
from 6% to 24% depending on the tumor type. 
The primary endpoint is the rate of patient presenting an objective response (defined as the 
proportion of patients with best response of a complete response (CR) or a partial response (PR) 
according to RECIST v1.1.) while on study protocol. 
The required number of evaluable patients for each cohort was determined using an A’Hern design 
(A’Hern, 2001) based on different hypotheses. Design parameters and decision rules for each cohort 
are summarized in the following table: 
Cohort 
p0 
p1 
Alpha 
Power 
Nb of 
evaluable / 
included 
patients 
Sufficiently active 
Head and Neck 
10% 
35% 
5% 
85% 
19 / 21 
≥5 CR/PR 
Cervix 
5% 
30% 
5% 
90% 
16 / 18 
≥3 CR/PR 
Lung 
15% 
40% 
5% 
85% 
23 / 25 
≥7 CR/PR 
Anus 
15% 
40% 
5% 
85% 
23 / 25 
≥7 CR/PR 
Penis 
5% 
30% 
10% 
85% 
10 /11 
≥2 CR/PR 
Vulva 
5% 
30% 
10% 
85% 
10 / 11 
≥2 CR/PR 
 
p0: maximal unacceptable rate of patient presenting an objective response for whom the 
experimental treatment will be considered as insufficiently active. 
 
p1: minimal acceptable rate of patient presenting an objective response for whom the 
experimental treatment will be considered as sufficiently active. 
To compensate for drop out, we plan to include an additional 10% of patients in each cohort; 
therefore a total of 111 patients are required this study. 
10.2. Trial populations to be analyzed 
The following populations will be considered for analyses: 
 
Per-protocol: all eligible patients with at least one valid post-baseline disease assessment (or 
with disease progression) and have received at least one dose of the study treatment 
(pembrolizumab or vorinostat). 
 
Safety population: all patients who have started their allocated treatment (at least one dose of 
the study treatments). 

 
 
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10.3. Planned statistical analysis 
Demographic and clinical characteristics (including HPV status) will be presented in the overall 
population and per cohort using usual statistics. Quantitative data will be summarized as median, 
min, max and number of missing data. Qualitative variables will be described as number, percentage 
and number of missing data. 
Primary endpoint  
The primary endpoint will be assessed in the per protocol population and will be reported per cohort. 
The primary endpoint is the rate of patients presenting an objective response according to RECIST 
v1.1 It will be presented as number, percentage, and 95% confidence interval (CI): by the binomial 
exact distribution. 
Secondary efficacy endpoints  
The secondary endpoint will be assessed in the per protocol population and will be reported per 
cohort: 
 
ORR, iORR, and DOR will be presented using frequency, percentage frequencies, 
percentages, and the 95% CI (Binomial exact distribution). 
 
A radiological panel will centrally assess the ORR, iORR, and iPFS.  
 
Survival rates (PFS, iPFS OS) will be estimated at different time points using the Kaplan-Meier 
method. Median survival times will be estimated and reported with the corresponding 95% CI. 
 
Number of pembrolizumab injections and dose intensity of vorinostat will also be recorded. 
 
Incidence rates of adverse events and serious adverse events will be presented using 
frequencies and percentages by system organ class and MedDRA preferred term. 
Pharmacovigilance will be handled by UNICANCER. 
 
Safety Analysis will be performed on the safety population, by cohort and on the overall 
population. Each of the following will be assessed: 
o AEs by toxicity grade 
o SAEs 
o Investigated drug-related AE 
o AE leading to interruption or dose reduction 
o Occurrence of AE with toxicity grade >2 
Frequency and percentage will be computed for each event 
Pharmacovigilance will be handled by UNICANCER. 
 Modifications of SAP and initial statistical analysis strategy 
Any modification/change made to the initial statistical analysis plan (SAP) will be described in details, 
well-argued and commented in an updated version of the SAP. These modifications may be 
complementary/exploratory analyses not envisaged initially. 

 
 
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1 1 .  O V E R S I G H T  C O M M I T T E E S  
11.1. Independent data monitoring committee 
An IDMC, with expertise and experience in the pathologies, and without direct involvement in the 
conduct of the trial, will be set up specifically to guarantee: 
 
Effective protection of patients. 
 
Insure the ethical conduct of the trial. 
 
Benefit/risk ratio of the trial. 
 
Ensure the independent review of the scientific results during the trial and at the end of the trial. 
The IDMC will meet every year and will be composed of at least: 
 
2 oncologists 
 
A statistician 
Data presented to IDMC are strictly confidential. Interim analyses, if applicable, will be presented to 
the IDMC. 
The IDMC may recommend the early termination of the trial if one of the following conditions is met: 
 
An unacceptable toxicity. 
 
Data available from the trial or any other source of information are sufficiently convincing to 
influence the therapeutic practice of the majority of clinicians. 
The IDMC has only a consultative role; it will inform the sponsor who will decide whether the IDMC 
recommendation will be followed. 
11.2. Steering Executive Committee 
 
A Steering executive committee has been implemented for this trial. The Steering executive 
committee will meet physically (or at least through a teleconference) in a regular basis (at least twice 
a year) to discuss key questions related to the protocol (see examples listed below). Additional 
meetings may be organized, as required. 
The Steering executive committee is composed of (non-exhaustive list): 
 
The principal investigator 
 
UNICANCER project manager 
 
The ancillary/translational program coordinator 
 
The study statistician 
 
The referent pathologist 
 
Some investigators involved in the study 
The steering committee will be responsible for: 
 
Approving the protocol and any amendments thereof. 

 
 
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 
Maintaining the scientific integrity of the study, according to the protocol. 
 Ensuring the trial is conducted in an ethical manner; reviewing recommendations of the 
IDMC and determining actions to be taken as applicable in order to ensure the safety of 
the participants. 
 Reviewing the recruitment rate and any kind of issues raised during the conduct of the 
study to adjust the protocol conditions via a protocol amendment, if needed. 
 Reviewing and deciding on research projects requiring access to and use of study data 
and/or biological samples. 
 Publications and presentations of the study data. 
The steering executive committee will assist UNICANCER in resolving issues and/or questions 
encountered during the trial and will consider with UNICANCER changes to the protocol as 
necessary. 
 

 
 
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1 2 .  Q U A L I T Y  A S S U R A N C E  
12.1. Data collection 
All data necessary for the research must be entered into the trial eCRFs in a timely manner. eCRFs 
will be completed by the principal investigator and other staff members duly designated. The data 
entered must be accurate and complete. 
The trial database will be hosted by: 
Institut du Cancer Montpellier (ICM) – Val d’Aurelle 
Unité de Biométrie – CTD INCa 
208 rue des Apothicaires - Parc Euromédecine 
34298 Montpellier Cedex 5 – France 
Mrs. Sophie Gourgou will be responsible for the trial database. 
 
Database management will be provided by an eCRF developed using the CSOnline module of Ennov 
Clinical® software. In case of technical problem with the eCRF, the investigator may refer to the 
specific operating procedure of the eCRF or directly contact:  
ICM – Unité de Biométrie – CTD INCa 
Data centre UNICANCER 
from Monday to Friday 9 am-5 pm 
Email: support.ecrf@icm.unicancer.fr 
Fax: +33 (0)4 67 61 37 18 
Tel: +33 (0)4 67 61 45 48/24 52 
The access code (login) and passwords to access the eCRF will be sent directly to each users 
personal email account. The logins and personal passwords to connect to the eCRF, via the website 
- https://ecrf.icm.unicancer.fr/CSOnline - will automatically be generated by CSOnline. 
A password non-disclosure certificate will be signed by the principal investigator of each center 
engaging his/her responsibility regarding the confidentiality of the access codes for all users of the 
eCRF at their center.  
Trial data will be entered directly by the principal investigator or by designated staff members of each 
center, via the eCRF, and will be controlled and validated according to the standard procedures 
(included those in the software and the sponsor’s quality assurance procedures). When using the 
eCRF, traceability of access and changes made to the eCRF are traced by the software (audit trail). 
At the end of the trial and once all the eCRF data are validated, the investigator will login to the eCRF 
to sign all the pages to validate the data entered for each patient. 

 
 
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The sponsor will create and send an electronic copy (PDF file) of each patient’s CRF to the 
corresponding investigator. This pdf file must be printed and signed by the investigator, and then 
archived at the investigator’s site. 
12.2. Access to data 
The sponsor has direct access to all investigator sites, original records, source data/document and 
reports to allow quality control and auditing by the sponsor or on behalf of the sponsor. 
Investigators will make available to the authorized persons the documents and the patients’ 
individual data that are essential to monitor the trial on an ongoing basis, to perform quality control 
and audit of this research in accordance with national regulatory requirements. 
12.3. Trial monitoring 
To ensure the patient integrity and safety, and authenticity and credibility of data in accordance with 
the “Décision portant sur les Bonnes Pratiques Cliniques, 24 November 2006”, the sponsor had 
established a quality assurance system that consists of: 
 
The management and the monitoring of the trial according to UNICANCER procedures. The 
monitoring strategy is built according to a systematic, prioritized, risk-based approach, and is 
documented in the monitoring plan. 
 
The quality control of data at the investigational centers by the monitor(s), which involves: 
 Verifying that the protocol, as well as the current guidelines ICH-GCP, the national 
regulatory requirements, are adhered to. 
 Verifying the informed consent and the eligibility of each patient participating in the trial. 
 Verifying that the CRF data is consistent and in agreement with the source documents. 
 Verifying the notification of each SAE. 
 Verifying the drug traceability (dispatching, storage, and accountability). 
 Verifying that patients are not already participating in another clinical study making them 
ineligible for this protocol. The monitor will also verify that patients have not participated 
in another study within the delay indicated in the non-inclusion criterion N°18. 
 
The quality control of data by a centralized monitoring process. Centralized monitoring is a 
remote evaluation of data, performed in a timely manner, supported by appropriately qualified 
and trained persons (e.g., data managers, biostatisticians). Review, that may include statistical 
analyses, of accumulating data from centralized monitoring can be used to: 
 Identify missing data, inconsistent data, data outliers, unexpected lack of variability, and 
protocol deviations. 
 Examine data trends such as the range, consistency, and variability of data within and 
across sites. 
 Evaluate for systematic or significant errors in data collection and reporting at a site or 
across sites; or potential data manipulation or data integrity problems. 
 Analyze site characteristics and performance metrics. 

 
 
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 Select sites and/or processes for targeted on-site monitoring. 
 
The audit of participating investigational centers when deemed necessary 
The monitors/CRAs in charge of trial monitoring will be mandated by the sponsor. They must have 
direct access to all patient data required to perform their duty in accordance with the national 
regulatory requirements. The monitors/CRAs are bound by professional secrecy under the national 
regulatory requirements. Written reports must be issued to ensure the traceability of monitoring visits. 
To ensure optimal research quality control the investigator will ensure that the monitor/CRA has 
direct access to all trial patient files.  
12.4. Audits and inspections 
As part of UNICANCER’s audit program, the sponsor may audit some investigational centers. The 
center and the investigator agree that audits be carried out by Sponsor or any person duly authorized 
during the trial and for at least 15 years after the trial.  
The investigational center and the investigator agree to devote the time necessary for the audit 
procedures, allow the control of the trial documentation, and provide additional information requested 
by the sponsor. 
A Competent Authority may also request a trial inspection (during the trial or after its completion). If 
a Competent Authority requests an inspection, the investigator must inform the sponsor immediately 
of this request. The investigator must allow the inspectors direct access to the trial documents and 
source documents. 
The investigational center and the investigator agrees to devote the time necessary for inspections 
procedures, allow the control of the trial documentation, and provide additional information requested 
by the inspectors of the concerned Competent Authority. 

 
 
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1 3 .  E T H I C A L  A N D  R E G U L A T O R Y  C O N S I D E R A T I O N S  
13.1. General requirements 
The trial must be conducted in accordance with the French national regulatory requirements: 
 
The principles of ethics as stated in the last version of the Declaration of Helsinki. 
 
Loi n°2012-300 du 5 mars 2012 relative aux recherches impliquant la personne humaine, as 
modified in 2016. 
 
Regulation (EU) 2016/679 on the protection of natural persons with regard to the processing 
of personal data and on the free movement of such data (General Data Protection 
Regulation). 
 
Amended Loi Informatique et Libertés n° 78-17 du 6 janvier 1978, relative à la protection des 
personnes physiques à l'égard des traitements de données à caractère personnel. 
 
Amended Loi n° 2004-800 du 6 août 2004, relative à la bioéthique. 
 
Décision du 24 novembre 2006 fixant les règles de bonnes pratiques cliniques pour les 
recherches biomédicales portant sur des médicaments à usage humain. 
 
Good Manufacturing Practices, in particular, Annex 13 on investigational medicinal products. 
13.2. Patient identification 
All patients will receive a unique patient identification number when signing the informed consent 
form by the patient and before any trial procedure is performed. This number will be used to identify 
the patient throughout the trial and must be used on all trial documentation related to this patient. 
The patient identification number must remain constant throughout the trial. 
13.3. Patient information and consent 
Patient information and informed consent from the patient must be handled in accordance with the 
“French regulation, especially article L.1122-1 and subsequent articles. 
Prior to the participation of a patient in the trial, this patient will be informed both verbally and in 
writing about the objectives of the trial, its methods, anticipated benefits and potential risks and the 
discomfort to which they may be exposed. All items must be explained by the investigator in a 
language and in terms that are easy to understand by the patient. The patients must be given enough 
time to consider their participation and decide whether they wish to participate or not in the trial. 
Patients will also be informed that their participation is voluntary and that they have the right to 
withdraw from the trial at any time without giving the reasons and without this impacting their 
subsequent medical care. 
The patient information sheet and the informed consent form must be associated within the same 
document to ensure that all information regarding the trial is provided to the patient. Patients will 
confirm their consent in writing prior to starting the trial and before undergoing any trial-related 
procedure. Two original informed consent forms must be personally dated and signed by the patient 
and investigator. An original copy will be filed in the Trial Master File (TMF). The other original patient 
information sheet and the signed informed consent form will be given to the patient. 

 
 
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If the patient decides to withdraw from the trial, the patient is not obliged to give reason(s) for 
withdrawing. However, the investigator should make a reasonable effort to obtain the reason(s) while 
fully respecting the patient’s rights. 
In conformance with the data protection regulation, the patient may use their right to access to, rectify 
or oppose the use of their personal data in the research. In these situations, the investigator shall 
inform the sponsor without delay in order to take the appropriate steps. 
If any changes in the written patient information or informed consent form occur during the trial, the 
investigator will ensures that all patients impacted by the changes and still participating in the trial 
receive the updated patient information in a timely manner and are asked for written consent for the 
changes made. 
13.4. Insurance compensation 
UNICANCER, the sponsor of the trial certifies that it has taken out a civil liability insurance policy 
covering its civil liability for this clinical trial under its sponsorship. This insurance policy is in 
accordance with local laws and requirements. The insurance of the sponsor does not exempt the 
investigator and its team from maintaining their own liability insurance policy.  
13.5. Investigator responsibilities 
The principal investigator of each investigator site participating in the trial commits to conduct the 
trial as specified in this protocol and in accordance with the “Décision portant sur les Bonnes 
Pratiques Cliniques, 24 November 2006”. 
 
It is the responsibility of the principal investigator to: 
 Provide to the sponsor with their curriculum vitae (CV) and those of their collaborators, 
and evidence that the center will be able to conduct the trial. The CV must be current (no 
older than 1 year), dated and signed. 
 Identify the members of their team who participate in the trial and define each team 
member’s role and responsibilities. 
 Start recruiting patients only after receiving approval from the sponsor. 
 Be available for monitoring visits, audits, and investigator meetings. 
 
It is the responsibility of each principal investigator and each investigator team member to: 
 Ensure the confidentiality of all data recorded during the trial. 
 Collect the informed consent, written, dated, and signed personally by each individual 
research participant before any specific selection procedure for the trial. 
 Regularly complete the eCRF for each patient included in the trial and allow CRA(s), 
mandated by the sponsor, direct access to the source documents in order to validate the 
data collected in the CRF. 
 Declare to the sponsor as soon as being aware of, any serious adverse event occurring 
during the trial according to provisions of this protocol; 

 
 
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 Accept regular visits by the CRA(s) and possibly those of auditors mandated by the 
sponsor or the inspectors of the respective regulatory authorities; 
 Date, correct, and sign the corrections made in the CRF and the requests of the data 
correction forms (DCF) for each patient included in the trial. 
13.6. Federation of the Patient Committees for Clinical Research in Cancerology 
This committee reviews trial documents provided to patients in oncology clinical studies, and makes 
suggestions for improving these, in terms of the quality of information given to patients. 
The “Ligue Nationale Contre le Cancer” and the French NCI (INCa) coordinate the French patient 
committees’ federation. 
13.7. Human biological samples collection 
Biological studies are necessary to increase the knowledge of diseases, which may allow the 
development of new and more effective treatments. These studies use human biological samples 
(blood and tumor samples) than are collected from patients either while they receive medical care 
(examination, surgery) or specifically for the research purpose. 
These biological samples will be prepared, stored, shipped, and used for the purpose of research. 
These biological samples are subject to written consent from the patient. This consent is revocable 
at any time during the trial. Similarly, at any time during the research, the patient has the possibility 
to request the destruction of their samples. 
Furthermore, it must be noted that the results of biological studies may be published only if all data 
relative to the patients are made anonymous. 
Concerning genetic research, patients must consent to participation in these studies after being 
informed of the proposed research, irrespective of the type of sample collected (already existing or 
specifically collected). 
Furthermore, it must be noted that the results of biological studies may be published only if all data 
relative to the patients are made anonymous. 
Refer to the Appendix 12 for more detailed information. 
 Storage and use of disease assessment samples (blood, biopsy, tumor 
specimen, etc.) 
During the medical cares that are going to be realized, biological samples of tissues and/or cells 
(blood, tumor tissue) will be collected for medical purposes. A part of these samples may be stored 
and used for scientific researches. 
These samples will be used to investigate potential biomarkers predictive of response to 
pembrolizumab, vorinostat, or their combination in the PEVOsq study. 
The patient will be informed via a patient information sheet and, in the absence of opposition of his 
part, biological samples for research will be prepared, stored and used for this research. 
The preparation, storage and use of the biological samples does not modify or imply any change 
with respect to the diagnosis, cares and treatments that will be administrated to the patient. 

 
 
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Refer to the Appendix 12 for more detailed information. 
 Collecting additional biological samples for research purpose 
Tumor and blood sampling will be performed at several time points during the course of the treatment 
in order to collect molecular and immune parameters for integrative analyses with the aim to better 
understand the mechanisms of response or resistance to this combination. This research also aim 
to determine how integrate these data to determine the best treatment option appropriate to specific 
patients. 
To perform this research, additional blood and tumor samples will be collected: 
 
Mandatory tumor samples to be obtained for all the patients 
 Tumor biopsy at baseline (2 frozen + 2 FFPE) 
 
Optional tumor samples to be obtained for willing patients 
 Tumor biopsy at D1 of cycle 3 (2 frozen + 2 FFPE) 
 Tumor biopsy at disease progression (2 frozen + 2 FFPE) 
 
Mandatory blood samples 
 Whole blood for germline DNA at baseline. 
o 1 x 4 mL EDTA tubes for constitutional DNA and HLA sequencing 
 Blood for ctDNA analysis at baseline: 
o 2 x 10 mL PACgene CCF tubes for plasma +buffy coat. 
o 2 x 8.5 mL CPT tubes for phenotyping of PBMC. 
 Then at D1 cycle 3, at D1 cycle 5 and if applicable, at progression: 
o 2 x 10 mL PACgene CCF tubes for plasma +buffy coat. 
o 2 x 8.5 mL CPT tubes for phenotyping of PBMC. 
These biological samples should be prepared, stored and used for the purpose of the research, as 
described in the Manual Lab provided by the Sponsor. 
These additional samples are subject to a specific additional written consent from the patient. This 
specific consent for the ancillary/translational research is revocable at any time. In addition, the 
patient has the right to request the destruction of their samples at any moment. 

 
 
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1 4 .  D A T A  P R O C E S S I N G  A N D  C O N S E R V A T I O N  O F  
D O C U M E N T S  A N D  D A T A  O F  T H E  R E S E A R C H  
14.1. Data processing 
 Under the responsibility of the sponsor 
The statistical data will be transferred to the trial statistician for analysis. The trial data remain the 
property of UNICANCER, the research sponsor. 
The software Clinsight® will be used for data entry, management, and archiving of data. The 
statistical analysis will be performed using the SAS and/or stata softwares software. 
 In the investigational center, when computerized medical records are used 
If computerized patient records are used in a participating center to process or store trial data, the 
center must: 
 
Verify and document that the computer system used to process the data conforms to the 
requirements concerning data completeness, accuracy, and reliability with respect to expected 
performances (quality validation). 
 
Define and follow the standardized procedures related to these systems. 
 
Ensure that these systems allow modifications of collected data, that each modification is 
automatically authenticated, and that the data cannot be removed (i.e. any change or 
modification of the data must be traceable). 
 
Set up and maintain a security control to prevent unauthorized access to the data. 
 
Establish and regularly update the list of persons authorized to have access and modify the 
data. 
 
Carry out appropriate backups of the data. 
 
Ensure confidentiality, whenever it is applicable (e.g. during data input). 
 
Ensure that the individual computerized patient data are processed in accordance with the “Loi 
Informatique et Libertés n° 78-17, 6 January 1978 modified”. 
If data are transformed while being processed, it should always be possible to compare them with 
the original observations/records. 
The computerized system used to identify trial patients must not be ambiguous must allow the 
identification of all data collected for each patient while maintaining confidentiality in accordance with 
the “Loi Informatique et Libertés n° 78-17, 6 January 1978 modified”. 
14.2. Retention of documents by investigator sites  
The investigator must maintain source documents for each trial patient. 
All information in case report forms must be traceable and consistent with source documents, which 
are generally maintained in the patient’s file. The source documents should contain all demographic 
and medical information, laboratory data, radiology, electrocardiograms, etc., including the original 
copy of the signed patient information sheet and informed consent form. 

 
 
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The investigator must retain essential documents as described below. The investigator agrees to 
adhere to the document retention procedures by signing the protocol. Essential documents include: 
 
Approvals from the CPP for the trial protocol and all relevant amendments. 
 
Authorizations from the ANSM for the trial protocol and all relevant amendments. 
 
All source documents and laboratory records. 
 
CRF copies. 
 
Patients’ informed consent forms. 
 
Investigator master file (IMF) and Investigator master file-pharmacy (IMF-P). 
 
Any other pertinent trial document. 
All trial documents must be kept in a locked and secured place and be considered as confidential. 
Data will be archived under the responsibility of the principal investigator of each participating center 
according to the “Décision portant sur les Bonnes Pratiques Cliniques, 24 November 2006”. The trial 
documents, including a list of patient’s identifications for a minimum period of 25 years after the end 
of the trial. UNICANCER will inform the investigational centers when the trial-related records are no 
longer required.  
The investigational center may destroy the data only after written authorization from the sponsor. 

 
 
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1 5 .  D A T A  O W N E R S H I P  A N D  C O N F I D E N T I A L I T Y  
By signing the protocol, the investigator agrees to keep all information provided by UNICANCER 
strictly confidential and to ensure similar confidentiality from their staff. This obligation does not cover 
information provided to the patients and information already publically available. 
Trial documents provided by UNICANCER (protocols, investigators’ brochures, CRFs, and other 
material) will be stored appropriately to ensure their confidentiality. The information provided by 
UNICANCER to the physician-investigator may not be disclosed to others without direct written 
authorization from UNICANCER.  
The physician-investigator commits to not publish, spread or use in any manner, directly or indirectly, 
the scientific and technical information and results related to the trial. 
1 6 .  P U B L I C A T I O N  R U L E S  
All information resulting from this trial is considered to be confidential, at least until appropriate 
analysis and checking has been completed by the sponsor, the principal investigator and the 
statistician of the trial. 
Any publication, abstract or oral presentations including results of the trial must be submitted to the 
sponsor (UNICANCER) for approval. 
Additionally, all communications, manuscripts or oral presentations must include a section 
mentioning UNICANCER as well as any institution, physician-investigators, collaborative research 
group, scientific society that has contributed to the trial, including organizations that have provided 
financial support. 
The first author and writer of the main publication will be the principal investigator. The principal 
investigator may however designate another person to (co-) write the publication.  
As for the main publication, authors are listed in the following order: 
 
The trial coordinator (first or last author). 
 
The other investigators will appear in the list of co-authors in decreasing order, according to 
the number of recruited patients regardless of their affiliation to a cooperative group. 
 
A person representing each cooperating group, if a representative is not listed in the sites 
with the highest recruitment rates. 
 
The statistician (the statistician’s position is among the first three authors or the last author 
of the publication). 
 
The ancillary/translational coordinator 
 
A R&D UNICANCER representative. 
Similarly, publication of the sub-studies (e.g. biological/ancillary studies) will include persons who 
have carried out the sub-studies as well as the names of all individuals who have contributed to 
these sub-studies and a sponsor representative. 
It is desirable to include the contributors from weakly recruiting centers who have not been 
mentioned in the first article in the later publications. 

 
 
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Any conflict regarding publication authorship will initially be submitted to the trial IDMC and then to 
the CSR (Comité Stratégique Recherche [Strategic Research Committee]) for resolution in case of 
major disagreement. 
UNICANCER will arbitrate and rule any dispute that may arise. 
 
 

 
 
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1 7 .  R E F E R E N C E S  
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Duvic, M. and J. Vu (2007). "Vorinostat: a new oral histone deacetylase inhibitor approved for 
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Kasper, E. E. Vokes, C. Even, F. Worden, N. F. Saba, L. C. Iglesias Docampo, R. Haddad, T. 
Rordorf, N. Kiyota, M. Tahara, M. Monga, M. Lynch, W. J. Geese, J. Kopit, J. W. Shaw and M. L. 
Gillison (2016). "Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck." N 
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Zheng, W. Dai, J. J. Saller, Z. Chen, N. Tchekmedyian, K. Goas, R. Thapa, T. A. Boyle, D. T. Chen 
and A. A. Beg (2019). "Phase I/Ib Study of Pembrolizumab Plus Vorinostat in Advanced/Metastatic 
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Heist, R. S., M. Mino-Kenudson, L. V. Sequist, S. Tammireddy, L. Morrissey, D. C. Christiani, J. A. 
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"Concomitant use of pembrolizumab and entinostat in adult patients with metastatic uveal 
melanoma (PEMDAC study): protocol for a multicenter phase II open label study." BMC Cancer 
19(1): 415. 
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Trochon-Joseph, B. Vasseur, G. Dixon, B. Sangro and P. Sarobe (2019). "Enhanced anti-tumor 
efficacy of checkpoint inhibitors in combination with the histone deacetylase inhibitor Belinostat in a 
murine hepatocellular carcinoma model." Cancer Immunol Immunother 68(3): 379-393. 

 
 
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Mangano, A., A. Mangano, G. D. Lianos, D. H. Roukos, L. Boni and G. Dionigi (2015). "Head and 
neck squamous cell carcinoma and human papillomavirus: epidemiology, treatment and future 
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Marur, S. and A. A. Forastiere (2016). "Head and Neck Squamous Cell Carcinoma: Update on 
Epidemiology, Diagnosis, and Treatment." Mayo Clin Proc 91(3): 386-396. 
Mazzone, R., C. Zwergel, A. Mai and S. Valente (2017). "Epi-drugs in combination with 
immunotherapy: a new avenue to improve anticancer efficacy." Clin Epigenetics 9: 59. 
Morris, V. K., M. E. Salem, H. Nimeiri, S. Iqbal, P. Singh, K. Ciombor, B. Polite, D. Deming, E. 
Chan, J. L. Wade, L. Xiao, T. Bekaii-Saab, L. Vence, J. Blando, A. Mahvash, W. C. Foo, C. Ohaji, 
M. Pasia, G. Bland, A. Ohinata, J. Rogers, A. Mehdizadeh, K. Banks, R. Lanman, R. A. Wolff, H. 
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Wang, W., S. Wang, X. Chu, H. Liu and M. Xiang (2019). "Predicting the Lung Squamous Cell 
Carcinoma Diagnosis and Prognosis Markers by Unique DNA Methylation and Gene Expression 
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1 8 .  A P P E N D I C E S  
 Appendix 1 - Performance status evaluation – WHO scale 
 Appendix 2 - World Medical Association - Declaration of Helsinki 
 Appendix 3ICH Harmonised Tripartite Guideline for Good Clinical Practice (ICH-GCP) 
 Appendix 4 - List of medications with (a) defined risk, (b) possible, and (c) conditional risk of 
Torsade de Pointes 
 Appendix 5 - Corticosteroid Dose Equivalents 
 Appendix 6 - A brief summary of tumor classification RECIST v1.1 
 Appendix 7 - Description of the iRECIST Process for Assessment of Disease Progression 
 Appendix 8 -Toxicity criteria (NCI-CTCAE)  
 Appendix 9 - Dose modification and toxicity management guidelines for immune-related AEs 
associated with pembrolizumab 
 Appendix 10 - Dose modification and toxicity management of infusion-reactions related to 
pembrolizumab 
 Appendix 11. Dose modification and toxicity management of drug reactions related to 
vorinostat 
 Appendix 12 - Translational studies 
 
 
 

 
 
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 Performance status evaluation – WHO scale  
 
 
 
Performance status 
ECOG-ZUBROD/ WHO 
Grade 
Fully active, able to carry on all pre-disease performance without Restriction. 
0 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, e.g. light house work, office work. 
1 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
2 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
3 
Completely disabled. Cannot carry on any self-care. Totally confined to bed 
or chair. 
4 
Dead 
5 
 
Developed by the Eastern Cooperative Oncology Group and published by Oken M, Creech R, Tormey D, et 
al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982; 5:649-
655. 
 
 

 
 
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 World Medical Association - Declaration of Helsinki 
 
 
 
The current Declaration of Helsinki can be found on the World Medical Association web 
page via the link provided below: 
 
https://www.wma.net/ 
 

 
 
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 ICH Harmonised Tripartite Guideline for Good Clinical Practice (ICH-GCP) 
 
 
 
The current ICH-GCP can be found on the European Medicine Agency web page via the link 
provided below: 
 
https://www.ema.europa.eu/ 
 
 

 
 
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 List of medications with (a) defined risk, (b) possible, and (c) conditional risk 
of Torsade de Pointes 
 
 
https://crediblemeds.org/index.php/login/dlcheck 
 
 
 
 
 
 
Woosley, RL, Heise, CW and Romero, KA,  www.Crediblemeds.org,  QTdrugs List, Accession 
Date, AZCERT, Inc. 1822 Innovation Park Dr., Oro Valley, AZ  85755  
 

 
 
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 Corticosteroid Dose Equivalents 
 
Equivalent Dose  
Steroid  
1.2 mg  
Betamethasone (long-acting)  
1.5 mg  
Dexamethasone (long-acting)  
8 mg  
Methylprednisolone 
(intermediate-acting)  
8 mg  
Triamcinolone (intermediate-
acting)  
10 mg  
Prednisone (intermediate-acting)  
10 mg  
Prednisolone (intermediate-
acting)  
40 mg  
Hydrocortisone (short-acting)  
50 mg  
Cortisone (short-acting)  
 
Mager DE, Lin SX, Blum RA, Lates CD, Jusko WJ. Dose equivalency evaluation of major corticosteroids: 
pharmacokinetics and cell trafficking and cortisol dynamics. J Clin Pharmacol. 2003 Nov. 43(11):1216-27..  
Webb R, Singer M. Oxford Handbook of Critical Care. Oxford University Press. 2005. 
 
 
 

 
 
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 A brief summary of tumor classification RECIST v1.1 
(Eur. J. Cancer, 45(2009), 228-247 [47]) 
Full article available at: https://ctep.cancer.gov/ 
 “New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1)” E.A. Eisenhauer, 
P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. Arbuck, S. Gwyther, M. Mooney, 
L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe, J. Verweij. 
Summary:  
Measurability of tumor at baseline: 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as follows: 
Measurable 
Tumor lesions: Must be accurately measured in a least one dimension (longest diameter in the plane of 
measurement is to be recorded) with a minimum size of:  
 ≥10 mm by CT scan (CT scan slice thickness no greater than 5 mm. 
 ≥10 mm caliper measurement by clinical exam. 
 20 mm by chest (=X-ray). 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node must be ≥15 
mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 
mm). At baseline and in follow-up, only the short axis will be measured and followed. 
Non-measurable 
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes with ≥10 to 
<15 mm short axis) as well as truly non-measurable lesions. Lesions considered truly non-measurable include: 
leptomeningeal disease, ascites, pleural or pericardial effusion, inﬂammatory breast disease, lymphangitic 
involvement of skin or lung, abdominal masses/abdominal organomegaly identiﬁed by physical exam that is 
not measurable by reproducible imaging techniques. 
Remark: 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require special considerations 
regarding lesion measurability (see below): 
Bone lesions: 
 Bone scan, PET scan or plain films are not considered adequate imaging techniques to measure bone 
lesions. However, these techniques can be used to confirm the presence or disappearance of bone 
lesions. 
 Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that can be 
evaluated by cross sectional imaging techniques such as CT or MRI can be considered as measurable 
lesions if the soft tissue component meets the definition of measurability described above. 
 Blastic bone lesions are non-measurable. 
 
Target lesions 

 
 
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When more than one measurable lesion is present at baseline all lesions up to a maximum of ﬁve lesions 
total (and a maximum of two lesions per organ) representative of all involved organs should be identiﬁed 
as target lesions and will be recorded and measured at baseline. Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved organs, but in addition 
should be those that lend themselves to reproducible repeated measurements. Pathological nodes which are 
deﬁned as measurable and may be identiﬁed as target lesions must meet the criterion of a short axis of ≥ 15 
mm by CT scan. 
The baseline sum diameters will be used as reference to further characterise any objective tumour regression 
in the measurable dimension of the disease. 
Non-target lesions 
All other lesions (or sites of disease) including pathological lymph nodes should be identiﬁed as non-target 
lesions and should also be recorded at baseline. Measurements are not required and these lesions should be 
followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ during the trial. 
Response criteria 
Target lesions 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target 
or non-target) must have reduction in short axis to <10 mm. 
Warning: lymph nodes identiﬁed as target lesions should always have the actual short axis measurement 
recorded (measured in the same anatomical plane as the baseline examination), even if the nodes regress to 
below 10 mm on trial. This means that when lymph nodes are included as target lesions, the ‘sum’ of lesions 
may not be zero even if complete response criteria are met, since a normal lymph node is deﬁned as having 
a short axis of <10 mm. In order to qualify for CR, each node must achieve a short axis <10 mm.  
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference 
the baseline sum diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition 
to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: 
the appearance of one or more new lesions is also considered progression). 
Warning: when a progression is recorded with respect to the Nadir but there is a response with respect to 
baseline, progression must be considered. 
Stable Disease (SD): Neither sufﬁcient shrinkage to qualify for PR nor sufﬁcient increase to qualify for PD, 
taking as reference the smallest sum diameters while on trial. 
Non-target lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalisation of tumour marker level. 
All lymph nodes must be non-pathological in size (<10 mm short axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumour marker level 
above the normal limits. 
Progressive Disease (PD): Unequivocal progression (see comments below) of existing non-target lesions. 
(Note: the appearance of one or more new lesions is also considered progression). 
 
 

 
 
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Overall response: 
Target lesions 
Non-target lesions 
New lesions 
 
Overall response 
CR 
CR 
No 
= 
CR 
CR 
Non CR/Non PD 
No 
= 
PR 
CR 
PR 
Not evaluated 
Non PD or not all evaluated 
No 
No 
= 
= 
PR 
PR 
SD 
Non PD or not all evaluated 
No 
= 
SD 
Not all evaluated 
PD 
Non PD 
No change 
No 
Yes or No 
= 
= 
Not-evaluable 
PD 
No change 
PD 
Yes or No 
= 
PD 
No change 
No change 
Yes 
= 
PD 
 
Special considerations regarding baseline lesion measurability 
Bone lesions: 
 Bone scan, PET scan or plain ﬁlms are not considered adequate imaging techniques to measure bone 
lesions. However, these techniques can be used to conﬁrm the presence or disappearance of bone 
lesions. 
 Lytic bone lesions or mixed lytic-blastic lesions, with identiﬁable soft tissue components, that can be 
evaluated by cross sectional imaging techniques such as CT or MRI can be considered as measurable 
lesions if the soft tissue component meets the deﬁnition of measurability described above. 
 
Cystic lesions: 
 Lesions that meet the criteria for radiographically deﬁned simple cysts should not be considered as 
malignant lesions (neither measurable nor non-measurable) since they are, by deﬁnition, simple cysts. 
 ‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, if they 
meet the deﬁnition of measurability described above. However, if non-cystic lesions are present in the 
same patient, these are preferred for selection as target lesions. 
 
Lesions with prior local treatment: 
 Tumour lesions situated in a previously irradiated area, or in an area subjected to other loco-regional 
therapy, are usually not considered measurable unless there has been demonstrated progression in the 
lesion. Trial protocols should detail the conditions under which such lesions would be considered 
measurable. 

 
 
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 Description of the iRECIST Process for Assessment of Disease Progression 
1. Assessment at Screening and Prior to RECIST v1.1 Progression 
Until radiographic progression based on RECIST v1.1, there is no distinct iRECIST assessment. 
2. Assessment and Decision at RECIST v1.1 Progression 
In participants who show evidence of radiological PD by RECIST v1.1 the Investigator will decide 
whether to continue a participant on study treatment until repeat imaging is obtained (using 
iRECIST for participant management. This decision by the Investigator should be based on the 
participant’s overall clinical condition. 
Clinical stability is defined as the following:  
 
Absence of symptoms and signs indicating clinically significant progression of disease 
 
No decline in ECOG performance status  
 
No requirements for intensified management, including increased analgesia, radiation, or 
other palliative care 
Any participant deemed clinically unstable should be discontinued from study treatment at site-
assessed first radiologic evidence of PD, and is not required to have repeat tumor imaging for 
confirmation of PD by iRECIST. 
If the Investigator decides to continue treatment, the participant may continue to receive study 
treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm PD by 
iRECIST, per Investigator assessment.  I 
Tumor flare may manifest as any factor causing radiographic progression per RECIST v1.1, 
including: 
 
Increase in the sum of diameters of target lesion(s) identified at baseline to ≥ 20% and 
≥ 5 mm from nadir 
o Please note: the iRECIST publication uses the terminology “sum of measurements”, but 
“sum of diameters” will be used in this protocol, consistent with the original RECIST 
v1.1 terminology. 
 
Unequivocal progression of non-target lesion(s) identified at baseline 
 
Development of new lesion(s) 
iRECIST defines new response categories, including iUPD (unconfirmed progressive disease) and 
iCPD (confirmed progressive disease).  For purposes of iRECIST assessment, the first visit 
showing progression according to RECIST v1.1 will be assigned a visit (overall) response of iUPD, 
regardless of which factors caused the progression. 
At this visit, target and non-target lesions identified at baseline by RECIST v1.1 will be assessed as 
usual. 
New lesions will be classified as measurable or non-measurable, using the same size thresholds 
and rules as for baseline lesion assessment in RECIST v1.1.  From measurable new lesions, up to 
5 lesions total (up to 2 per organ), may be selected as New Lesions – Target.  The sum of 
diameters of these lesions will be calculated, and kept distinct from the sum of diameters for target 

 
 
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lesions at baseline.  All other new lesions will be followed qualitatively as New Lesions – Non-
target. 
Assessment at the Confirmatory Imaging 
On the confirmatory imaging, the participant will be classified as progression confirmed (with an 
overall response of iCPD), or as showing persistent unconfirmed progression (with an overall 
response of iUPD), or as showing disease stability or response (iSD/iPR/iCR). 
Confirmation of Progression 
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the following 
occurs: 
 
Any of the factors that were the basis for the initial iUPD show worsening 
o For target lesions, worsening is a further increase in the sum of diameters of ≥ 5 mm, 
compared to any prior iUPD time point 
o For non-target lesions, worsening is any significant growth in lesions overall, compared 
to a prior iUPD time point; this does not have to meet the “unequivocal” standard of 
RECIST 1.1 
o For new lesions, worsening is any of these: 
 
An increase in the new lesion sum of diameters by ≥ 5 mm from a prior iUPD time 
point  
 
Visible growth of new non-target lesions  
 
The appearance of additional new lesions 
 
Any new factor appears that would have triggered PD by RECIST 1.1 
Persistent iUPD 
Progression is considered not confirmed, and the overall response remains iUPD, if: 
 
None of the progression-confirming factors identified above occurs AND 
 
The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST v1.1) 
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the scan on which 
iUPD is seen.  This may correspond to the next visit in the original visit schedule.  The assessment 
of the subsequent confirmation scan proceeds in an identical manner, with possible outcomes of 
iCPD, iUPD, and iSD/iPR/iCR. 
Resolution of iUPD 
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if: 
 
None of the progression-confirming factors identified above occurs, AND 
 
The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold.  

 
 
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The response is classified as iSD or iPR (depending on the sum of diameters of the target lesions), 
or iCR if all lesions resolve. 
In this case, the initial iUPD is considered to be pseudo-progression, and the level of suspicion for 
progression is “reset”.  This means that the next visit that shows radiographic progression, 
whenever it occurs, is again classified as iUPD by iRECIST, and the confirmation process is 
repeated before a response of iCPD can be assigned. 
3. Management Following the Confirmatory Imaging 
If repeat imaging does not confirm PD per iRECIST, as assessed by the Investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the regular 
imaging schedule.  If PD is confirmed, participants will be discontinued from study treatment. 
NOTE: If a participant has confirmed radiographic progression (iCPD) as defined above, but the 
participant is achieving a clinically meaningful benefit, an exception to continue study treatment 
may be considered.  In this case, if study treatment is continued, tumor imaging should continue to 
be performed following the intervals as outlined in Section 6. 
4. Detection of Progression at Visits After Pseudo-progression Resolves 
After resolution of pseudo-progression (i.e., achievement of iSD/iPR/iCR), iUPD is indicated by any 
of the following events: 
 
Target lesions 
o Sum of diameters reaches the PD threshold (≥ 20% and ≥ 5 mm increase from nadir) 
either for the first time, or after resolution of previous pseudo-progression.  The nadir is 
always the smallest sum of diameters seen during the entire trial, either before or after 
an instance of pseudo-progression. 
 
Non-target lesions 
o If non-target lesions have never shown unequivocal progression, their doing so for the 
first time results in iUPD. 
o If non-target lesions had shown previous unequivocal progression, and this progression 
has not resolved, iUPD results from any significant further growth of non-target lesions, 
taken as a whole. 
 
New lesions 
o New lesions appear for the first time 
o Additional new lesions appear 
o Previously identified new target lesions show an increase of ≥ 5 mm in the new lesion 
sum of diameters, from the nadir value of that sum 
o Previously identified non-target lesions show any significant growth 
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging above) is repeated.  Progression 
must be confirmed before iCPD can occur. 

 
 
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CONFIDENTIEL 
The decision process is identical to the iUPD confirmation process for the initial PD, except in one 
respect. If new lesions occurred at a prior instance of iUPD, and at the confirmatory scan the 
burden of new lesions has increased from its smallest value (for new target lesions, their sum of 
diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve to iSD or iPR. It will remain 
iUPD until either a decrease in the new lesion burden allows resolution to iSD or iPR, or until a 
confirmatory factor causes iCPD. 
Additional details about iRECIST are provided in the iRECIST publication [Seymour et al, 2017]. 
 
 
 
iRECIST information: http://www.eortc.org/recist/irecist/ 
 
 
 

 
 
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CONFIDENTIEL 
 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
First radiologic evidence of PD 
by RECIST v1.1  
Repeat imaging at 4 to 
8 weeks to confirm PD. 
May continue study treatment at 
the Investigator’s discretion while 
awaiting confirmatory tumor 
imaging by site by iRECIST. 
Repeat imaging at 4 to 
8 weeks to confirm PD per 
Investigator’s discretion only. 
Discontinue treatment 
Repeat tumor imaging 
confirms PD (iCPD) by 
iRECIST per Investigator 
assessment 
No additional imaging 
required. 
Discontinue treatment (exception 
is possible upon consultation with 
Sponsor). 
No additional imaging 
required. 
Not applicable 
Repeat tumor imaging shows 
iUPD by iRECIST per 
Investigator assessment 
Repeat imaging at 4 to 
8 weeks to confirm PD.  May 
occur at next regularly 
scheduled imaging visit. 
Continue study treatment at the 
Investigator’s discretion. 
Repeat imaging at 4 to 
8 weeks to confirm PD per 
Investigator’s discretion only. 
Discontinue treatment 
Repeat tumor imaging shows 
iSD, iPR, or iCR by iRECIST 
per Investigator assessment. 
Continue regularly 
scheduled imaging 
assessments. 
Continue study treatment at the 
Investigator’s discretion. 
Continue regularly 
scheduled imaging 
assessments. 
May restart study treatment if 
condition has improved and/or 
clinically stable per Investigator’s 
discretion.  Next tumor image should 
occur according to the regular 
imaging schedule. 
iCPD = iRECIST confirmed progressive disease; iCR = iRECIST complete response; iRECIST = modified Response Evaluation Criteria in Solid Tumors 1.1 for immune-
based therapeutics; iSD = iRECIST stable disease; iUPD = iRECIST unconfirmed progressive disease; PD = progressive disease; RECIST v1.1 = Response Evaluation 
Criteria in Solid Tumors 1.1.. 
 
 

 
 
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CONFIDENTIEL 
 Toxicity criteria (NCI-CTCAE) 
 
 
 
In the present trial, adverse events will be recorded according to the 
Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0, (Published: 
November 27, 2017) 
 
Toxicity evaluation scale provided separately in attached documents or download it from 
the NCI website  
 
 
 
 
 
 
https://ctep.cancer.gov/ 
 

 
 
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CONFIDENTIEL 
 Dose modification and toxicity management guidelines for immune-related AEs associated with pembrolizumab 
 
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 immune-related adverse events (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 (CTCAEv5.0) 
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 
 
Evaluate participants with suspected 
pneumonitis with radiographic imaging 
and initiate corticosteroid treatment 
 
Add prophylactic antibiotics for 
opportunistic infections 
Grade 3 or 4, or recurrent 
Grade 2 
Permanently 
discontinue 
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 
Grade 4 
Permanently 
discontinue 

 
 
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CONFIDENTIEL 
Immune-related 
AEs 
Toxicity grade or 
conditions (CTCAEv5.0) 
Action taken to 
pembrolizumab 
irAE management with corticosteroid 
and/or other therapies  
Monitor and follow-up  
is not feasible, fluid and electrolytes 
should be substituted via IV infusion. 
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 1 
 
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 1 
Grade 2 
Withhold 
 Administer corticosteroids and initiate 
hormonal replacements as clinically 
indicated. 
 
Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism 
and adrenal insufficiency). 
Grade 3 or 4  
Withhold or 
permanently 
discontinue 2 
Hyperthyroidism 1 
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 
discontinue 2 
Hypothyroidism 1 
Grade 2-4 
Continue  
 Initiate thyroid replacement hormones 
(eg, levothyroxine or liothyroinine) per 
standard of care 
 
Monitor for signs and symptoms of 
thyroid disorders.  
 

 
 
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CONFIDENTIEL 
Immune-related 
AEs 
Toxicity grade or 
conditions (CTCAEv5.0) 
Action taken to 
pembrolizumab 
irAE management with corticosteroid 
and/or other therapies  
Monitor and follow-up  
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 
 
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. 
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). 
2. 
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. 
 

 
 
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CONFIDENTIEL 
 Dose modification and toxicity management of infusion-reactions related to pembrolizumab 
 
Pembrolizumab may cause severe or life threatening infusion-reactions including severe hypersensitivity or anaphylaxis. Signs and symptoms usually 
develop during or shortly after drug infusion and generally resolve completely within 24 hours of completion of infusion. Dose modification and toxicity 
management guidelines on pembrolizumab associated infusion reaction the table below. 
 
NCI CTCAE Grade 
Treatment 
Premedication at Subsequent Dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as medically indicated until the participant is 
deemed medically stable in the opinion of the investigator. 
None 
Grade 2 
Requires therapy or infusion 
interruption but responds promptly 
to symptomatic treatment (e.g., 
antihistamines, NSAIDs, 
narcotics, IV fluids); prophylactic 
medications indicated for ≤24 
hours 
Stop Infusion. 
Additional appropriate medical therapy may include but is not limited to: 
 
IV fluids 
 
Antihistamines 
 
NSAIDs 
 
Acetaminophen 
 
Narcotics 
Increase monitoring of vital signs as medically indicated until the participant is 
deemed medically stable in the opinion of the investigator. 
If symptoms resolve within 1 hour of stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate (e.g. from 100 mL/hr to 50 mL/hr). 
Otherwise dosing will be held until symptoms resolve and the participant should 
be premedicated for the next scheduled dose. 
Participants who develop Grade 2 toxicity despite adequate premedication 
should be permanently discontinued from further study drug treatment. 
Participant may be premedicated 1.5 hours 
(± 30 minutes) prior to infusion of vorinostat 
with: 
 
Diphenhydramine 50 mg orally (or 
equivalent dose of antihistamine). 
 
Acetaminophen 500-1000 mg orally (or 
equivalent dose of analgesic). 

 
 
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CONFIDENTIEL 
NCI CTCAE Grade 
Treatment 
Premedication at Subsequent Dosing 
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: 
 
Epinephrine** 
 
IV fluids 
 
Antihistamines 
 
NSAIDs 
 
Acetaminophen 
 
Narcotics 
 
Oxygen 
 
Pressors 
 
Corticosteroids 
Increase monitoring of vital signs as medically indicated until the participant is 
deemed medically stable in the opinion of the investigator. 
Hospitalization may be indicated. 
Participant is permanently discontinued from further study drug treatment. 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (Appendix 8). 
** In cases of anaphylaxis, epinephrine should be used immediately. 
 
 

 
 
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CONFIDENTIEL 
 Dose modification and toxicity management of drug reactions related to 
vorinostat 
 
 
ADVERSE REACTION 
MANAGEMENT 
GUIDELINES 
AND 
DOSE 
MODIFICATION ALGORITHMS 
Non hematologic toxicity 
Grade 1 
Continue at the same dose level 
Grade 2  
Continue at the same dose level. Consider introducing supportive 
therapies or concomitant medications if appropriate 
Intolerable Grade 2 
Grade 3 or 4 
(except for alopecia, nausea, vomiting, or 
diarrhea adequately controlled with systemic 
antiemetic/antidiarrheal medication) 
 1st occurrence : withhold current dose for up to 14 days until 
toxicity improves to grade ≤ 2 and then resume to the same 
dose or lower dose 
 2nd occurrence at the same dose: resume treatment at a lower 
dose after toxicity improves to grade ≤ 2. 
 If the patient continues to experience toxicity, additional dose 
reduction steps should be considered in accordance with table 
1.  
 If a patient continues to experience toxicity at the lower dose or 
if dosing with vorinostat is interrupted for >14 consecutive days 
due to toxicity, under optimal supportive therapy, then treatment 
should be permanently discontinued and patient observed until 
resolution 
Hematologic toxicity 
Grade 1 
Continue at the same dose level 
Grade 2  
 
Platelet count decreased 
Resume treatment at a lower dose after toxicity improves to grade 
≤ 1. 
Other hematological toxicities 
Continue at the same dose level. 
Intolerable Grade 2 
Grade 3 or 4 
 
 1st occurrence : withhold current dose for up to 14 days until 
toxicity improves to grade ≤ 2 and then resume to the same 
dose or lower dose 
 2nd occurrence at the same dose: resume treatment at a lower 
dose after toxicity improves to grade ≤ 2. 
 If the patient continues to experience toxicity, additional dose 
reduction steps should be considered in accordance with table 
1. 
 If a patient continues to experience toxicity at the lower dose or 
if dosing with vorinostat is interrupted for >14 consecutive days 
due to toxicity, under optimal supportive therapy, then treatment 
should be permanently discontinued and patient observed until 
resolution 
Recommended criteria for starting treatment cycles 
 
 ANC ≥1.0 x 109/L 
 Platelet count ≥75 x 109/L 
 Non-hematologic toxicities have returned to baseline or 
≤CTCAE Grade 1 severity or ≤CTCAE Grade 2 severity if not 
considered a safety risk for the patient. 

 
 
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CONFIDENTIEL 
 Translational studies 
The translational studies will allow the generation of a comprehensive dataset with mutational, epigenomic and 
expression profiles of the primary tumor and quantification of the viral load for each patient in order to: 
 
Assess the link between the tumor molecular profile including epigenetics features and immune 
parameters of the tumor microenvironment (TME) and the blood. 
 
Assess the link between immune-related biomarkers in the TME and blood (including but not limited 
to tumor tissue PD-L1 expression by IHC, RNA gene expression profiling and DNA mutation analysis), 
and measures of efficacy. 
 
Explore the modification of immune-related and molecular epigenetic biomarkers following treatment. 
 
Analyze the impact of TME and epigenetics parameters on sensitivity/response to treatment. 
 
Assess the predictive value of circulating biomarkers on sensitivity or resistance to treatment. 
All bioinformatics analyses will be centralized at Leipzig University in collaborations with Institut Curie. Data 
integration with a focus on confounding elements for the success of treatment with the pembrolizumab and 
vorinostat combination will be done. Confounding factors influencing the treatment's success will be translated 
onto biomarkers that can be easily analyzed prior to the start of a treatment. Even if there are no apparent 
differentially expressed genes or DMRs common to all cancer types, there are very likely common pathways 
that are affected.  
A/ WHOLE EXOME SEQUENCING 
STUDY COORDINATOR:  Istituto Europeo di Oncologia (IEO) 
CONTACT DETAILS: Luca Mazzarella , Department of Oncology and Hemato-Oncology - Division of Early 
Drug Development for Innovative Therapies, Via Ripamonti, 435, 20141, Milan , Italy. +39 0257489439, 
luca.mazzarella@ieo.it 
OBJECTIVES: TO ASSESS :  
1. tumor mutational load and mutational signatures, 
2. most frequently altered genes (SNV and CNV), and 
3. other molecular signatures (microsatellite instability [MSI], Homologous recombination deficiency 
[HRD], etc). Mutational signatures can point to malfunctioning mechanisms like DNA strand break 
repair, DNA mismatch repair or AID/APOBEC driven cytosin deamination in certain cancers. This 
can have an impact on treatment success. Likewise, SNVs, CNVs, MSI or HRD may also influence 
the applicability of certain drugs and may therefore be used as biomarkers. Molecular alterations 
detected at baselines will be followed in the ctDNA at different time points. 
SAMPLES REQUIRED:  Frozen tumors and blood (PBMC) at baseline as well as ctDNA 
SAMPLE STORAGE AND COLLECTION: Collected on study site and stored at IBBL 
PROCESSING OF SAMPLES: DNA will be extracted at IBBL and sent to EIO 
 
 
 
 

 
 
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CONFIDENTIEL 
B/ RNA SEQUENCING 
STUDY COORDINATOR:  Istituto Europeo di Oncologia (IEO) 
CONTACT DETAILS: Luca Mazzarella , Department of Oncology and Hemato-Oncology - Division of Early 
Drug Development for Innovative Therapies, Via Ripamonti, 435, 20141, Milan , Italy. +39 0257489439, 
luca.mazzarella@ieo.it 
OBJECTIVES: To assess changes in expression profile : 
1. Study gene expression,  
2. Identify splice variants, differential isoform usage, intron retention and fusion transcripts on both 
tumor and stromal components, and 3) analyse RNA editing and quantify allelic expression of SNVs 
and expression impact of CNVs. The existence or abundance of certain isoforms and the expression 
levels of certain genes are good candidates for biomarkers that can be used to choose a treatment. 
SAMPLES REQUIRED:  RNA from all patient’ frozen tumors at baseline, during treatment and at progression 
SAMPLE STORAGE AND COLLECTION: Collected on study site and stored at IBBL 
PROCESSING OF SAMPLES: RNA will be extracted at IBBL and sent to EIO 
 
C/ IHC ANALYSIS 
STUDY COORDINATOR:  ISTITUTO EUROPEO DI ONCOLOGIA (IEO) 
CONTACT DETAILS: Luca Mazzarella, Department of Oncology and Hemato-Oncology - Division of Early 
Drug Development for Innovative Therapies, Via Ripamonti, 435, 20141, Milan, Italy. +39 0257489439, 
luca.mazzarella@ieo.it 
OBJECTIVES:  
Expression profiles at different time points will be correlated to IHC analyses on FFPE samples. Several 
markers, but not limited to, CD45, CD8, CD68, PD-L1, PD-L2, CD3CD8FoxP3 and CD14CD33CD163 will 
be performed in addition to other panels specific to a cellular compartments (dendritic cell, T cell, myeloid 
cell, tumor…). 
SAMPLES REQUIRED:  FFPE samples from all patient at baseline, during treatment and at progression 
SAMPLE STORAGE AND COLLECTION: Collected on study site and stored at IBBL 
PROCESSING OF SAMPLES: Slide from FFPE tumour will be prepared by IBBL and send to IEO 
 
D/ GLOBAL AND GENOME-WIDE EPIGENETIC ANALYSIS 
STUDY COORDINATOR:  Istituto Europeo di Oncologia (IEO), Insitut Curie (IC) 
CONTACT DETAILS:  
Luca Mazzarella, Department of Oncology and Hemato-Oncology - Division of Early Drug Development for 
Innovative Therapies, Via Ripamonti, 435, 20141, Milan, Italy. +39 0257489439, luca.mazzarella@ieo.it 
 
Christophe LE TOURNEAU, Department of Drug Development and Innovation, 26 rue d’Ulm, 75005, Paris 
France, +33144324675,  christophe.letourneau@curie.fr 
 

 
 
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CONFIDENTIEL 
OBJECTIVES: To assess changes in expression profile : 
Global and genome-wide epigenetic analysis (techniques to be defined later) will be performed to evaluate 
the possible role of key epigenetic modifications as predictors of response to investigational drugs. 
Methylation data will be analyzed with respect to : 
1. Differentially methylated regions (DMRs) distinguishing cancer types.  
2. DMRs that do not correspond to the cancer types, but partition the data into groups that consist of 
examples from several cancer types. Methylation data from these DMRs are candidates for a 
correlation to treatment success. A global methylation pattern of samples will be extracted from the 
data, as well as the methylation status of promoters and gene bodies. 
SAMPLES REQUIRED:  DNA from all patients’ tumors at different time points 
SAMPLE STORAGE AND COLLECTION: Collected on study site and stored at IBBL 
PROCESSING OF SAMPLES: DNA will be extracted at IBBL and sent to EIO 
 
E/ CIRCULATING HPV 
STUDY COORDINATOR:  Institut Curie (IC) 
CONTACT DETAILS:  Christophe LE TOURNEAU, Department of Drug Development and Innovation, 26 rue 
d’Ulm, 75005, Paris France, +33144324675,  christophe.letourneau@curie.fr 
 
OBJECTIVES: Circulating HPV DNA (HPV ctDNA from plasma samples) levels will be assessed by droplet 
digital dPCR (ddPCR) on HPV positive patients at different time points. The HPV ctDNA concentration will 
be expressed in copies/mL of plasma. 
SAMPLES REQUIRED:  DNA from all patients’ tumors at different time points 
SAMPLE STORAGE AND COLLECTION: Collected on study site and stored at IBBL 
PROCESSING OF SAMPLES: DNA will be extracted at IBBL and sent to IC 
 
F/ HLA SEQUENCING 
STUDY COORDINATOR: Integrated BioBank of Luxembourg (IBBL) 
CONTACT DETAILS:  Kristin Kornerup, 1, Rue Louis Rech, L-3555, Dudelange, Luxembourg, 
Kristin.kornerup@ibbl.lu, +352 26 970 – 532 
 
OBJECTIVES: Ultrahigh resolution sequencing of 11 HLA Loci (Class I HLA-A, -B, -C; Class II HLA-
DRB1/3/4/5, -DQA1, -DQB1, -DPA1, -DPB1) will be performed at IBBL to provide important information on 
the patient’s HLA type and an indication of the likely response to immunotherapy. 
SAMPLES REQUIRED:  DNA from all patients’ at baseline 
SAMPLE STORAGE AND COLLECTION: Collected on study site and stored at IBBL 
PROCESSING OF SAMPLES: DNA will be extracted at IBBL and proceed at IBBL