Combination of MK3475 and Metronomic Cyclophosphamide in Patients With Advanced Sarcomas : Multicentre Phase II Trial
Phase: PHASE2
Conditions: Sarcoma
Sponsor: Institut Bergonié

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COMBINATION OF MK3475 AND METRONOMIC CYCLOPHOSPHAMIDE IN 
PATIENTS WITH ADVANCED SARCOMAS : MULTICENTRE PHASE II TRIAL 
Protocol PEMBROSARC 
VERSION N°11.0 DU |07|07|2021|- N° : IB 2014-04  
Intégrant la modification substantielle n°1 du 30/04/2015 
Intégrant la modification substantielle n°2 du 20/07/2015 
Intégrant la modification substantielle n°3 du 20/01/2016 
Intégrant la modification substantielle n°4 du 17/08/2016 
Intégrant la modification substantielle n°4.1 du 14/02/2017 
Intégrant la modification substantielle n°6.1 du 18/07/2018 
Intégrant la modification substantielle n°7 du 23/11/2018 
Intégrant la modification substantielle n°8 du 25/04/2019 
Intégrant la modification substantielle (MUS) n°9 du 31/01/2020 
Intégrant la modification substantielle (MSI) n°10 du 16/04/2020 
Intégrant la modification substantielle (MSI) n°11 du 04/06/2020 
Intégrant la modification substantielle n°12 du 08/06/2020 
Intégrant la modification substantielle n°13 du 25/09/2020 
Intégrant la modification substantielle n°14 du 22/01/2021 
Intégrant la modification substantielle n°15 du 07/07/2021 
EudraCT n° 2014-004568-39 
Coordinating Investigator 
Antoine ITALIANO, MD, PhD  
 Department of Medical Oncology 
Medical Oncologist 
Institut Bergonié 
229, cours de l’Argonne – 33076 BORDEAUX Cedex, France 
Tél : 05.56.33.78.05 – Fax : 05.56.33.04.85 – E-mail : a.italiano@bordeaux.unicancer.fr 
Scientific responsive 
Thomas GRELLETY, MD     
  Department of Medical Oncology 
Medical Oncologist 
Institut Bergonié 
229, cours de l’Argonne – 33076 BORDEAUX Cedex, France 
Tél : 05.56.33.78.05 – Fax : 05.56.33.04.85 – E-mail : t.grellety@bordeaux.unicancer.fr 
Clinical Research Unit 
Simone MATHOULIN-PÉLISSIER, MD, PhD 
Institut Bergonié, Bordeaux 
Head of the Unit 
Marina Pulido,Ms 
Institut Bergonié, Bordeaux 
Biostatistician senior 
Sabrina SELLAN-ALBERT, MSc 
Institut Bergonié, Bordeaux 
Clinical Reseach Assistant 
Pharmacovigilance 
Emilie TOULZA,  PharmD 
Institut Bergonié, Bordeaux 
SPONSOR 
INSTITUT BERGONIE 

 
 
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TABLE O F  C O N T E N T  
TABLE OF CONTENT .................................................................................................................................. 2 
APPROVAL AND SIGNATURES OF PROTOCOL ..................................................................................... 6 
SYNOPSIS .................................................................................................................................................... 8 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ...................................................................... 23 
1. 
RATIONALE OF THE TRIAL .............................................................................................................. 25 
1.1. 
MANAGEMENT OF SOFT TISSUE SARCOMA, OSTEOSARCOMA AND GASTROINTERTINAL STROMAL TUMORS 
IN THE ADVANCED SETTING ......................................................................................................................... 25 
1.2. 
METRONOMIC CYCLOPHOSPHAMIDE ................................................................................................. 26 
1.2.1. 
Background ............................................................................................................................ 26 
1.2.2. 
Structure and mechanism of action - Pharmacokinetics ....................................................... 26 
1.2.3. 
Preclinical and clinical data ................................................................................................... 26 
1.2.4. 
Safety ..................................................................................................................................... 27 
1.3. 
PEMBROLIZUMAB ............................................................................................................................. 27 
1.3.1. 
Pharmaceutical and therapeutic background ........................................................................ 27 
1.3.2. 
Rational for dose selection/regimen/modification .................................................................. 28 
1.4. 
G100 ............................................................................................................................................. 29 
1.4.1. 
Background ............................................................................................................................ 29 
1.4.2. 
Structure and mechanism of action of G100 - Glucopyranosyl Lipid A Stable Emulsion, 
GLA-SE 29 
1.4.3. 
Preclinical studies .................................................................................................................. 30 
1.4.4. 
Clinical studies ....................................................................................................................... 33 
1.4.5. 
Safety - Summary of Known and Potential Risks to Human Patients ................................... 35 
1.4.6. 
Rationale for G100 Therapy in combination with anti PDL1 and Radiotherapy in sarcoma . 36 
1.5. 
SARCOMA IMMUNE CLASSES ............................................................................................................ 37 
1.6. 
HYPOTHESIS ................................................................................................................................... 38 
2. 
OBJECTIVES ...................................................................................................................................... 40 
2.1. 
PRIMARY OBJECTIVE ........................................................................................................................ 40 
2.1.1. 
For treatment strategy A (strata 1 to 6) ................................................................................. 40 
2.1.2. 
For treatment strategy B (stratum 7) ..................................................................................... 40 
2.2. 
SECONDARY OBJECTIVES................................................................................................................. 40 
3. 
STUDY DESIGN .................................................................................................................................. 41 
4. 
SELECTION OF PATIENTS ................................................................................................................ 42 
4.1. 
INCLUSION CRITERIA ....................................................................................................................... 42 
4.1.1. 
For strata 1 to 5 ..................................................................................................................... 42 
4.1.2. 
For stratum 6 ......................................................................................................................... 43 
4.1.3. 
For stratum 7 ......................................................................................................................... 44 
4.2. 
EXCLUSION CRITERIA ...................................................................................................................... 45 
4.2.1. 
For strata 1 to 5 ..................................................................................................................... 45 
4.2.2. 
For stratum 6 ......................................................................................................................... 45 
4.2.3. 
For stratum 7 ......................................................................................................................... 46 
5. 
STUDY PLAN ...................................................................................................................................... 46 
5.1. 
DURATION OF STUDY (WHOLE POPULATION) .................................................................................... 46 
5.2. 
DEFINITIONS OF DURATION OF STUDY AND TREATMENT (PER PATIENT) .............................................. 47 
5.3. 
PROTOCOL DEVIATION ..................................................................................................................... 48 
5.4. 
SCREENING EVALUATION ................................................................................................................. 48 
5.5. 
EVALUATIONS DURING TREATMENT ................................................................................................... 50 
5.5.1. 
For strata 1 to 6 ..................................................................................................................... 50 
5.5.2. 
For stratum 7 ......................................................................................................................... 51 
5.6. 
EVALUATION AT THE END OF TREATMENT .......................................................................................... 52 
5.7. 
FOLLOW-UP AFTER END-OF-TREATMENT VISIT ................................................................................... 52 

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6. 
REGISTRATION PROCEDURES ....................................................................................................... 52 
6.1. 
SCREENING .................................................................................................................................... 52 
6.2. 
INCLUSION ...................................................................................................................................... 53 
7. 
STUDY TREATMENT .......................................................................................................................... 54 
7.1. 
DESCRIPTION OF TREATMENT........................................................................................................... 54 
7.2. 
PHARMACEUTICAL INFORMATIONS .................................................................................................... 54 
7.3. 
ADMINISTRATION OF TREATMENT ...................................................................................................... 54 
7.3.1. 
Cyclophosphamide ................................................................................................................ 55 
7.3.2. 
Pembrolizumab ...................................................................................................................... 55 
7.3.3. 
G100 ...................................................................................................................................... 55 
7.4. 
GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES ........................................ 56 
7.4.1. 
Acceptable concomitant medication ...................................................................................... 56 
7.4.2. 
Prohibited concomitant medication ........................................................................................ 56 
7.4.3. 
Restriction during the study ................................................................................................... 57 
7.4.4. 
Supportive care guideline for pembrolizumab ....................................................................... 57 
7.5. 
DOSING DELAYS/DOSE MODIFICATIONS AND ADVERSE EVENT MANAGEMENT ....................................... 60 
7.5.1. 
General rules for dose modification ....................................................................................... 60 
7.5.2. 
Immune related adverse event (irAE) .................................................................................... 62 
7.6. 
PACKAGING AND LABELING .............................................................................................................. 64 
7.7. 
SUPPLIES AND DRUG ACCOUNTABILITY ............................................................................................ 64 
7.8. 
TREATMENT COMPLIANCE ................................................................................................................ 64 
8. 
STUDY EVALUATIONS ...................................................................................................................... 65 
8.1. 
CENTRAL REVIEW FOR DIAGNOSIS OF SARCOMA/GIST AND PROGRESSIVE DISEASE ........................ 65 
8.1.1. 
Diagnosis ............................................................................................................................... 65 
8.1.2. 
Diagnosis of progressive disease – Central review before registration ................................ 65 
8.2. 
BIOPATHOLOGICAL CONFIRMATION FOR STRATUM 6 .......................................................................... 66 
8.2.1. 
General procedure ................................................................................................................. 66 
8.2.2. 
Review process schedule and practical implementation ....................................................... 66 
8.3. 
EFFICACY ....................................................................................................................................... 66 
8.3.1. 
Assessing Tumor Response (RECIST v1.1) ......................................................................... 66 
8.3.2. 
Centralized Radiological Review (Institut Bergonié) ............................................................. 66 
8.3.3. 
Assessing immune-related response by centralized Radiological Review (Institut Bergonié)
 
67 
8.4. 
SAFETY .......................................................................................................................................... 67 
9. 
STUDY ENDPOINTS ........................................................................................................................... 67 
9.1. 
PRIMARY ENDPOINT ......................................................................................................................... 67 
9.1.1. 
Advanced leiomyosarcoma (stratum 1) ................................................................................. 67 
9.1.2. 
Advanced undifferentiated sarcoma (stratum 2) ................................................................... 68 
9.1.3. 
Advanced other sarcoma (stratum 3) .................................................................................... 68 
9.1.4. 
Advanced osteosarcoma (stratum 4) ..................................................................................... 68 
9.1.5. 
Advanced GIST (stratum 5) ................................................................................................... 68 
9.1.6. 
Advanced soft tissue sarcomas with immune signature (stratum 6) ..................................... 68 
9.1.7. 
Metastatic STS (stratum 7) .................................................................................................... 68 
9.2. 
SECONDARY ENDPOINTS .................................................................................................................. 68 
10. 
STATISTICAL CONSIDERATIONS ................................................................................................ 70 
10.1. HYPOTHESES AND NUMBER OF SUBJECTS NEEDED ............................................................................ 70 
10.1.1. Advanced leiomyosarcoma (stratum 1) ................................................................................. 70 
10.1.2. Advanced undifferentiated sarcoma (stratum 2) ................................................................... 70 
10.1.3. Advanced other sarcoma (stratum 3) .................................................................................... 71 
10.1.4. Advanced osteosarcoma (stratum 4) ..................................................................................... 71 
10.1.5. Advanced GIST (stratum 5) ................................................................................................... 71 
10.1.6. Advanced soft tissue sarcomas with immune signature (stratum 6) ..................................... 72 
10.1.7. Metastatic STS (stratum 7) .................................................................................................... 72 
10.2. DEFINITION OF STUDY POPULATIONS ................................................................................................ 73 
10.2.1. Advanced leiomyosarcoma (stratum 1) ................................................................................. 73 
10.2.2. Advanced undifferentiated sarcoma (stratum 2) ................................................................... 73 
10.2.3. Advanced other sarcoma (stratum 3) .................................................................................... 73 

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10.2.4. Advanced osteosarcoma (stratum 4) ..................................................................................... 73 
10.2.5. Advanced GIST (stratum 5) ................................................................................................... 73 
10.2.6. Advanced soft tissue sarcomas with immune signature (stratum 6) ..................................... 73 
10.2.7. Metastatic STS (stratum 7) .................................................................................................... 73 
10.3. STATISTICAL ANALYSIS .................................................................................................................... 74 
10.3.1. Endpoint analysis ................................................................................................................... 74 
10.3.2. Interim Statistical Analyses .................................................................................................... 75 
11. 
ADVERSE EVENTS ......................................................................................................................... 77 
11.1. DESCRIPTION OF SAFETY EVALUATION CRITERIA ............................................................................... 77 
11.2. DEFINITION ..................................................................................................................................... 77 
11.2.1. Adverse event ........................................................................................................................ 77 
11.2.2. Serious adverse event ........................................................................................................... 77 
11.2.3. Non serious adverse event .................................................................................................... 78 
11.2.4. Adverse reaction .................................................................................................................... 78 
11.2.5. Expected/Unexpected character ........................................................................................... 78 
11.2.6. Intensity criterion .................................................................................................................... 79 
11.2.7. New information ..................................................................................................................... 79 
11.2.8. For trials of first administration or use of a health product in persons without any conditions: 
any serious adverse reactions. The study PEMBROSARC is not concerned by this situation.Causal 
relationship ........................................................................................................................................... 79 
11.2.9. Special considerations ........................................................................................................... 79 
11.3. SERIOUS ADVERSE EVENT AND NEW INFORMATION NOTIFICATION (RESPONSIBILITY OF THE 
INVESTIGATOR) .......................................................................................................................................... 80 
11.4. REPORTING PREGNANCY CASES OCCURRED WITHIN THE CLINICAL TRIAL............................................. 81 
11.5. REPORTING EVENTS OF CLINICAL INTEREST AND IMMUNE-RELATED ADVERSE EVENTS ......................... 82 
11.5.1. Cases of mediastinal lymph nodes ........................................................................................ 82 
11.6. NON SERIOUS ADVERSE EVENT ........................................................................................................ 83 
11.7. RESPONSIBILITY OF VIGILANCE UNIT AND SAE REPORTING ............................................................... 83 
11.8. REPORTING OF SAFETY DATA TO NATIONAL COMPETENT AUTHORITY AND ETHICS 
COMMITTEE (RESPONSIBILITY OF THE SPONSOR) ...................................................................................... 83 
12. 
QUALITY ASSURANCE AND TRIAL MONITORING ..................................................................... 83 
12.1. MONITORING OF THE TRIAL .............................................................................................................. 83 
12.1.1. Steering Committee ............................................................................................................... 83 
12.1.2. Independent Data Monitoring Committee .............................................................................. 84 
12.2. QUALITY ASSURANCE ...................................................................................................................... 84 
12.2.1. Data collection ....................................................................................................................... 84 
12.2.2. Monitoring .............................................................................................................................. 85 
12.2.3. Handling of missing data ....................................................................................................... 86 
12.2.4. Audits ..................................................................................................................................... 86 
13. 
REGULATORY ASPECTS AND ETHICAL CONSIDERATIONS ................................................... 87 
13.1. CLINICAL TRIAL AUTHORIZATION ....................................................................................................... 87 
13.2. INSURANCE POLICY.......................................................................................................................... 88 
13.3. INFORMING AND OBTAINING CONSENT FROM PATIENTS ...................................................................... 88 
13.4. SPONSOR’S RESPONSIBILITIES ......................................................................................................... 88 
13.5. INVESTIGATORS’ RESPONSIBILITIES .................................................................................................. 88 
13.6. AUTHORITY TO EXECUTE THE TRIAL .................................................................................................. 89 
13.7. REGULATIONS GOVERNING THE COLLECTION OF HUMAN BIOLOGICAL SAMPLES ................................... 89 
13.8. FÉDÉRATION DES COMITÉS DE PATIENTS POUR LA RECHERCHE CLINIQUE EN CANCÉROLOGIE 
(FCPRCC) (FEDERATION OF PATIENT COMMITTEES FOR CLINICAL RESEARCH IN ONCOLOGY) ...................... 90 
13.9. DATA PROCESSING .......................................................................................................................... 90 
14. 
CONFIDENTIALITY AND OWNERSHIP OF DATA ........................................................................ 91 
15. 
PUBLICATION AND VALORISATION ............................................................................................ 91 
15.1. SCIENTIFIC COMMUNICATION ............................................................................................................ 91 
15.2. INFORMATION TO PATIENTS .............................................................................................................. 91 
16. 
REFERENCES ................................................................................................................................. 92 

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17. 
TRANSLATIONAL STUDIES .......................................................................................................... 98 
17.1. BIOMARKER STUDY .......................................................................................................................... 98 
17.1.1. Collection of available specimen ........................................................................................... 98 
17.1.2. BM analysis ........................................................................................................................... 98 
17.2. PDL-1 EXPRESSION FOR STRATA 1 TO 5 ..................................................................................... 99 
17.2.1. Collection of specimen........................................................................................................... 99 
17.2.2. Handling and shipping of specimen ....................................................................................... 99 
17.2.3. Site performing PDL-1 expression research ......................................................................... 99 
17.2.4. PDL-1 expression analysis .................................................................................................... 99 
17.3. OPTIONAL BIOPSY FOR STRATA 1 TO 5 .............................................................................................. 99 
17.3.1. Collection of samples............................................................................................................. 99 
17.3.2. Handling and shipping of specimen ....................................................................................... 99 
17.3.3. Site performing PDL-1 expression research ......................................................................... 99 
17.4. MANDATORY BIOPSY FOR STRATA 6 TO 7 ........................................................................................ 100 
17.4.1. Collection of samples........................................................................................................... 100 
17.4.2. Handling and shipping of specimen ..................................................................................... 100 
17.4.3. Site performing analysis ...................................................................................................... 100 
17.4.4. Biomarkers expression analysis .......................................................................................... 100 
APPENDIX 1: ECOG PERFORMANCE STATUS ASSESSMENT SCALE ............................................ 101 
APPENDIX 2: EVALUATION OF RESPONSE. THE RECIST ................................................................. 102 
APPENDIX 3: SERIOUS ADVERSE EVENT FORM ............................................................................... 105 
APPENDIX 5: IMMUNE RELATED RESPONSE CRITERIA ................................................................... 109 
APPENDIX 6: PATIENT MEDICATION DIARY STRATEGY A ............................................................... 111 
APPENDIX 7: PATIENT MEDICATION DIARY STRATEGY B ............................................................... 115 
APPENDIX 8: EVENT OF CLINICAL INTEREST NOTIFICATION FORM .............................................. 119 
APPENDIX 9: DOSE MODIFICATION AND TOXICITY MANAGEMENT GUIDELINES FOR IMMUNE-
RELATED AES ASSOCIATED WITH PEMBROLIZUMAB ..................................................................... 120 
 

 
 
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APPROVAL AND SIGNATURES OF PROTOCOL  
Titre du protocole : Combination of MK3475 and Metronomic Cyclophosphamide in patients with 
Advanced Sarcomas: Multicentre Phase II trial. 
Competent 
authority 
Name : ANSM 
Date de l’autorisation initiale 
Autorisation de la modification substantielle 1 
Autorisation de la modification substantielle 2 
Autorisation de la modification substantielle 3 
Autorisation de la modification substantielle 4 
Autorisation de la modification substantielle 4.1 
Autorisation de la modification substantielle 5 
Autorisation de la modification substantielle 6.1 
Autorisation de la modification substantielle 7 
Autorisation de la modification substantielle 8 
Autorisation de la modification substantielle 9 
Autorisation de la modification substantielle 10 
Autorisation de la modification substantielle 11 
Autorisation de la modification substantielle 12 
Autorisation de la modification substantielle 13 
Autorisation de la modification substantielle 14 
18/02/2015 
24/07/2015 
09/09/2015 
10/03/2016 
09/03/2017 
27/04/2017 
20/12/2017 
30/07/2018 
29/01/2019 
07/06/2019 
18/02/2020 
NA 
NA 
12/08/2020 
03/11/2020 
10/02/2021 
Autorisation de la modification substantielle 15 
28/07/2021 
Référence :  
141573A-12 
Ethic  
Committee 
Name : CPP du Sud-
Ouest et d'Outre-Mer 
III 
Date de l’avis favorable initial 
Avis favorable de la modification substantielle 1 
Avis favorable de la modification substantielle 2 
Avis favorable de la modification substantielle 3 
Avis favorable de la modification substantielle 4 
Avis favorable de la modification substantielle 4.1 
Autorisation de la modification substantielle 6.1 
Autorisation de la modification substantielle 7 
Avis favorable de la modification substantielle 8 
Avis favorable de la modification substantielle 9 
Avis favorable de la modification substantielle 10 
Avis favorable de la modification substantielle 11 
Avis favorable de la modification substantielle 12 
Avis favorable de la modification substantielle 13 
Avis favorable de la modification substantielle 14 
17/12/2014 
27/05/2015 
26/08/2015 
24/02/2016 
26/09/2016 
29/03/2017 
29/08/2018 
30/01/2019 
29/05/2019 
19/02/2020 
NA 
NA 
26/08/2020 
25/11/2020 
24/02/2021 
Avis favorable de la modification substantielle 15 
25/08/2021 
Référence :  
2014/106 
 
Name and 
responsability 
Address 
Date 
Signature 
Managing 
Director 
Pr  François-Xavier MAHON 
Institut Bergonié – Bordeaux  
Tél:05.56.33.33.33 / Fax: 05.56.33.33.30 
 Mail :  f.mahon@bordeaux.unicancer.fr    
07/07/2021 
 
Scientific 
responsive 
Dr Thomas GRELLETY 
Institut Bergonié – Bordeaux  
Tél 05.56.33.78.05 / Fax : 05.56.33.04.85 
Mail : t.grellety@bordeaux.unicancer.fr 
07/07/2021 
 
Coordinating 
Investigator 
Pr Antoine ITALIANO  
Institut Bergonié – Bordeaux  
Tél 05.56.33.78.05 / Fax : 05.56.33.04.85 
 Mail : a.italiano@bordeaux.unicancer.fr  
07/07/2021 
 
Clinical 
Research 
Manager 
Pr Simone MATHOULIN-PÉLISSIER 
Institut Bergonié – Bordeaux  
Tél:05.56.33.33.98 / Fax: 05.56.33.04.66 
 Mail : s.mathoulin@bordeaux.unicancer.fr  
07/07/2021 
 

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Biostatistician 
senior  
Marina PULIDO 
Institut Bergonié – Bordeaux  
Tél:05.24.07.19.30/Fax:05.24.07.19.49 
 Mail : m.pulido@bordeaux.unicancer.fr     
07/07/2021 
 
Clinical 
Research 
Assistant 
Sabrina SELLAN-ALBERT 
Institut Bergonié – Bordeaux  
Tél:05.56.33.78.05/Fax:05.56.33.04.85 
 Mail : s.albert@bordeaux.unicancer.fr         
07/07/2021 
 
Pharmacist 
Emilie TOULZA 
Institut Bergonié – Bordeaux  
Tél:05.47.30.60.53/Fax: 05.24.07.19.08 
 Mail : e.toulza@bordeaux.unicancer.fr  
07/07/2021 
I acknowledge having read the whole protocol, and I pledge to lead this protocol in accordance with the Good 
Clinical Practice (decision of 24 November 2006), the Public Health Law No. 2006-806 of August 09, 2004 and the 
implementing Decree n° 2006-477 of April 26, 2006 and as described in this document.  
I assume my responsibilities as referent investigator including:  
- Collection of informed consent, dated and signed by patients before any selection procedure in the protocol, 
- Validation of case report forms, completed for each patient included in the study,  
- Direct access to source documents for verification by the clinical research assistant (CRA) commissioned by the 
sponsor,  
- Archiving of critical documents of the study for a 15 year-period. 
 
Name and address of the hospital 
 
Name of the Coordinating Investigator :  
 
Date : |__|__| |__|__| |__|__|__|__| 
 
Signature : 
 
 

 
 
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SYNOPSIS 
 
Title of the study  
Combination of MK3475 and Metronomic Cyclophosphamide in patients 
with Advanced Sarcomas : Multicentre Phase II  trial 
Abbreviation  
of the trial 
PEMBROSARC 
Sponsor 
Identification 
Institut Bergonié, Regional Comprehensive Cancer Center 
Coordinating 
Investigator 
Doctor Antoine ITALIANO  
Department of Medical Oncology 
Number of 
investigational 
sites planned 
8 centres:  
- Institut Bergonié, Pr Italiano  
- Centre Léon Bérard, Pr Blay 
- Institut Gustave Roussy, Dr Le Cesne 
- Centre Oscar Lambret, Dr Penel 
- Institut Curie, Dr Piperno-Neumann 
- Institut Paoli Calmette, Pr Bertucci 
- Institut Claudius Regaud, Dr Chevreau 
- Institut de Cancérologie de l’Ouest – Site René Gauducheau, Dr Bompas 
Note : for treatment strategy B, only 3 recruiting centers: 
- Institut Bergonié, Pr Italiano  
- Centre Léon Bérard, Pr Blay 
- Institut Gustave Roussy, Dr Le Cesne 
 
Number of patients 
Phase II, treatment by PEMBROLIZUMAB and Metronomic Cyclophosphamide 
(treatment strategy A), for each stratum: 
- 
Leiomyosarcoma : 33 patients 
- 
Undifferentiated sarcoma : 33 patients 
- 
Sarcomas others : 33 patients 
- 
Osteosarcoma : 33 patients 
- 
GIST : 31 patients 
- 
Advanced soft-tissue sarcomas with immune signature: 32 patients 
Phase II, treatment by PEMBROLIZUMAB, Metronomic Cyclophosphamide and 
G100 (treatment strategy B): 
- 
Metastatic soft-tissue sarcoma: 32 patients 
  
Duration of the 
study 
Planned enrollment period : 72 months 
Treatment duration : 2-years maximum 
Follow-up : 12 months 
Duration of study : 7 years 
Medical conditions 
Advanced /metastatic sarcomas: leiomyosarcoma, undifferentiated 
sarcoma, other sarcoma, GIST and osteosarcoma. 
Objectives 
 
Primary objective 
FOR TREATMENT STRATEGY A (STRATA 1 TO 6)  
Assessment 
of 
the 
efficacy 
of 
PEMBROLIZUMAB 
and 
Metronomic 
Cyclophosphamide (CP)  independently for 6 strata as per RECIST v1.1 criteria :  
 
Advanced leiomyosarcoma (in terms of 6-month objective response and 6-
month non-progression) 
 
Advanced undifferentiated sarcoma (in terms of 6-month objective 
response and 6-month non-progression) 
 
Advanced other sarcoma (in terms of 6-month objective response and 6-
month non-progression) 
 
Advanced osteosarcoma (in terms of 6-month objective response and 6-
month non-progression) 

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 
Advanced GIST (in terms of 6-month non-progression) 
 
Advanced soft-tissue sarcomas with immune signature (in terms of 6-
month non-progression) 
FOR TREATMENT STRATEGY B (STRATUM 7) 
Assessment 
of 
the 
efficacy 
of 
PEMBROLIZUMAB 
and 
Metronomic 
Cyclophosphamide (CP) + G100 in terms of 6-month non-progression (as per 
RECIST v1.1 criteria) in patients with metastatic soft-tissue sarcoma. 
 
Secondary objectives  
For each stratum 1 to 7: 
 
Assessment of the efficacy of the treatment strategy in terms of best 
overall response (as per RECIST v1.1 criteria), 1-year Progression-free 
survival (PFS, as per RECIST v1.1 criteria), 6-month immune-related 
response (Wolchok 2009; central radiological review data), and 1-year 
overall survival (OS).  
 
Assessment of the safety profile of the treatment strategy using the 
Common Terminology Criteria for Adverse Events (CTCAE) from the NCI 
v4.0. 
 
Assessment of the Growth modulation index (GMI), defined for each 
patient as the ratio of the PFS on the current treatment strategy to the PFS 
on the previous line of therapy (Von Hoff 1998), in patients with 
documented progression at inclusion. 
For each stratum 1 to 5: 
 
Translational research : pharmacodynamic (PD)/mechanism of action 
(MOA) biomarkers analysis as well as predictive biomarkers analysis (levels 
of angiogenic and immunologic biomarkers in blood at baseline and 
different study time points). 
 
Prospective determination of the proportion of STS that express PDL1.   
 
Identification of prognostic biomarkers of treatment response. 
For strata 6 and 7 : 
 
Translational research on blood and tumor tissue samples obtained at 
baseline and several time points during treatment for: 
- 
pharmacodynamic (PD)/mechanism of action (MOA) analysis 
assessing angiogenic and immunologic biomarkers, 
- 
identification of biomarkers predictive of treatment response. 
Study design  
 
This is a phase II trial with seven independent strata: 
 
FOR TREATMENT STRATEGY A (STRATA 1 TO 6):  
 
Advanced leiomyosarcoma (stratum 1) 
o 
Single-arm phase 2 trial 
o 
Treatment : PEMBROLIZUMAB + Metronomic CP at standard 
doses. 
o 
2-stage dual endpoint design (Goffin et al. 2008) 
 
Advanced undifferentiated sarcoma (stratum 2) 
o 
Single-arm phase 2 trial 
o 
Treatment : PEMBROLIZUMAB + Metronomic CP at standard 
doses. 
o 
2-stage dual endpoint design (Goffin et al. 2008) 
 
Advanced other sarcoma (stratum 3) 
o 
Single-arm phase 2 trial 
o 
Treatment : PEMBROLIZUMAB + Metronomic CP at standard 
doses. 
o 
2-stage dual endpoint design (Goffin et al. 2008) 

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 
Advanced osteosarcoma (stratum 4) 
o 
Single-arm phase 2 trial 
o 
Treatment : PEMBROLIZUMAB + Metronomic CP at standard 
doses. 
o 
2-stage dual endpoint design (Goffin et al. 2008) 
 
Advanced GIST (stratum 5) 
o 
Single-arm phase 2 trial 
o 
Treatment : PEMBROLIZUMAB + Metronomic CP at standard 
doses. 
o 
2-stage optimal Simon’s design (Simon, 1989) 
 
 Advanced soft-tissue sarcomas with immune signature (stratum 
6) 
o 
Single-arm phase 2 trial 
o 
Treatment : PEMBROLIZUMAB + Metronomic CP at standard 
doses. 
o 
2-stage optimal Simon’s design (Simon, 1989) 
 
FOR TREATMENT STRATEGY B (STRATUM 7): 
 
Metastatic soft-tissue sarcoma  
o 
Single-arm phase 2 trial 
o Treatment : PEMBROLIZUMAB + Metronomic CP at standard doses 
+ G100.  
o 
2-stage optimal Simon’s design (Simon 1989) 
Inclusion criteria 
For strata 1 to 5: 
1. Histology : Leiomyosarcoma, or UPS (undifferentiated pleomorphic sarcoma), 
or other sarcoma, or GIST (gastro intestinal stromal tumor) or osteosarcoma, 
histologically confirmed by central review (Pr Coindre team), except if the 
diagnosis was already confirmed by the RRePS Network, 
2. Advanced non resectable / metastatic disease 
3. Documented progression according to RECIST criteria. Progression on the last 
line of treatment should be confirmed by central review with two radiological 
assessments identical (CT scans or MRI) obtained at less than 6 months 
interval within the 12 months before inclusion. 
4. For stratum 5, documented disease progression according to RECIST criteria 
after the first line imatinib and second line sunitinib, 
5. Have provided tissue from an archival tissue sample obtained on metastasis or 
on locally advanced disease, or newly obtained core or excisional biopsy of a 
tumor lesion, 
6. For strata 1, 2 and 3: no more of four previous lines of systemic therapy for 
metastatic disease 
7. Age ≥ 18 years, 
8. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1, 
9. Measurable disease according to RECIST v1.1 outside any previously irradiated 
field. At least one site of disease must be uni-dimensionally ≥ 10 mm, 
10. Life expectancy > 3 months, 
11. For strata 1, 2 and 3 at least 1 previous line(s) of chemotherapy in the 
palliative setting 
12. No symptomatic central nervous system disease, 
13. No chronic use of glucocorticoids.  
14. Adequate hematological, renal, metabolic and hepatic function: 
a. Hemoglobin > 9 g/dl (patients may have received prior red blood cell [RBC] 
transfusion, if clinically indicated); absolute neutrophil count (ANC) > 1.5 x 
109/l and platelet count > 100 x 109/l,Alanine aminotransferase (ALT) and 
aspartate aminotransferase (AST) < 2.5 x upper limit of normality (ULN) (< 5 
in case of liver metastasis). 
b. Total bilirubin < 1.5 x ULN OR Direct bilirubin < ULN for subjects with total 
bilirubin levels > 1.5 x ULN. 
c. Albumin > 25g/l. 

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d. Serum creatinine < 1.5 x ULN OR Calculated creatinine clearance (CrCl) > 60 
ml/min (calculated per institutional standard) for subject with creatinine levels 
> 1.5 x ULN. 
e. Creatine phosphokinase (CPK) < 2.5 x ULN 
f. INR < 1.5 x ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use of 
anticoagulants 
g.  aPTT ≤ 1.5 X ULN unless subject is receiving anticoagulant therapy as long as 
PT or PTT is within therapeutic range of intended use of anticoagulants, 
h. Thyroid functions (T3, T4 and TSH) ≤ 1.5 x ULN and ≥ LLN. 
15. No prior or concurrent malignant disease diagnosed or treated in the last 2 
years except for adequately treated in situ carcinoma of the cervix, basal or 
squamous skin cell carcinoma, or in situ transitional bladder cell carcinoma, 
16. At least three weeks since last chemotherapy, immunotherapyor any other 
pharmacological treatment and/or radiotherapy, 
17. Recovery to grade ≤ 1 from any adverse event (AE) derived from previous 
treatment (excluding alopecia of any grade and non-painful peripheral 
neuropathy grade ≤ 2 (according to the National Cancer Institute Common 
Terminology Criteria for Adverse Event (NCI-CTCAE, version 4.0), 
18. Women of childbearing potential must have a negative serum pregnancy test 
within 72 hours prior to receiving the first dose of study medication. Both 
women and men must agree to use a medically acceptable method of 
contraception throughout the treatment period and for four months after 
discontinuation of treatment. Acceptable methods for contraception include 
intrauterine device (IUD), oral contraceptive, subdermal implant and double 
barrier. Subjects of childbearing potential are those who have not been 
surgically sterilized or have not been free from menses for ≥ 1 year. 
19. Voluntary signed and dated written informed consents prior to any specific 
study procedure, 
20. Patients with a French social security in compliance with the Law relating to 
biomedical research (Article 1121-11 of French Public Health Code). 
 
For stratum 6: 
1. Histology : soft-tissue sarcoma histologically confirmed by central review (Pr 
Coindre team), except if the diagnosis was already confirmed by the RRePS 
Network, 
2. Advanced non resectable / metastatic disease 
3. Documented progression according to RECIST criteria. Progression on the last 
line of treatment should be confirmed by central review with two radiological 
assessments identical (CT scans or MRI) obtained at less than 6 months 
interval within the 12 months before inclusion, except for patients with 
metastatic disease diagnosed less than 6 months before inclusion. 
4. Have provided tissue of a tumor lesion from an archival tissue sample obtained 
on metastasis or on locally advanced disease, or newly obtained core or 
excisional biopsy. Tissue < 3 months old and with no subsequent treatment 
since or from a newly obtained core or excisional biopsy, 
5. Presence of tertiary lymphoid structures on freshly obtained tumor biopsy or 
archival tumor material collected before any systemic treatment or radiation 
therapy, 
6. No more of four previous lines of systemic therapy for metastatic disease 
7. Age ≥ 18 years, 
8. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1, 
9. Measurable disease according to RECIST v1.1 outside any previously irradiated 
field. At least one site of disease must be uni-dimensionally ≥ 10 mm, 
10. Life expectancy > 3 months, 
11. Participant must have advanced disease and must not be a candidate for other 
approved therapeutic regimen known to provide significant clinical benefit 
based on investigator judgement, 
12. No symptomatic central nervous system disease, 

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13. No chronic use of glucocorticoids.  
14. Adequate hematological, renal, metabolic and hepatic function: 
a. Hemoglobin ≥ 9 g/dl (patients may have received prior red blood cell 
[RBC] transfusion, if clinically indicated); absolute neutrophil count (ANC) 
≥ 1.5 x 109/l and platelet count ≥ 100 x 109/l, 
b. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 
2.5 x upper limit of normality (ULN) (≤ 5 in case of liver metastasis). 
c. Total bilirubin ≤ 1.5 x ULN OR Direct bilirubin ≤ ULN for subjects with total 
bilirubin levels ≥ 1.5 x ULN. 
d. Albumin ≥ 25g/l. 
e. Serum creatinine ≤ 1.5 x ULN OR Calculated creatinine clearance (CrCl) ≥ 60 
ml/min (calculated per institutional standard) for subject with creatinine levels 
≥ 1.5 x ULN. 
f. Creatine phosphokinase (CPK) ≤ 2.5 x ULN 
g. INR ≤ 1.5 x ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use of 
anticoagulants 
h.  aPTT ≤ 1.5 X ULN unless subject is receiving anticoagulant therapy as long as 
PT or PTT is within therapeutic range of intended use of anticoagulants, 
i. Thyroid functions (T3, T4 and TSH) ≤ 1.5 x ULN and ≥ LLN. 
15. No prior or concurrent malignant disease diagnosed or treated in the last 2 
years except for adequately treated in situ carcinoma of the cervix, basal or 
squamous skin cell carcinoma, or in situ transitional bladder cell carcinoma, 
16. At least three weeks since last chemotherapy, immunotherapyor any other 
pharmacological treatment and/or radiotherapy, 
17. Recovery to grade ≤ 1 from any adverse event (AE) derived from previous 
treatment (excluding alopecia of any grade, non-painful peripheral neuropathy 
grade ≤ 2  and endocrine-related grade ≤ 2 requiring treatment or hormone 
replacement) (according to the National Cancer Institute Common Terminology 
Criteria for Adverse Event (NCI-CTCAE, version 4.0), 
18. Women of childbearing potential must have a negative serum pregnancy test 
within 72 hours prior to receiving the first dose of study medication. Both 
women and men must agree to use 2 medically acceptable methods of 
contraception throughout the treatment period and for 180 days after 
discontinuation of treatment. Subjects of childbearing potential are those who 
have not been surgically sterilized or have not been free from menses for ≥ 1 
year, 
19. Voluntary signed and dated written informed consents prior to any specific 
study procedure, 
20. Patients with a social security in compliance with the French Law. 
 
For stratum 7: 
1. Histology : soft-tissue sarcoma histologically confirmed by central review (Pr 
Coindre team), except if the diagnosis was already confirmed by the RRePS 
Network, 
2. Locally advanced or metastatic disease with at least one injectable lesion. Note 
that lesion must be cutaneous, subcutaneous or intramuscular. Nethertheless, 
it would be allowed to inject deeper lesion, either if patient is not on 
anticoagulation or per the guidelines in the protocol, the lesion is compressible; 
either if patient is on ASA or anti-platelet agent and the lesion is not 
compressing or involving organs or vessels, 
3. Documented progression according to RECIST criteria. Progression on the last 
line of treatment should be confirmed by central review with two radiological 
assessments identical (CT scans or MRI) obtained at less than 6 months 
interval within the 12 months before inclusion, except for patients with 
metastatic disease diagnosed less than 6 months before inclusion. 
4. Patients whose disease has progressed despite standard therapy and for whom 
no standard therapy exists, 
5. Have provided tissue of a tumor lesion from an archival tissue sample obtained 

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on metastasis or on locally advanced disease, or newly obtained core or 
excisional biopsy. Tissue < 3 months old and with no subsequent treatment 
since or from a newly obtained core or excisional biopsy 
6. No more than 2 previous lines of systemic therapy in the palliative setting, 
7. Age ≥ 18 years, 
8. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1, 
9. Measurable disease according to RECIST v1.1 outside any previously irradiated 
field. At least one site of disease must be uni-dimensionally ≥ 10 mm, 
10. Life expectancy > 6 months, 
11. At least 1 previous line(s) of chemotherapy in the palliative setting 
12. No symptomatic central nervous system disease, 
13. No chronic use of glucocorticoids.  
14. Adequate hematological, renal, metabolic and hepatic function: 
a. Hemoglobin ≥ 9 g/dl (patients may have received prior red blood cell 
[RBC] transfusion, if clinically indicated); absolute neutrophil count (ANC) 
≥ 1.5 x 109/l, leukocyte count ≥ 2.5 x 109/l and platelet count ≥ 100 x 
109/l, and lymphocyte count ≥ 0.5 x 109/l.  
b. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x 
upper limit of normality (ULN) (≤ 5 in case of liver metastasis). 
c. Total bilirubin ≤ 1.5 x ULN OR Direct bilirubin ≤ ULN for subjects with total 
bilirubin levels ≥ 1.5 x ULN. 
d. Albumin ≥ 25g/l. 
e. Serum creatinine ≤ 1.5 x ULN OR Calculated creatinine clearance (CrCl) ≥ 60 
ml/min (calculated per institutional standard) for subject with creatinine levels 
≥ 1.5 x ULN. 
f. Creatine phosphokinase (CPK) ≤ 2.5 x ULN 
g. INR ≤ 1.5 x ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use of 
anticoagulants 
h.  aPTT ≤ 1.5 X ULN unless subject is receiving anticoagulant therapy as long as 
PT or PTT is within therapeutic range of intended use of anticoagulants, 
i. Thyroid functions (T3, T4 and TSH) ≤ 1.5 x ULN and ≥ LLN. 
15. No prior or concurrent malignant disease diagnosed or treated in the last 2 
years except for adequately treated in situ carcinoma of the cervix, basal or 
squamous skin cell carcinoma, or in situ transitional bladder cell carcinoma, 
16. At least three weeks since last chemotherapy, and 14 days since last 
immunotherapy or any other pharmacological treatment and/or radiotherapy, 
17. Recovery to grade ≤ 1 from any adverse event (AE) derived from previous 
treatment (excluding alopecia of any grade and non-painful peripheral 
neuropathy grade ≤ 2 (according to the National Cancer Institute Common 
Terminology Criteria for Adverse Event (NCI-CTCAE, version 4.0), 
18. Women of childbearing potential must have a negative serum pregnancy test 
within 72 hours prior to receiving the first dose of study medication. Both 
women and men must agree to use 2 medically acceptable methods of 
contraception throughout the treatment period and for 180 days after 
discontinuation of treatment. Subjects of childbearing potential are those who 
have not been surgically sterilized or have not been free from menses for ≥ 1 
year.  
19. Voluntary signed and dated written informed consents prior to any specific 
study procedure, 
20. Patients with a social security in compliance with the French Law . 
 
Exclusion criteria 
For strate 1 to 5: 
1. Previous treatment with MK3475 or CP, 
2. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-
CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody 
(including ipilimumab or any other antibody or drug specifically targeting T-cell 
co-stimulation or checkpoint pathways), 

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3. Evidence of progressive or symptomatic central nervous system (CNS) or 
leptomeningeal metastases, 
4. Men or women of childbearing potential who are not using an effective method 
of contraception as previously described; women who are pregnant or breast 
feeding, 
5. Participation to a study involving a medical or therapeutic intervention in the 
last 30 days, 
6. Previous enrolment in the present study, 
7. Patient unable to follow and comply with the study procedures because of any 
geographical, familial, social or psychological reasons, 
8. Known hypersensitivity to any involved study drug or of its formulation 
components, 
9. Has an active autoimmune disease requiring systemic treatment within the 
past 3 months or a documented history of clinically severe autoimmune 
disease, or a syndrome that requires systemic steroids or immunosuppressive 
agents.  Subjects with vitiligo or resolved childhood asthma/atopy would be an 
exception to this rule.  Subjects that require intermittent use of bronchodilators 
or local steroid injections would not be excluded from the study.  Subjects with 
hypothyroidism stable on hormone replacement or Sjorgen’s syndrome will not 
be excluded from the study, 
10. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or 
any other form of immunosuppressive therapy within 7 days prior to the first 
dose of trial treatment, 
11. History of idiopathic pulmonary fibrosis, history of non-infectious pneumonitis 
that required steroids, drug-induced pneumonitis, organizing pneumonia, or 
evidence of active pneumonitis on screening chest CT scan. History of radiation 
pneumonitis in the radiation field (fibrosis) is permitted, 
12. Has known active hepatitis B or hepatitis C, 
13. Has a known history of Human Immunodeficiency Virus (HIV) (HIV1/2 
antibodies), 
14. Has received a live vaccine within 30 days prior to the first dose of trial 
treatment. 
 
For stratum 6: 
1. Previous treatment with PEMBROLIZUMAB 
2. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-
CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody 
(including ipilimumabor any other antibody or drug specifically targeting T-cell 
co-stimulation or checkpoint pathways), 
3. Evidence of progressive or symptomatic central nervous system (CNS) or 
leptomeningeal metastases, 
4. Men or women of childbearing potential who are not using an effective method 
of contraception; women who are pregnant or breast feeding, 
5. Participation to a study involving a medical or therapeutic intervention in the 
last 30 days, 
6. Previous enrolment in the present study, 
7. Patient unable to follow and comply with the study procedures because of any 
geographical, familial, social or psychological reasons, 
8. Known hypersensitivity to any involved study drug or of its formulation 
components, 
9. Has an active autoimmune disease requiring systemic treatment within the 

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past 3 months or a documented history of clinically severe autoimmune 
disease, or a syndrome that requires systemic steroids or immunosuppressive 
agents.  Subjects with vitiligo or resolved childhood asthma/atopy would be an 
exception to this rule.  Subjects that require intermittent use of bronchodilators 
or local steroid injections would not be excluded from the study.  Subjects with 
hypothyroidism stable on hormone replacement or Sjorgen’s syndrome will not 
be excluded from the study, 
10. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or 
any other form of immunosuppressive therapy within 7 days prior to the first 
dose of trial treatment, 
11. History of idiopathic pulmonary fibrosis, history of non-infectious pneumonitis 
that required steroids, drug-induced pneumonitis, organizing pneumonia, or 
evidence of active pneumonitis on screening chest CT scan. History of radiation 
pneumonitis in the radiation field (fibrosis) is permitted, 
12. Has known history of or is positive for Hepatitis B (HBsAg reactive) or Hepatitis 
C.  
13. Has a known history of Human Immunodeficiency Virus (HIV) infection (HIV1/2 
antibodies), 
14. Has received a live vaccine within 30 days prior to the first dose of trial 
treatment. 
15. Patients with oral anticoagulation therapy, 
16. Known urinary tract obstruction 
17. Previous allogenic bone marrow transplant or solid organ transplantation, 
18. Has an active infection requiring systemic treatment within 14 days prior to 
study entry. 
 
For stratum 7: 
1. Previous treatment with PEMBROLIZUMAB  or G100 
2. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-
CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody 
(including ipilimumabor any other antibody or drug specifically targeting T-cell 
co-stimulation or checkpoint pathways), 
3. Evidence of progressive or symptomatic central nervous system (CNS) or 
leptomeningeal metastases, 
4. Men or women of childbearing potential who are not using an effective method 
of contraception; women who are pregnant or breast feeding, 
5. Participation to a study involving a medical or therapeutic intervention in the 
last 30 days, 
6. Previous enrolment in the present study, 
7. Patient unable to follow and comply with the study procedures because of any 
geographical, familial, social or psychological reasons, 
8. Known hypersensitivity to any involved study drug or of its formulation 
components, 
9. Has an active autoimmune disease requiring systemic treatment within the 
past 3 months or a documented history of clinically severe autoimmune 
disease, or a syndrome that requires systemic steroids or immunosuppressive 
agents.  Subjects with vitiligo or resolved childhood asthma/atopy would be an 
exception to this rule.  Subjects that require intermittent use of bronchodilators 
or local steroid injections would not be excluded from the study.  Subjects with 
hypothyroidism stable on hormone replacement or Sjorgen’s syndrome will not 
be excluded from the study, 

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10. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or 
any other form of immunosuppressive therapy within 7 days prior to the first 
dose of trial treatment, 
11. History of idiopathic pulmonary fibrosis, history of non-infectious pneumonitis 
that required steroids, drug-induced pneumonitis, organizing pneumonia, or 
evidence of active pneumonitis on screening chest CT scan. History of radiation 
pneumonitis in the radiation field (fibrosis) is permitted, 
12. Has known history of or is positive for Hepatitis B (HBsAg reactive) or Hepatitis 
C.  
13. Has a known history of Human Immunodeficiency Virus (HIV) infection (HIV1/2 
antibodies), 
14. Has received a live vaccine within 30 days prior to the first dose of trial 
treatment. 
15. Patients with oral anticoagulation therapy, 
16. Known urinary tract obstruction. 
17. Previous allogenic bone marrow transplant or solid organ transplantation, 
18. Has an active infection requiring systemic treatment within 14 days prior to 
study. 
Route of 
administration 
Cyclophosphamide will be administered per os bi-daily (50 mg x 2), and given on a 
week on/ week off schedule. 
PEMBROLIZUMAB will be administered intraveinously, and given every 3 weeks on 
day 8. 
G100 will be administered by intra-tumoral injection (20µg), one weekly injection 
for at least 6 weeks and for a maximum of 12 weeks. Note that only one lesion 
can be treated. 
Treatment 
schedule 
TREATMENT STRATEGY A 
 
Regimen description  
Agent 
Dose 
Route 
Schedule 
Cycle 
length 
CP 
50mg x 2 
Per os 
Daily, 1 week on/1 week off 
3 weeks 
PEMBROLIZU
MAB 
200 mg 
IV 
On day 8, every 3 weeks 
 
TREATMENT STRATEGY B 
 
Regimen description  
Agent 
Dose 
Route 
Schedule 
Cycle 
length 
CP 
50mg x 2 
Per os 
Daily, 1 week on/1 week off 
3 weeks 
PEMBRO
LIZUMAB 
200 mg 
IV 
On day 8, every 3 weeks 
G100 
20µg 
ITum 
One weekly for at least 6 
weeks and for a maximum 
of 12 weeks 
Start one week before CP 
administration, ie. Day -7 
(“impregnation phase”) 
 

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A treatment cycle consists of 3 weeks. Treatment may continue until disease 
progression or study discontinuation (withdrawal of consent, intercurrent illness, 
unacceptable adverse event or any other changes rendering further treatment 
unacceptable, etc. see section 5.2). 
Endpoints 
 
Primary endpoint 
 
The primary efficacy endpoint for advanced leiomyosarcoma (stratum 1), 
advanced undifferentiated sarcoma (stratum 2), advanced other 
sarcoma (stratum 3), advanced osteosarcoma (stratum 4) is a dual 
endpoint encompassing non-progression and objective response at 6 
months (as per RECIST evaluation criteria v1.1). 
 
The primary efficacy endpoint for advanced GIST (stratum 5), Advanced 
soft-tissue sarcomas with immune signature (stratum 6) and 
metastatic STS (stratum 7) is 6-month non-progression (as per RECIST 
evaluation criteria v1.1). 
 
Non-progression: complete response, partial response or stable disease 
more than 24 weeks as per RECIST evaluation criteria v1.1. 
 
Objective response: complete response or partial response as per RECIST 
evaluation criteria v1.1. 
 
Following RECIST v1.1 recommendations:  
o claimed responses (complete or partial response) will  have to be 
confirmed at least 4 weeks later;  
o 6-month radiological data will be reviewed by an independent 
expert radiologist. 
o Primary efficacy analysis will be based on the central radiological 
review data. 
o Each patient will be assigned one of the following categories: 
Complete 
response, 
Partial 
response, 
Stable 
disease, 
Progression,not evaluated for response. 
 
Other endpoints 
For each stratum: 
 
Best overall response defined as per RECIST v1.1 criteria.  
 
1-year progression-free survival (PFS): PFS is defined as the time from study 
treatment initiation to the first occurrence of disease progression or death (of 
any cause), whichever occurs first. 
 
1-year overall survival (OS): OS is defined as the time from study treatment 
initiation to death (of any cause). 
 
Growth modulation index (GMI), defined for each patient as the ratio of the 
PFS on the current treatment strategy to the PFS on the previous line of 
therapy (Von Hoff, 1998), in patients with documented progression at 
inclusion. 
 
Immune-related response is defined following Wolchok et al. (Clinical Cancer 
Research 2009). Analysis will be based on data centrally reviewed by an expert 
radiologist. 
 
Toxicity will be graded using the Common Terminology Criteria for Adverse 
Events (CTCAE) from the NCI v4.0.  
 
For each stratum 1 to 5:Performance of pharmacodynamic (PD)/mechanism 
of action (MOA) biomarkers analysis as well as predictive biomarkers analysis 
(levels of angiogenic and immunologic biomarkers in blood at baseline and 
different study time points. Blood samples will be collected at predefined time 
points: 

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o  Serum/plasma cytokines levels (TNFγ, TNFα, TGFβ, IL2, 4, 6, 10) (ELISA) 
o Serum/plasma VEGF and TPS-1 levels (ELISA)  
o Treg, CD4+ CD8+ and DR lymphocytes subpopulations monitoring, 
CD8+/Treg ratio (flow cytometry)  
o Plasma levels of Kynurenine and Kynurenine to Tryptophan ratio (ELISA 
and LC/MS) 
 
Fresh pre-treatment (or archival material obtained from less than 12 weeks 
before inclusion) will be collected in consenting patients to assess 
pharmacodynamics biomarkers.  
 
Formalin-fixed, paraffin-embedded biopsy samples will be analysed for (but not 
limited to) PDL1, CSF-1R, CD68/CD163, CD68/MHC class II, CD31 (microvessel 
density), Ki67 and other exploratory markers. 
For strata 6 and 7: 
 
Performance 
of 
pharmacodynamic 
(PD)/mechanism 
of 
action 
(MOA) 
biomarkers analysis as well as predictive biomarkers analysis (levels of 
angiogenic and immunologic biomarkers) in blood and tumor tissue at baseline 
and different study time points. 
o  Blood samples will be mandatory collected at predefined timepoints for 
assessment of: 
- 
Serum/plasma cytokines levels (TNFγ, TNFα, TGFβ, IL2, 4, 6, 10) 
(ELISA) 
- 
Treg, CD4+ CD8+ and DR lymphocytes subpopulations monitoring, 
CD8+/Treg ratio (flow cytometry)  
- 
Plasma levels of Kynurenine and Kynurenine to Tryptophan ratio 
(ELISA and LC/MS) 
 
Fresh tumor samples will be mandatorily collected at baseline and during 
treatment. Formalin-fixed, paraffin-embedded biopsy samples will be analysed 
for (but not limited to) CD8+ effectors, CD68 and 163 Macrophages and 
FOXP3+ cells infiltrates as well as PDL1, IDO1, CD31 (microvessel density), 
Ki67 expression by IHC. Frozen samples will be analysed by (but not limited to) 
RNA sequencing in search for a predictive signature for response. 
 
Statistical 
considerations 
 
NUMBER OF SUBJECTS NEEDED  
 
Advanced leiomyosarcoma (stratum 1) 
 
Single-arm phase 2 trial 
 
2-stage dual endpoint design (Goffin et al. 2008).  
 
PEMBROLIZUMAB + metronomic CP will be considered promising if 6-month 
non-progression or 6-month objective reponse rate is promising 
 
30 eligible and assessable patients:  PEMBROLIZUMAB + metronomic CP will 
be considered worthy of further testing in this indication if at least 8 objective 
responses or at least 20 non-progressions at six months are observed among 
the 30 evaluable patients.  
 
In order to account for not evaluable patients (+/- 10%), 33 patients with 
advanced leiomyosarcoma will be recruited. 
 
Advanced undifferentiated sarcoma (stratum 2) 
 
Single-arm phase 2 trial 
 
2-stage dual endpoint design (Goffin et al. 2008).  
 
PEMBROLIZUMAB + metronomic CP will be considered promising if 6-month 

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non-progression or 6-month objective reponse rate is promising 
 
30 eligible and assessable patients:  PEMBROLIZUMAB + metronomic CP will 
be considered worthy of further testing in this indication if at least 8 objective 
responses or at least 20 non-progressions at six months are observed among 
the 30 evaluable patients.  
 
In order to account for not evaluable patients (+/- 10%), 33 patients with 
advanced undifferentiated sarcoma will be recruited. 
 
Advanced other sarcoma (stratum 3) 
 
Single-arm phase 2 trial 
 
2-stage dual endpoint design (Goffin et al. 2008).  
 
PEMBROLIZUMAB + metronomic CP will be considered promising if 6-month 
non-progression or 6-month objective reponse rate is promising 
 
30 eligible and assessable patients:  PEMBROLIZUMAB + metronomic CP will 
be considered worthy of further testing in this indication if at least 8 objective 
responses or at least 20 non-progressions at six months are observed among 
the 30 evaluable patients.  
 
In order to account for not evaluable patients (+/- 10%), 33 patients with 
advanced other sarcoma will be recruited. 
 
Advanced osteosarcoma (stratum 4) 
 
Single-arm phase 2 trial 
 
2-stage dual endpoint design (Goffin et al. 2008).  
 
PEMBROLIZUMAB + metronomic CP will be considered promising if 6-month 
non-progression or 6-month objective reponse rate is promising 
 
30 eligible and assessable patients:  PEMBROLIZUMAB + metronomic CP will 
be considered worthy of further testing in this indication if at least 8 objective 
responses or at least 20 non-progressions at six months are observed among 
the 30 evaluable patients.  
 
In order to account for not evaluable patients (+/- 10%), 33 patients with 
advanced osteosarcoma will be recruited. 
 
Advanced GIST (stratum 5) 
 
Single-arm phase 2 trial 
 
2-stage Simon’s design (Simon 1989).  
 
PEMBROLIZUMAB + metronomic CP will be considered promising if 6-month 
non-progression rate is promising 
 
28 eligible and assessable patients:  PEMBROLIZUMAB + metronomic CP will 
be considered worthy of further testing in this indication if at least 13 patients 
are progression-free (out of the 28 evaluable patients). 
 
Control arm: none 
 
In order to account for not evaluable patients (+/- 10%), 31 patients with 
advanced GIST will be recruited. 
 
Advanced soft-tissue sarcomas with immune signature (stratum 6) 
 
Single-arm phase 2 trial 
 
2-stage optimal Simon’s design (Simon, 1989).  
 
PEMBROLIZUMAB + metronomic CP will be considered promising if 6-month 
non-progression is promising. 
 
29 eligible and assessable patients:   
o 
Stage 1: Following the inclusion of the first 13 assessable patients, if 2 
or less patients are progression-free at 6 months (complete response, 
partial response or stable disease), the study will be terminated early. 
Otherwise, the second group of 16 subjects will be recruited.  
o 
PEMBROLIZUMAB + metronomic CP will be considered worthy of 
further testing in this indication if at least 8 non-progressions at six 
months are observed among the 29 evaluable patients.   

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 
In order to account for not evaluable patients (+/- 10%), 32 patients with 
sarcoma with immune signature will be recruited. 
 
Metastatic soft-tissue sarcoma (stratum 7) 
 
Single-arm phase 2 trial 
 
2-stage optimal Simon’s design (Simon, 1989).  
 
PEMBROLIZUMAB + metronomic CP + G100 will be considered promising if 6-
month non-progression is promising. 
 
29 eligible and assessable patients:   
o 
Stage 1: Following the inclusion of the first 13 assessable patients, if 2 
or less patients are progression-free at 6 months (complete response, 
partial response or stable disease), the study will be terminated early. 
Otherwise, the second group of 16 subjects will be recruited.  
o 
PEMBROLIZUMAB + metronomic CP + G100 will be considered worthy 
of further testing in this indication if at least 8 non-progressions at six 
months are observed among the 29 evaluable patients.   
 
In order to account for not evaluable patients (+/- 10%), 32 patients with 
metastatic soft-tissue sarcoma will be recruited. 
 
STATISTICAL ANALYSIS 
 
Each stratum will be analysed independently. No statistical comparison will be 
performed between strata. 
 
The primary efficacy endpoint will be analysed based on the eligible and 
assessable population and based on the central radiological review data.  
 
Efficacy will be assessed in terms of : 
o 
6-month objective response (complete response and partial response) 
and 6-month non-progression (complete response, partial response or 
stable disease more than 24 weeks) for leiomyosarcoma (stratum 1), 
undifferentiated sarcoma (stratum 2), other sarcoma (stratum 3), 
osteosarcoma (stratum 4) (dual endpoint).  
o 
6-month non-progression for GIST (stratum 5), advanced soft-tissue 
sarcomas with immune signature (stratum 6) and metastatic STS 
(stratum 7) (single endpoint). 
 
Objective response and non-progression are defined as per RECIST v1.1 
criteria. 
 
Each patient will be assigned one of the following categories: Complete 
response, Partial response, Stable disease, Progression, Not evaluated for 
response. 
 
The rates of objective response and non-progression at 6 months will be 
reported 
 
The safety analysis will be performed on the safety population.  
 
Interim Statistical Analyses 
 
Early review of safety data: for each therapeutic strategy (except for stratum 
6), safety data will be reviewed following the inclusion of the first 3 treated 
patient with at least 2-month follow-up data (independently of the stratum), 
then after 6 and 10 treated patients. 
Additionally, for each stratum, an interim statistical analysis will be performed at 
the end of the 1st stage of recruitment. Results of these interim statistical analyses 
will be presented to the IDMC members. 
 

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Schedule of assessments and procedures for treatment strategy A by the combination of PEMBROLIZUMAB plus metronomic cyclophosphamide 
 
SCREENING 
CYCLE 1 
CYCLE 2 
CYCLE 3 
CYCLE 4 
CYCLE N 
END OF 
TREATMENT 
W1 
W2 
W3 
W1 
W2 
W3 
W1 
W2 
W3 
W1 
W2 
W3 
W 
CP 50 mg (per os) 
 
D1 to D7 
 
D15 to D21 
 
D8 to D14 
 
D1 to D7 
 
D15 to D21 
 
D8 to D14 
 
1 week/2 
 
PEMBROLIZUMAB (i.v) 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
D8 
 
Consultation 
X 
D1 
 
D15 
 
 
 
D1 
 
 
 
 
 
D1f 
X 
Day-hospitalization 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
D8  
 
Written Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
history/baseline 
condition 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant treatments 
X 
X………………………………………………………………………………………….…………Throughout the study…………………………………………………………………..X 
 
Physical examination 
Xe 
X 
X 
X 
 
X 
 
X 
X 
 
 
X 
 
D1 f -D8 
X 
Assessment of signs and 
symptoms 
Xe 
 
X 
X 
 
X 
 
X 
X 
 
 
X 
 
D1 f -D8 
X 
Performance status (ECOG) 
Xe 
 
X 
X 
 
X 
 
X 
X 
 
 
X 
 
D1 f -D8 
X 
Vital signs (heart rate, blood 
pressure, temperature) 
Xe 
X 
X 
X 
 
X 
 
X 
X 
 
 
X 
 
D1 f -D8 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
Xe 
X 
X 
X 
 
X 
 
X 
X 
 
 
X 
 
D1 f -D8 
X 
Hematologya 
Xe 
X 
X 
X 
 
X 
 
X 
X 
 
 
X 
 
D1 f -D8 
X 
Biochemistryb 
Xe 
X 
X 
X 
 
X 
 
X 
X 
 
 
X 
 
D1 f -D8 
X 
Thyroid test: T3, T4 and TSH 
Xe 
X 
 
 
 
X 
 
 
X 
 
 
 
 
Every 3 cycles 
 
Urinalysisc 
Xe 
X 
X 
X 
 
X 
 
X 
X 
 
 
X 
 
D1 f -D8 
X 
ECG  
Xe 
Repeated if indicated 
 
Serum pregnancy test (if 
indicated) 
Xe 
Repeat if applicable 
 
Adverse Events 
 
X………………………………………………………………………………………….…………Throughout the study…………………………………………………………………..X 
X 
Tumor measurement 
Xd 
Repeated every 6 weeks. Documentation (radiologic) must be provided  for patients removed from study for progressive disease, and response 
must be confirmed  > 4 weeks 
 
PD 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
C6 and 
progression 
 
biopsy (optional for strata 1 
to 5) 
X 
 
 
 
 
D8 
 
 
 
 
 
 
 
 
 
a: NFS, platelets, PT/INR, aPTT 
b: albumin, total bilirubin (direct bilirubin in case of abnormality), uric acid, urea, calcium, chloride, creatinine, creatinine clearance, glucose, LDH, phosphorus, potassium, totalprotein, alkaline phosphatase, 
AST, ALT, GGT, sodium, magnesium, CPK 
c: blood, glucose, protein, specific gravity 
d: baseline tumor assessment should be performed within 28 days (+/- 1 week) before treatment initiation 
e:to be done or repeated in the 7 days before treatment initiation and within the 72 hours for pregnancy test 
f: one week/2 (CP administration) 

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Schedule of assessments and procedures for treatment strategy B by the combination of PEMBROLIZUMAB + metronomic CP + G100 
 
SCREENING 
IMPREGN
ATION 
D-7 
CYCLE 1 
CYCLE 2 
CYCLE 3 
CYCLE 4 
CYCLE N 
EOT 
W1 
W2 
W3 
W1 
W2 
W3 
W1 
W2 
W3 
W1 
W2 
W3 
W 
CP 50 mg (per os) 
 
 
D1 to D7 
 
D15 to D21 
 
D8 to D14 
 
D1 to D7 
 
D15 to D21 
 
D8 to D14 
 
1 week/2 
 
G100 (ITum) 
 
X 
D1 
D8 
D15 
D1 
D8 
D15 
D1 
D8 
D15 
D1 
D8 
 
 
 
PEMBROLIZUMAB (i.v) 
 
 
 
D8 
 
 
D8 
 
 
D8 
 
 
D8 
 
D8 
 
Consultation 
X 
X 
D1 
 
D15 
X 
 
 
D1 
 
 
 
 
 
D1f 
X 
Day-hospitalization 
 
 
 
D8 
 
 
D8 
 
 
D8 
 
 
D8 
 
D8  
 
Written Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
history/baseline 
condition 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant treatments 
X 
 
X………………………………………………………………………………………….…………Throughout the study…………………………………………………………………..X 
 
Physical examination 
Xe 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
X 
 
D1 f -D8 
X 
Assessment of signs and 
symptoms 
Xe 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
X 
 
D1 f -D8 
X 
Performance status (ECOG) 
Xe 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
X 
 
D1 f -D8 
X 
Vital 
signs 
(heart 
rate, 
blood 
pressure, 
temperature) 
Xe 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
X 
 
D1 f -D8 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
Xe 
X 
X 
X 
X 
 
X 
 
X 
X 
 
 
X 
 
D1 f -D8 
X 
Hematologya 
Xe 
X 
X 
X 
X 
 
X 
 
X 
X 
 
 
X 
 
D1 f -D8 
X 
Biochemistryb 
Xe 
X 
X 
X 
X 
 
X 
 
X 
X 
 
 
X 
 
D1 f -D8 
X 
Thyroid test: T3, T4 and TSH 
Xe 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
Every 3 cycles 
 
Urinalysisc 
Xe 
X 
X 
X 
X 
 
X 
 
X 
X 
 
 
X 
 
D1 f -D8 
X 
ECG  
Xe 
 
Repeated if indicated 
 
Serum pregnancy test (if 
indicated) 
Xe 
Xe 
Repeat if applicable 
 
Adverse Events 
 
 
X………………………………………………………………………………………….…………Throughout the study…………………………………………………………………..X 
X 
Tumor measurement 
Xd 
 
Repeated at week#9, week#18 and week#24, and every 6 weeks thereafter. Documentation (radiologic) must be provided  for patients removed from 
study for progressive disease, and response must be confirmed  > 4 weeks 
 
PD 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Xh 
 
Biopsy 
 
X 
 
 
 
Xi 
 
 
 
 
 
 
 
 
a: differential WBC, haemoglobin, platelets, PT/INR, aPTT 
b: Serum electrolytes (Na+, Mg++, K+, Cl-, Ca++ and phosphorus), liver function tests (AST, ALT, AP, GGT and total bilirubin/direct bilirubin), LDH, creatinine, glucose, total proteins, urea, uric acid, CPK, albumin and creatinine clearance 
c: blood, glucose, protein, specific gravity 
d: baseline tumor assessment should be performed within 28 days (+/- 1 week) before treatment initiation 
e:to be done or repeated in the 7 days before treatment initiation and within the 72 hours for pregnancy test 
f: one week/2 (CP administration) 
h: at cycle 6 and at progression 
i: At day 8 of cycle 2, except in case of irradiation. In case of irradiation, 1st on-treatment biopsy must be done before RT initiation and an additional biopsy must be performed within 3-4 weeks after RT termination. 
 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
AE (s) 
Adverse Event (s) 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
ANSM 
Agence Nationale de sécurité du Médicament 
AP 
Alkaline Phosphatase 
aPTT 
Activate Partial Prothrombin Time 
AST 
Aspartate Aminotransferase 
BCG 
Bacille de Calmette et Guérin 
BM 
Biomarker 
C 
Common 
CI 
Confidence Interval 
CNS 
Central Nervous System 
CP 
Cyclophosphamide 
CPP 
Ethic Committee 
CR 
Complete Response 
CRA 
Clinical Research Assistant 
CrCL 
Creatinine Clearance 
CRF 
Case Report Form 
CT 
Computerized Tomography 
CTLA 
anti-Cytotoxic T-lymphocyte-associated antigen 
DNA 
Deoxyribonucleic Acid 
DQF 
Data Query Form 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EMA 
European Medicines Agency 
EMEA 
European Medicines Evaluation Agency 
FFPE 
Formalin-Fixed Paraffin-Embedded 
FUP 
Follow-Up 
GCP 
Good Clinical Practice 
GGT 
Gamma Glutyl-transferase 
GIST 
Gastro Intestinal Stromal Tumour 
GMI 
Growth Modulation Index 
HCG 
Human Chorionic Gonadotropin 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IDMC 
Independent Data Monitoring Committee 
IEC 
Institutional Ethics Committee 
IHC 
Immunohistochemistry 
IMP 
Investigational Medical Product 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IrEICS 
Events of Clinical Interest Immune-related 
ITum 
Intratumoral 
ITIM 
Immunoreceptor Tyrosine-based Inhibition Motif 
ITSM 
Immunoreceptor Tyrosine-based Switch Motif 
IUD 
IntraUterine Device 
IV 
Intravenous 
LDH 
Lactate Dehydrogenase 
mAb 
Monoclonal Antibody 
MC 
Metronomic chemotherapy 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEL 
Melanoma 
MRI 
Magnetic Resonance Imaging 
MT 
Methotrexate 
MTD 
Maximum Tolerated Dose 

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NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NK 
Natural Killer 
NPR 
Non Progression Rate 
NSCLC 
Non-Small Cell Lung Cancer 
ORR 
Overall Response Rate 
OS 
Overall Survival 
OSS 
Osteosarcoma 
OTC 
Over The Count 
PD 
Progressive Disease 
PDGFR 
Platelet-Derived GrowthFactor Receptor 
PFS 
Progression Free Survival 
PK 
Pharmacokinetic 
PR 
Partial Response 
PRE TT 
Pre-Treatment 
PS 
Performance Status 
PT 
Prothrombin 
PTT 
Prothrombin Time 
Q2W 
Every two weeks 
RBC 
Red Blood Cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RRePS 
Réseau de Référence en Pathologie des Sarcomes des Tissus mous et des 
Viscères 
RT 
Radiotherapy 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SIC 
Sarcoma Immune Classes 
SmPC 
Summary Product Characteristic 
SPC 
Summary of Product Characteristics 
STS 
Soft Tissue Sarcoma 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TIL 
Tumor Infiltrating Lymphocyte 
U 
Uncommon 
ULN 
Upper Limit of Normality 
UPS 
Undifferentiated Pleomorphic Sarcoma 
US 
United States 
TNF 
Tumor Necrosis Factor 
TSH 
Thyroid Stimulating Hormon 
TT 
Treatment 
VEGF 
Vascular Endothelial Growth Factor 
 

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1. RATIONALE OF THE TRIAL 
1.1. MANAGEMENT 
OF 
SOFT 
TISSUE 
SARCOMA, 
OSTEOSARCOMA 
AND 
GASTROINTERTINAL STROMAL TUMORS IN THE ADVANCED SETTING 
Well-planned wide surgical excision complemented by adjuvant radiotherapy in cases of large (> 5 
cm) and/or deep tumors is the standard loco-regional treatment for soft-tissue sarcoma (STS) patients 
(1, 2). However, despite optimal local treatment, 40 to 50% of patients will develop metastatic 
disease (3). Doxorubicin is considered as the standard first-line therapy. Several chemotherapy 
regimens have been administered to patients with soft tissue sarcomas who have relapsed after being 
treated with first line chemotherapy. In 2007, the European Medicines Agency (EMA) approved 
trabectedin (ET-743, Yondelis®, Pharmamar, Madrid, Spain) for the treatment of patients with 
advanced STS after failure of anthracyclines and ifosfamide, or who are unsuited to receive these 
agents. This approval was based on phase 2 clinical trials showing a 6-months non-progression rate of 
about 30% (5-7). Pazopanib was more recently approved in both the US and European Union for the 
treatment of patients with soft tissue sarcomas (except liposarcomas) who have either not responded 
or were refractory to a doxorubicin-containing first line treatment regimen. Approval was based on a 
single phase 3 study comparing pazopanib to placebo in these patients. Neither arm demonstrated a 
significant ORR; pazopanib patients had a median PFS of 4.6 months (CI 3.7-4.8) compared to 
placebo (PFS 1.6 months; CI 0.9-1.8). The hazard ratio was 0.31, with a 95% CI of 0.24-0.40 
(p<0.0001). OS did not differ significantly between the two arms (8) Overall only few drugs have 
shown activity in the advanced setting (3) and the median overall survival has only slightly improved 
in the last 20 years from 12 months to 18 months. (1, 3). There is a compelling unmet medical need 
for effective therapy for patients with recurrent metastatic STS following chemotherapy. 
 
Osteosarcoma (OSS) is the most common primary malignancy of bone in children and adolescents, 
and the fifth most common malignancy among adolescents and young adults aged 15 to 19 (9). 
Indeed, OSS incidence rate has two peaks of about 4 per million per year, one in children and young 
adults ≤ 24 years, and the second after 60 (10). Use of chemotherapy in the neoadjuvant/adjuvant 
setting has dramatically improved overall survival (OS) in OSS. Most active agents in OSS are 
anthracyclines, platinum salts, ifosfamide and methotrexate given in combination in different protocols 
(11). At relapse, combination protocols with the same drugs are favoured when complete surgery of 
the metastases is considered achievable. However, patients (pts) not amenable to this strategy have a 
very poor prognosis and there is no standard therapy in this setting (12-14). 
 
Gastrointestinal stromal tumors (GIST) are the most frequent mesenchymal tumors of the 
gastrointestinal tract. In most cases of GIST, somatic mutations can be found in the gene encoding 
the KIT protein, typically in exons 11 and 9 (more rarely in exon 13 or exon 17) (15-16). These 
mutations confer a gain of function to the receptor, which becomes constitutively activated regardless 
of the presence of its ligand, stemcell factor. In some cases of GIST, no mutation is found in KIT. The 
search for additional molecular abnormalities led to the discovery that in many KIT-negative GIST 
there is a somatic mutation in the gene encoding the platelet-derived growthfactor receptor (PDGFR) 
(17-18). PDGFR is closely related to KIT, and also belongs to the type III family of receptor tyrosine 
kinases (19). Mutated KIT or PDGFR confer a growth advantage to tumor cells, and have recently 
become targets for therapeutic intervention. Imatinib is an oral tyrosine-kinase inhibitor that has 
revolutionized the treatment of GIST, since this drug is able to inhibit the tyrosine-kinase activities of 
KIT and PDGFR (18, 20, 21). Imatinib was approved in February 2002 for the treatment of patients 
with metastatic and/or unresectable GIST (22-23). 
Among patients with unresectable or metastatic disease at diagnosis, the ESMO guidelines 
recommend treatment with imatinib until disease progression (ESMO Guidelines, 2010). 
When there is disease progression, the ESMO guidelines recommend continuing tyrosine kinase 
inhibition with increased daily doses of imatinib (800 mg) or with sunitinib. However, resistance to 

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imatinib may develop and represents a clinical challenge. Sunitinib has been approved in 2009 by the 
European Commission for patients whose disease has progressed or who are intolerant to imatinib 
therapy. However, clinical progression and drug resistance to sunitinib subsequently evolve, generally 
within 1 year of treatment. More recently regorafenib was approved by the FDA for patients refractory 
to imatinib and sunitinib based on the results of a phase III of regorafenib versus placebo in patients 
who had progressed during sunitinib therapy. Progression-free survival on regorafenib (4.8 months) 
was significantly superior to that observed on placebo (0.9 month) but remained modest (24). 
Therefore, new treatments are needed.  
Overall there is a compelling unmet medical need for effective therapy for patients with recurrent 
metastatic mesenchymal tumors following standard treatment. Immunotherapy could represent a new 
efficient therapeutic strategy for this group of tumors (79, 80).  
 
1.2. METRONOMIC CYCLOPHOSPHAMIDE 
1.2.1. 
Background 
Metronomic chemotherapy (MC) is defined as frequent and regular administration of low dose of a 
cytotoxic agent (25). Cyclophosphamide (CP) is the cytotoxic the most widely used with a metronomic 
schedule. Metronomic CP combines both antiangiogenic and immunomodulatory properties that make 
it a ‘niche’ multi-targeted therapy interesting to explore both on the clinical and translational level (26-
30). Metronomic CP specifically decreases the number of circulating Treg, restores T cell proliferation, 
stable anti-tumor T–cell response and NK cell effector functions (30, 31). STS is the most frequent 
indication for routine use of metronomic CP in adult solid tumors, with a very favourable toxicity 
profile and encouraging results in prospective and retrospective studies (32-35). An EORTC sponsored 
clinical trial is under development to assess metronomic CP compared to doxorubicin in first line 
treatment of advanced STS. 
1.2.2. 
Structure and mechanism of action - Pharmacokinetics 
Cyclophosphamide (CP) is a nitrogen mustard alkylating agent from the oxazophorines group. CP 
mustard forms DNA crosslinks between and within DNA strands at guanine N-7 positions.  
Cytotoxic effects occur only after activation in the liver, where CP is converted by enzymes of the 
Cytochrome P450, (namely 2B6 and in a lesser extent 3A4/5) to active metabolites. The main active 
metabolite, 4-hydroxy-cyclophosphamide (4-OH-CP), exists in equilibrium with its tautomer 
aldophosphamide. Oral CP biodisponibility is > 75%. Its half-life is 4 to 7 hours. It does not bind to 
protein (12-14%) but its metabolites do (52-60%). CP is excreted principally (36–99%) in urine within 
48 hours, 5–30% as unchanged drug. 
1.2.3. 
Preclinical and clinical data 
Several preclinical studies demonstrated that low-dose CP has a selective effect against cycling 
vascular endothelial cells (26, 28, 27). Metronomic CP not only directly induces apoptosis of 
endothelial cells but also alters their functionality, inducing modifications in angiogenic signalling (29, 
36). 
In several tumor-bearing mice models, low-dose CP has also demonstrated an impact on immune 
dynamics that can be potentiated by administration of immuno-stimulant agents (37-42). Preclinical 
data showed that low-dose CP decreases levels of immunosuppressive lymphocytes “Treg” (CD4(+), 
CD25(High) Foxp3(+) regulatory T cells), as well as levels of immunosuppressive cytokines such as 
TGF-β, IL-10 and IL-2 produced by effector CD4 cells, and triggers T cell and INF-γ producing NK cell 
effector functions as well as maturation of dendritic cells (40-42). 
Oral CP is the most widely studied drug in metronomic regimen, and a large number of retrospective 
and prospective clinical studies have investigated metronomic CP in various tumors as single-agent or 
in combination, notably with methotrexate (MT) (35). Metronomic CP is also routinely used in 
advanced STS (32-35). Protocols include combination of oral CP (50 mg/d continuously) and MT (2.5 
mg b.i.d. on days 1 and 2 each week) (32), oral CP alone at 50mg b.i.d. continuously (33, 34, 43) or 

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at 100mg b.i.d. combined with 20mg of prednisolone both given one week/2 (34). The best efficacy 
has been demonstrated with the latter dose but 200 mg per day has been associated with loss of 
immuno-stimulating effect (30). Alternating schedule such as one week on /one week off appears to 
be the best tolerated and the most interesting in terms of immunological effects (30, 44, 45). 
Therefore CP given 50mg b.i.d on a one week on /one week off schedule appears to be the best 
compromise between efficacy and immunomodulatory effect when considering a combination. 
1.2.4. 
Safety 
Main toxicities of CP when used at conventional doses are listed below (Table 1). These toxicities are 
mostly dose-dependent with the most common being myelosuppression. Reported toxicities in 
published series and clinical trials assessing metronomic CP are very mild. In STS, Penel et al. 
reported 4% of grade 3/4 toxicities (33). With a higher dose, Mir et al. reported 7.7% grade 3/4 
anaemia or thrombocytopenia, no febrile neutropenia, and no organ impairment on treatment (34). 
Table 1 CP side effects at usual MTD doses 
Blood/bone marrow 
Leukocytopenia, thrombocytopenia, anaemia  
Gastro-intestinal 
C: Nausea, vomiting, anorexia, diarrhea, constipation, stomatitis  
U: Hemorrhagic colitis, oral ulceration  
Renal and urinary  
C: Hemorrhagic cystitis, micro/macro-haematuria 
Hepato-biliary  
U: Increase in SGOT, SGPT, gamma-GT, PAL, bilirubin 
Cardiac /respiratory  
U: Pneumonitis, interstitial pneumonia, chronic interstitial lung fibrosis 
Secondary malignancies 
U: carcinoma of urinary tract, myelodysplastic syndrome/acute leukemia 
Other side effects 
C: Alopecia (reversible), skin inflammation (palm of hand, finger nails, sole of foot), 
mucositis 
C: Common; U: Uncommon 
1.3. PEMBROLIZUMAB 
1.3.1. 
Pharmaceutical and therapeutic background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic transformation 
has been known for decades (46). Accumulating evidence shows a correlation between tumor-
infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in various malignancies (47-
51).  In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector T-cells / FoxP3+ 
regulatory T-cells seems to correlate with improved prognosis and long-term survival in many solid 
tumors. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control.  The normal function of PD-1, expressed on the cell surface of activated T-cells under healthy 
conditions, is to down-modulate unwanted or excessive immune responses, including autoimmune 
reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig superfamily member related to CD28 and 
CTLA-4 which has been shown to negatively regulate antigen receptor signaling upon engagement of 
its ligands (PD-L1 and/or PD L2) (52, 53).  The structure of murine PD-1 has been resolved (54).  PD-
1 and family members are type I transmembrane glycoproteins containing an Ig Variable-type (V-
type) domain responsible for ligand binding and a cytoplasmic tail which is responsible for the binding 
of signaling molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch 
motif (ITSM).  Following T-cell stimulation, PD 1 recruits the tyrosine phosphatases SHP-1 and SHP-2 
to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of effector molecules 
such as CD3ζ, PKCθ and ZAP70 which are involved in the CD3 T-cell signaling cascade (52, 55-57).  
The mechanism by which PD-1 down modulates T-cell responses is similar to, but distinct from that of 

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CTLA-4 as both molecules regulate an overlapping set of signaling proteins (58, 59).  PD-1 was shown 
to be expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs 
and Natural Killer cells (60, 61). Expression has also been shown during thymic development on CD4-
CD8- (double negative) T-cells as well as subsets of macrophages and dendritic cells (62).  The 
ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a variety of cell 
types, including non-hematopoietic tissues as well as in various tumors (63-65, 58).  Both ligands are 
type I transmembrane receptors containing both IgV- and IgC-like domains in the extracellular region 
and contain short cytoplasmic regions with no known signaling motifs.  Binding of either PD-1 ligand 
to PD-1 inhibits T-cell activation triggered through the T-cell receptor.  PD-L1 is expressed at low 
levels on various non-hematopoietic tissues, most notably on vascular endothelium, whereas PD-L2 
protein is only detectably expressed on antigen-presenting cells found in lymphoid tissue or chronic 
inflammatory environments.  PD-L2 is thought to control immune T-cell activation in lymphoid organs, 
whereas PD-L1 serves to dampen unwarranted T-cell function in peripheral tissues (58).  Although 
healthy organs express little (if any) PD-L1, a variety of cancers were demonstrated to express 
abundant levels of this T-cell inhibitor.  PD-1 has been suggested to regulate tumor-specific T-cell 
expansion in subjects with melanoma (MEL) (66).  This suggests that the PD-1/PD-L1 pathway plays a 
critical role in tumor immune evasion and should be considered as an attractive target for therapeutic 
intervention. 
PEMBROLIZUMAB (previously known as SCH 900475) is a potent and highly selective humanized 
monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction 
between PD-1 and its ligands, PD-L1 and PD-L2. 
 
As of today, PEMBROLIZUMAB is FDA approved in the treatment of metastatic melanoma, metastatic 
non-small lung cancer, recurrent or metastatic head and neck squamous cell carcinoma, urothelial 
bladder carcinoma, cancers molecularly defined as Microsatellite Instability-High (MSI-high) and 
mismatch repair-deficient (MMR-deficient), and classical Hodgkin lymphoma. 
1.3.2. 
Rational for dose selection/regimen/modification 
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and clinical 
activity of single agent PEMBROLIZUMAB.  The dose escalation portion of this trial evaluated three 
dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects with 
advanced solid tumors.  All three dose levels were well tolerated and no dose-limiting toxicities were 
observed.  This first in human study of PEMBROLIZUMAB showed evidence of target engagement and 
objective evidence of tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W).  
No MTD has been identified to date.  10.0 mg/kg Q2W, the highest dose tested in PN001, will be the 
dose and schedule utilized in Cohorts A, B, C and D of this protocol to test for initial tumor activity.  
Recent data from other clinical studies within the PEMBROLIZUMAB program has shown that a lower 
dose of PEMBROLIZUMAB and a less frequent schedule may be sufficient for target engagement and 
clinical activity. 
PK data analysis of PEMBROLIZUMAB administered Q2W and Q3W showed slow systemic clearance, 
limited volume of distribution, and a long half-life (refer to IB).  Pharmacodynamic data (IL-2 release 
assay) suggested that peripheral target engagement is durable (>21 days).  This early PK and 
pharmacodynamic data provides scientific rationale for testing a Q2W and Q3W dosing schedule.   
A population pharmacokinetic analysis has been performed using serum concentration time data from 
476 patients. Within the resulting population PK model, clearance and volume parameters of 
PEMBROLIZUMAB were found to be dependent on body weight. The relationship between clearance 
and body weight, with an allometric exponent of 0.59, is within the range observed for other 
antibodies and would support both body weight normalized dosing or a fixed dose across all body 
weights.  PEMBROLIZUMAB has been found to have a wide therapeutic range based on the melanoma 
indication.  The differences in exposure for a 200 mg fixed dose regimen relative to a 200 mg Q3W 
body weight based regimen are anticipated to remain well within the established exposure margins of 

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0.5 – 5.0 for PEMBROLIZUMAB in the melanoma indication. The exposure margins are based on the 
notion of similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. the proposed dose regimen of 
200 mg Q3W (i.e. 5-fold higher dose and exposure). The population PK evaluation revealed that there 
was no significant impact of tumor burden on exposure. In addition, exposure was similar between 
the NSCLC and melanoma indications. Therefore, there are no anticipated changes in exposure 
between different indication settings. 
1.4. G100 
1.4.1. 
Background 
The activation of immune responses in cancer patients has been challenging because DCs at the 
tumor site are often dysfunctional and unable to prime T cells efficiently. Several biological agents, 
such as CD40L, 4-1BBL, TNF, oligodeoxynucleotides containing certain unmethylated C-G motifs (CpG) 
[83] and toll-like receptor-4 (TLR4) agonists activate DCs and B cells by inducing their expression of 
costimulatory molecules and by triggering cytokine production. TLR4 agonists are particularly suited 
for this approach. (Figure 1). TLR4 is a cell surface receptor that is critical for the recognition of 
lipopolysaccharide (LPS), an integral component of gram-negative bacteria. TLR4 reside on the cell 
surface as opposed to TLR 9, a common target of CpGs, which is mainly expressed in the endosomal 
compartment. TLR4 agonists activate APCs and induce acute inflammatory responses including 
production of chemokines and cytokines that mediate inflammatory reactions. Activation of TLR4 
induces two distinct signaling pathways controlled by (i) MyD88/MAL which results in activation of 
nuclear factor (NF)-kB for induction of a number of NF-kB- dependent genes and inflammatory 
cytokines, and (ii) TRIF/ TRAM which induces production of type I interferons (IFN) [84] TLR4 also 
plays a non-redundant role in eliciting DC maturation, which is of key importance for effective priming 
naive T cells and initiating potent immune responses. Recent studies have demonstrated that both 
MyD88 and TRIF synergize for maximal DC activation. 
 
Figure 1: TLR Ligands and Signaling 
 
 
Toll-like receptors (TLRs) recognize bacterial and viral components. TLR ligands induce TLRs homodimer or 
heterodimer to trigger the activation of signaling molecules. TLR4 recognizes LPS to form a homodimer. TLR3, 
TLR7, and TLR9 localize in intracellular compartment and recognize pathogen-derived nucleotides like double-
strand RNA, single- strand RNA, and CpG-containing DNA, respectively. TLR1/TLR2, TLR2/TLR6, and TLR4 
activate MyD88 pathway through TIRAP, which is a membrane-association molecule, to induce inflammatory 
cytokines. In addition, TLR4 activates TRAM and TRIF to induce type I interferon through activating IRF3. (from 
Saitoh, Chapter 4, Innate Immune Regulation and Cancer Immunotherapy, Springer, Editor Wang). 
 
1.4.2. 
Structure and mechanism of action of G100 - Glucopyranosyl 
Lipid A Stable Emulsion, GLA-SE 
Immune Design’s G100 agent is a fully synthetic toll-like receptor-4 (TLR4) agonist that is a potent 
stimulator of innate immune responses. G100 consists of a stable emulsion (SE) formulation of GLA, 

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or glucopyranosyl lipid A, a fully synthetic glycolipid acyl component of endotoxin lipid A with the 
molecular formula of C96H184N3O22P and a molecular weight of 1,762.31 (Figure 2). G100 is 
manufactured by high-pressure micro-fluidization followed by filter-sterilization. It contains squalene 
(oil), glycerol, tocopherol (vitamin E), synthetic dimyristoylphosphatidylcholine (DMPC), surfactant 
(polaxamer) and ammonium phosphate buffer. The emulsion is filled aseptically into vials and appears 
as a milky-white liquid. 
GLA improves the immunogenicity of a wide variety of antigens by increasing the magnitude of the 
Th1 immune response marked by a high antigen-specific IgG2a:IgG1 ratio and increased production 
of IFN-γ, TNFα, and IL-12 compared to IL-4, IL-5, and IL-13.  
GLA has been extensively evaluated in human subjects formulated in stable oil-in-water emulsion or in 
an aqueous formulation and has been examined in over 1000 patients as an adjuvant for various 
infectious agent and cancer vaccines (Investigational Brochure, IB). G100 has been examined in 2 
ongoing clinical studies involving patients with Merkel cell carcinoma or sarcoma where it has been 
administered intratumorally either alone or in combination with local radiation therapy. It has 
demonstrated the ability to stimulate immune responses with an acceptable safety profile.  
In this study, G100 will be administered intratumorally in order to generate an immune response 
against endogenous tumor antigens. 
 
Figure 2: Structure of GLA 
 
 
 
1.4.3. 
Preclinical studies 
GLA has demonstrated activity as an intratumoral monotherapy in various preclinical models such as 
mouse tumor models of melanoma or various lymphoma (IB). GLA has also demonstrated an abscopal 
effect with intratumoral injection in mice with A20 lymphoma (IAS15-071) (Figure 3). 

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Figure 3: Abscopal Effects of GLA-SE Adminstered Intratumorally in Mouse A20 Lymphoma 
 
GLA-SE = Glucopyranosyl Lipid A stable emulsion; PBS = phosphate buffered saline; SC = subcutaneously; SE = 
stable emulsion Note: A20 tumor cells (5 × 106) were implanted SC at both the right and left of the flank. GLA-SE 
(10 μg of GLA in 2% SE) or vehicle control (SE) or PBS was injected to the tumor on the right side (treated 
tumor) three times a week for a total of three weeks. The graph on the top left shows tumor growth in treated 
tumors and the graph on the top right shows the tumor growth in the untreated tumors. The graph on the 
bottom shows the survival of the mice. ***, p<0.001; ****, p<0.0001 from control PBS group. 
 
Combination of intratumoral GLA-SE with systemic administration of anti-PD-1 mAb has also shown 
enhanced anti-tumor effects in various mouse models such as lymphoma (Figure 4). Combination of 
intratumoral GLA-SE with local irradiation also enhances anti-tumor effects in mouse models of 
melanoma and lymphoma (Figure 5). 

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Figure 4: Synergy Between Intratumoral Injection of GLA-SE and Systemic Administration of 
Checkpoint Inhibitors in Mouse A20 Lymphoma. 
 
GLA= Glucopyranosyl Lipid A; GLA-SE = Glucopyranosyl Lipid A stable emulsion; PBS = phosphate buffered 
saline; SE = stable emulsion; SEM = standard error of the means Note: Balb/c mice were inoculated with A20 
tumor cells (5 × 106) subcutaneously on both the right and left abdomen. Tumor growth was monitored with a 
digital caliper. Irradiation (10 Gy) was given on Day 10 to the tumor on the right side. Intratumoral injection of 
GLA-SE alone (10 μg of GLA in 2% SE) was given 3x/week starting on the day after irradiation, also on the right 
side. (A) Tumor growth curve of the tumors on the treated side. Shown are the group average (mean±SEM) in 
each group. (B) Tumor growth curve of the tumors on the untreated side. 
 

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Figure 5: Synergy Between Intratumoral Injection of GLA-SE and Local Irradiation in A20 lymphoma 
 
CD= cluster of differentiation; GLA = Glucopyranosyl Lipid A; i.p. = intraperitoneal; IT = intratumoral; mAb = 
monoclonal antibody; PD-1 = programmed death-1; SC = subcutaneously; SE = stable emulsion  
Note: BALB/c mice were inoculated with A20 tumor cells (5 × 106) subcutaneously on both the right and left of 
the abdomen. Tumor growth was monitored with a digital caliper. Treatment started on Day 6 after tumor 
inoculation when tumor reached 5-7 mm in the largest diameter. Mice were treated with GLA-SE alone (20 μg of 
GLA in 2% SE), anti-PD-1 mAb alone (clone RMP1-14, 150 μg), or GLA plus anti-PD-1 mAb. GLA was injected into 
the right tumor; anti-PD-1 mAb was injected intraperitoneally. Both agents were injected 3 times a week for a 
total of 5 injections. The graph on the top left shows tumor growth curve in the right tumor (treated, Tr). The 
graph on the top right shows tumor growth curve in the left tumor (untreated [NT]). The graph on the bottom 
shows overall survival in each group. *, p<0.05 from vehicle control group; ****, p<0.0001 from vehicle control 
group. 
1.4.4. 
Clinical studies 
G100 (GLA-SE used alone) is being evaluated as an IT immunotherapeutic product in cancer in Merkel 
cell carcinoma (MCC) and in sarcoma. 
In 2013, IMDZ opened a pilot study of IT GLA-SE (G100) in patients with MCC. In this study, patients 
with metastatic or locoregional MCC were enrolled and treated using 5 μg G100 prior to definitive 
planned surgery or radiation therapy. IMDZ is currently conducting a randomized study in follicular 
NHL that will examine up to 3 dose levels of G100 (5 μg, 10 μg, and 20 μg) following low dose local 
radiation therapy and a group will also receive pembrolizumab. A separate investigator sponsored 
study was initiated late 2014 in sarcomas. In this ongoing study, 3 G100 IT dose levels are being 
examined: 5 μg, 10 μg, and 20 μg/dose in combination with radiation therapy. 
A Phase 1 Trial of G100 in MCC, Protocol IDC-G100-2013-001  
This is a single-arm, open-label, single center pilot trial that assessed the safety of IT G100 injections 
in 10 patients with MCC and injectable lesions and examined the feasibility of this approach as an anti-
cancer immunotherapy. Eligible patients with MCC were enrolled into 2 cohorts, according to their 
disease status, and received G100 (5 μg total daily dose) intratumorally into MCC tumor(s) on 
treatment days as specified below:  
• COHORT A (Patients with loco-regional disease who were candidates for definitive therapy): Patients 
received IT G100 injections on Days 1 and 8 (± 2 days) followed by a post-treatment biopsy on Day 
22 (± 3 days). After the biopsy, the patients received definitive treatment that included surgery 
and/or radiation per standard care guidelines as determined by the team of treating physicians. Three 
patients with loco-regional disease were enrolled into Cohort A.  
• COHORT B (Patients with disseminated disease who were not candidates for definitive therapy): 
Seven patients have received IT G100 injections on Days 1, 8 (± 2 days), and 22 (± 2 days) over a 6-
week long cycle. A post-treatment biopsy was obtained on Day 22 (± 3 days) of the first cycle. These 
patients had their first overall tumor response assessment at week 6 (± 1 week) after the first 
injection. 
In this study, treatment was completed on all 10 planned patients and long-term follow-up continues. 
An update on the data from the 10 patients was reported at ASCO 2016 (IB). No DLTs or treatment-
related SAEs occurred and nearly all reported related AEs were grade 1 or 2. There was 1 possibly 

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related grade 3 AE consisting of mild skin breakdown at the site of injection and possibly associated 
with the tumor biopsy site. As of 18-May-2016, of the patients with locoregional disease, 3/3 patients 
successfully completed G100 followed by surgery plus RT; of these, 2 patients are free of recurrence 
(27.5+ and 23+ months). One patient (002) had a pathologic CR following two G100 injections alone. 
Of the 7 patients with metastatic disease, 2 have had ongoing objective responses (17+ and 18+ 
months) after G100 therapy and are in follow-up; 5/7 had progressive disease (PD). One patient with 
a partial response (PR) had a 28% regression in the injected tumor following G100 alone in the first 
cycle, suggesting an anti-tumor response from G100 monotherapy. This response was also associated 
with increased IT infiltration of CD8+ T cells. The injected lesion regressed completely after the 
second cycle, which consisted of radiotherapy plus G100. In this pilot study of MCC, IT administration 
of G100 demonstrated an acceptable safety profile and was associated with encouraging anti-tumor 
activity. 
 
A Phase 1/2 Trial of G100 in NHL, Protocol IMDZ-G142  
The overall goal of this study is to evaluate the safety and immunogenicity of repeat-dose 
intratumoral G100 administration in patients with NHL following standard local radiation therapy.  
In Part 1: Dose Escalation, two dose levels of G100 will be examined, 5 μg and 10 μg, using a 
standard 3+3 dose escalation design. Treatments consist of weekly intratumoral injections for 6 to 9 
doses.  
In Part 2, two groups of patients will be examined. In the first group, Patient Expansion With Or 
Without Pembrolizumab, up to 24 patients will be treated with G100 at the MTD or maximum safe 
dose determined in Part 1. In this portion of the study, patients will be randomized to receive either 
intratumoral G100 alone, or intratumoral G100 and sequential anti-PD-1 antibody therapy. This 
portion of the study is designed to be exploratory. The main goal of Part 2, Patient Expansion With Or 
Without Pembrolizumab, is to gain safety information regarding these approaches to allow planning 
for future studies with these agents. The G100 treatment regimen will be identical to that used in Part 
1, Dose Escalation. For patients randomized to receive pembrolizumab, the anti-PD-1 antibody begins 
on day 14 and follows a standard every 3-week schedule. In the second group, Part 2, Large Tumor, a 
higher dose of G100 (20μg) may be examined. If the G100 dose consisting of 10 μg of the GLA 
component is determined to be the maximal safe dose and the DMC agrees, an optional treatment 
group for Large Tumor patients will be treated. In this group, up to 4 patients with injectable 
lymphoma mass(es) >4 cm in total size (based on the sum of the measurements of the single 
greatest dimension of each the tumor(s)) will be enrolled and will receive G100 consisting of 20 μg of 
the GLA component per dose. This will allow greater distribution of the G100 within the large tumor 
mass(es) and the examination of safety and dose effect. Following the G100 course of treatment, if 
the patient meets certain eligibility requirements they may be able to receive an optional second 
course of therapy without radiation as a boost.  
Enrollment and safety evaluation of Part 1 (Dose Escalation) was completed in June 2016. On 21 June 
2016, an independent DMC reviewed all safety data following the DLT observational period for each 
cohort and determined that there were no safety issues with the 5 or 10 μg dose levels. The DMC 
recommended that Part 2 of the study could open and that the 10 μg dose could be used. They also 
recommended that the Part 2 Large Tumor group be open to use the 20 μg dose. 
As of 08-August-2016, Part 1 (Dose Escalation) has been completed and Part 2 is enrolling and 
treating patients. Three patients in Cohort 1 (5 μg/dose) and 3 patients in Cohort 2 (10 μg/dose) were 
sequentially enrolled in Part 1 (Dose Escalation) of the study. Two patients have been enrolled in the 
randomized portion of the study comparing G100 with G100 + pembrolizumab. Therefore, a total of 8 
patients have been or are being treated in this study. 
 
A Phase 1 Trial of G100 in Sarcoma  
This investigator-sponsored study, ongoing at the Fred Hutchinson Cancer Research Center, is a 
phase 1, pilot study examining the safety and efficacy of IT G100 in combination with or without 
radiation in patients with metastatic sarcoma.  
Patients requiring therapy and who have planned palliative radiation to a tumor mass that is also 
accessible for injection are eligible. The primary endpoint is the safety of G100 injected into the 
tumor. In the original protocol, patients were treated with full dose radiation to their tumor site with 
doses typically administered over 10-14 days. G100 was then given in 8 weekly injections beginning 
just prior to radiation. This study was originally designed to examine the 5 μg dose of G100. The 
protocol was then amended to examine 10 and 20 μg doses of G100 and was further amended to 
examine the effect of 20 μg/dose when given as a course of G100 intratumorally before radiation. As 
of November 2016, the study has enrolled 6 subjects in the 5 μg dose cohort and 6 subjects into the 

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10 μg dose cohort. The 20 μg dose cohort is currently enrolling and at the time of this report at least 
3 subjects are being treated at this dose level. 
 
1.4.5. 
Safety - Summary of Known and Potential Risks to Human 
Patients 
Over 1000 human subjects have been injected with GLA in either the SE formulation (GLA SE) or a 
second aqueous formulation (AF), with or without antigen. Dosing has ranged from 0.5 to 10 μg with 
repeat dosing and has primarily been given SC or IM. Eleven patients have received up to 7 doses of 
5µg G100 intratumorally with or without local radiation. More than 270 human subjects treated with 
GLA in different regimens (with or without antigen and via different dosing methods) have had 1 year 
of systematic post-vaccination follow-up, and there have been no long latency AEs or autoimmune or 
inflammatory AEs. (Table 1). 
 
Table 1: Total Subjects Treated and Total Doses of GLA Administered to Human Subjects Through 
August 2014 
Study 
Treatment 
 
Exposure 
N 
Any 
GLA 
Product 
Total 
doses 
administered 
2299 
 
Total subjects treated 
1065 
 
GLA 0.5 µg  
6 
 
GLA 1.0 µg  
274 
 
GLA 2.0 µg  
332 
 
GLA 2.5 µg  
63 
 
GLA 5.0 µg  
349 
 
GLA 10.0 µg  
41 
 GLA-AF 
Total 
doses 
administered 
576 
 
Total subjects treated 
255 
 GLA-SE 
Total 
doses 
administered 
1723 
 
Total subjects treated 
810 
 
The majority of the human experience to date with GLA has been as an adjuvant with infectious agent 
or cancer associated protein antigens. The most commonly observed AEs have been injection site 
reactions of mild to moderate severity using the conservative “2007 FDA Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials.” The only 
laboratory abnormalities of note have been transient increases in acute phase reactants (C-reactive 
protein [CRP] and fibrinogen) and peripheral blood neutrophils. 
The safety findings across multiple studies including different formulations of GLA suggest that the 
dose response for GLA safety will vary with different co-administered antigens. The 5 μg dose of GLA-
SE administered with a complex and highly immunogenic influenza (Fluzone®) split virus resulted in 3 
of 4 subjects developing Grade 2 AEs (2007 Preventive Vaccine Grading Scale above) of arthralgia, 
myalgia, fatigue, and chills. However, an investigator-initiated study performed in Brazil has indicated 
that 50 μg of recombinant hookworm protein administered with a 10 μg dose of GLA-SE 3 times over 
2 months was well tolerated. Fewer than 4% of AEs reported in association with GLA containing 
vaccines have been considered Grade 3 or higher in severity. 
The AEs considered expected include injection site reactions, fever, fatigue, chills, myalgia, and 
arthralgia. There are insufficient data to date to establish that the safety profile is substantially 
different when GLA-SE is administered by either the IM or subcutaneous route of administration or as 
the SE or AF formulation. 
Twenty-five SAEs have been reported from all GLA-SE clinical trials to date, most temporally 
dissociated from vaccination and no reports considered possibly, probably or definitely related to GLA 
treatment. The majority of these events were elective hospitalizations for surgical procedures. One 
SAE has been reported within 2 weeks of vaccine administration: A 37-year-old female was enrolled 
and vaccinated, with 3.8 μg investigational recombinant avian influenza protein + 1.0 μg GLA-SE and 

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eight days later was observed overnight in a hospital setting, where cardiac enzymes and 
electrocardiogram (ECG) were normal. The patient was discharged with ibuprofen 800 mg, aspirin 325 
mg, and omeprazole 40 mg with a discharge diagnosis of costochondritis. 
In separate pilot studies, intratumoral injections of 5µg G100 have been administered to patients with 
Merkel cell carcinoma and to patients with advanced sarcoma. As of February 5, 2015, 11 patients 
have been enrolled and treated in these ongoing studies. Six patients have received G100 treatment 
before, during and after radiation therapy. No grade 3 or higher adverse events have been reported 
and the majority of events have consisted of grade 1 or 2 local reaction, pain and fatigue. In early 
results, 1 patient with biopsy proven, locoregional Merkel cell carcinoma was found to have a 
pathologic CR following resection of the treated lesion. Tumor-specific cytotoxic T cells were found in 
a draining lymph node adjacent to the tumor mass, supporting the concept that clinically meaningful 
induction of anti-tumor immune activity can be achieved by this approach. 
 
1.4.6. 
Rationale for G100 Therapy in combination with anti PDL1 
and Radiotherapy in sarcoma 
Intratumoral administration of TLR4 agonists can activate local DCs and other immune cells to react to 
local cancer cells despite the immunosuppressive nature of the tumor microenvironment. This 
approach has the potential to stimulate immune responses against known “specific” as well as 
previously unrecognized “endogenous” tumor antigens. This locally generated anti-tumor response 
would be expected to result in a systemic immunity and lead to regression of distal untreated lesions 
(abscopal response). In preclinical models and in ongoing clinical studies of Merkel cell carcinoma and 
sarcoma patients, intratumoral G100 has demonstrated early evidence of clinical activity with a 
reasonable safety profile. 
 
Rationale for anti-PD-1 Therapy and Proposed Schedule 
Clinically, anti-PD-1/L1 blocking antibodies are active as a single agent but are limited in their ability to 
induce objective responses (CR and PR). For this treatment to have a clinical effect, it is hypothesized 
that tumor-reactive T cells are present, but are being suppressed by this pathway. Blocking this axis 
would restore anti-tumor immunity. One theory that can explain why anti-PD1/L1 blocking antibodies 
do not result in higher response rates is that non-responding patients do not have pre-existing 
effective anti-tumor T cells present that are being suppressed15. As a corollary, if more patients had 
pre-existing anti-tumor immune responses, then these anti-PD-1/L1 agents could potentially be more 
effective. In patients with cancer, the PD-1/L1 pathway would be expected to diminish any anti-tumor 
immune response, and it stands to reason that CD8 T cells generated by the immune response to 
G100 would eventually be affected by this pathway. Therefore, G100 activity might be enhanced by 
blocking the PD-1/L1 pathway, especially in the presence of tumor or cells within the tumor 
microenvironment expressing PD-L1. This effect can be demonstrated in tumor-bearing animals, 
where blocking PD-1 in combination with active immunization with G100 controlled tumor growth 
significantly better than animals treated with G100 alone (Figure 6). 
Figure 6: Intratumoral G100 plus check point inhibitors in the B16 Melanoma Model 
 
On Day 0, B6 mice were injected with 5 x 105 B16F10 cells, footpad. On Day 4 and every 3-4 days thereafter, G100 (5 µg 
GLA/2% SE) was administered intratumorally either with or without anti-PD-1, anti-PD-L1, anti-CTLA4 (2 antibody clones) or 

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control (100ug intraperitoneal injection). The anti-tumor effect of anti-PD-1, anti-PD-L1 and anti-CTLA4 antibodies were additive 
or synergistic when combined with G100. 
 
There is reasonable rationale that an optimal dose schedule of an active immune approach with an 
anti-PD-1/L1 may require that a T-cell response be induced before introducing PD-1/L1 blockade.  
 
Rationale for Radiotherapy with Intratumoral G100 
Recent studies with CpGs (a TLR9 agonist) administered intratumorally plus local radiation therapy 
have been associated with tumor responses at local and distant sites, both in mycosis fungoides [85] 
and B cell lymphoma [86]. Local radiation therapy is thought to increase tumor immunogenicity by 
inducing tumor cell apoptosis and death and thereby releasing endogenous tumor antigens for cross-
presentation by local DCs. In addition, radiation can increase tumor MHC Class I expression and help 
facilitate DC migration [87]. 
As discussed, G100 is a very potent TLR4 agonist that can promote the stimulation of DCs and 
immune effector cells. The combination of intratumoral G100 and radiation would be expected to 
augment the release of tumor antigens and enhance cross-presentation by DCs and the effective 
stimulation of anti-tumor immunity. TLR4 agonists may have an advantage over TLR9 agonists such 
as CpGs in this approach. TLR4 reside and are accessible on the cell surface as opposed to TLR 9, 
which is mainly expressed in the endosomal compartment. TLR4 agonists also stimulate both the 
MyD88 and TRIF pathways leading to broad immune stimulation through NF-kB and induction of type 
I interferon (Figure 1: TLR Ligands And Signaling). 
 
Rationale for use of this approach in sarcoma 
Historically, sarcoma represent the first tumor model for which immunotherapy has been suggested as 
a relevant therapeutic strategy. In 1866, Busch et al. described tumor shrinkage in sarcoma patients 
suffering from postoperative wound infections. In 1891, Coley et al. reported the first description of 
immunotherapy of malignant tumors. The highest incidence of sarcoma in immunocompromised 
people such as allograft transplant recipient or HIV positive individuals supports also the relevance of 
the immune system in this disease. Approaches currently developed in immunotherapy for sarcoma 
with anti-PD1 have shown that using antiPD1 alone is not sufficient despite CD8 effectors cells present 
on site. This suggests other mechanisms imparing efficacious immune response. A synergistic 
approach with TLR4 agonist could help trigger more efficacious CD8 effectors activity and obtain a 
better antitumor immune response in these tumors. 
 
1.5. SARCOMA IMMUNE CLASSES 
We have recently reported a comprehensive analysis of transcriptomic data of four independent 
publicly-available complex genomic STS and used these data to propose an immune classification of 
STS (93). This classification highlighted 5 sarcoma immune classes (SIC) differing in the level of 
immune infiltration. Tumours of SIC C2 exhibit the largest infiltrate of CD8+ T cells), and expresses 
the PDCD1 gene (coding for PD-1) more highly than tumours of any other SIC. Thus, we hypothesized 
that this immune classification can predict response to immunotherapy and that tumours of SIC C may 
respond better to treatment with PD-1 blockade compared to tumours of SIC A or B. An analysis of 15 
pretreatment STS biopsies from the SARC028  clinical trial15 which enrolled  patients with advanced, 
unresectable sarcomas who were treated with the anti-PD-1 monoclonal antibody pembrolizumab was 
performed. Pretreatment tumours were characterized and classified by SIC. Of these 15 patients, 1 
achieved complete response (CR), 3 partial response (PR), 4 stable disease (SD) and 7 had 
progressive disease (PD) (Fig. 7). All 4 patients who achieved objective clinical response by RECIST 
(CR or PR) were found to be assigned to SIC C2, and all C2 tumours responded to anti-PD-1 therapy. 
Of the 4 patients who achieved SD, 3 had tumours assigned to SIC A1 and 1 to SIC B (Fig 7). 
Patients with tumours classified as SIC C had a significantly longer PFS compared to SIC A (p=0.0079, 
log-rank test, Fig. 7) and trended towards longer PFS compared to SIC B (p=0.0574, although only 2 
tumours were assigned to SIC B). 
 
Among responders, 2 patients achieving 100% reduction in the target lesions (Fig. 7) (including 1 
patient who had non-CR in non-target lesions but -100% change in target lesions and thus did not 
qualify for CR) (94). 
 

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Figure. 7: SIC are accurate predictors of STS response to PD-1 blockade therapy. 
This figure refers to the SARC028 cohort (n=15). a Progression-free survival of patients from the SARC028 trial, depending on 
the SIC group of their tumours. b Relationship between SIC, histology and response to treatment in the SARC028 cohort. c 
Waterfall plot showing the best response to pembrolizumab as percentage change of target lesions from baseline in size. 
Tumour sizes were calculated as the sum of target lesion diameters. The colours indicate the SIC to which each tumour was 
assigned. Dashed lines indicate +20%, -30% and -100% change from baseline levels. DDLPS: dedifferentiated liposarcoma, 
LMS: leiomyosarcoma, UPS: undifferentiated pleomorphic sarcoma, SS: synovial sarcoma. 
 
These results indicate that SIC is associated with patient outcome and accurately predicts response to 
PD-1 blockade therapy. The presence of tertiary lymphoid structures (TLS) is an important hallmark of 
the immune high group that responds to immunotherapy; this enables identification of this population 
by generic immunohistochemistry. Overall, these findings lay the foundation for a tool to risk-stratify 
STS patients, identify those who may be more likely to benefit from immunotherapies, inform clinical 
decision-making, and can guide future immunotherapy drug development in STS.  
 
1.6. HYPOTHESIS 
Recent studies have shown that PDL1 is expressed to 58% of cases of STS, osteosarcomas and GIST 
(67-69). This overexpression has been associated with poor prognosis. Besides, preliminary 
unpublished data from our lab corroborates the finding that a proportion of STS express PDL1 
(Italiano, personal communication), leading to speculate that drugs targeting this immune checkpoint 
would be of great interest in these tumors and particularly in complex genomics sarcomas (including 
leiomyosarcomas, undifferentiated sarcomas). Targeting the PD1/DPL1 interaction was associated 
with impressive anti-tumor activity in a pre-clinical model of osteosarcoma (70).  Metronomic CP has 

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shown a synergistic effect on immuno-stimulation when combined with immunotherapies such as 
oncolytic adenovirus (44) or survivin HLA-I peptides vaccine (45) and a French NCI sponsored trial is 
underway with metronomic CP in association with an oncolytic virus in breast cancer and STS. 
Metronomic CP has also shown synergy with the antitumor effect of an anti- PD1 antibody in a pre-
clinical model (71). 
 
We therefore hypothesized that the association of metronomic CP and PEMBROLIZUMAB could have a 
synergistic antitumor, antiangiogenic and immuno-stimulating activity together with excellent toxicity 
profile in patients with advanced or metastatic STS, osteosarcoma and GIST. 
Preliminary results of ancillary studies from the PEMBROSARC trial on strata 1, 2 , 3 , 5 (Toulmonde et 
al. Jama Oncol 2017, In Press) demonstrated a moderate and differential expression of PD-L1 in 
specific subtypes of sarcomas. Importantly there was a high correlation between efficacy and PD-L1 
expression on immune cells. 
 
Several studies have recently highlighted the complex relationship between epigenetics and immune 
checkpoint expression and activity [88-90]. Epigenetic therapy drugs not only boost immune attraction 
properties of cancer cells, they also exert important Regulation of Host Immune Cells themselves [91]. 
 

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2. OBJECTIVES 
2.1. PRIMARY OBJECTIVE 
2.1.1. 
For treatment strategy A (strata 1 to 6)  
Assessment of the efficacy of PEMBROLIZUMAB and Metronomic Cyclophosphamide (CP) 
independently for 6 strata (as per RECIST v1.1 criteria):  
 
Advanced leiomyosarcoma (in terms of 6-month objective response and 6-month non-
progression), 
 
Advanced undifferentiated sarcoma (in terms of 6-month objective response and 6-month 
non-progression), 
 
Advanced other sarcoma (in terms of 6-month objective response and 6-month non-
progression), 
 
Advanced osteosarcoma (in terms of 6-month objective response and 6-month non-
progression), 
 
Advanced GIST (in terms of 6-month non-progression). 
 
Advanced soft-tissue sarcomas with immune signature (in terms of 6-month non-progression) 
2.1.2. 
For treatment strategy B (stratum 7) 
Assessment of the efficacy of PEMBROLIZUMAB and Metronomic Cyclophosphamide (CP) + G100 in 
terms of 6-month non-progression (as per RECIST v1.1 criteria) in patients with metastatic soft-tissue 
sarcoma. 
 
2.2. SECONDARY OBJECTIVES  
For each stratum: 
 
Assessment of the efficacy of the treatment strategy  in terms of best overall response (as per 
RECIST v1.1 criteria), 1-year Progression-free survival (PFS, as per RECIST v1.1 criteria), and 
1-year overall survival (OS).  
 
Assessment of the efficacy of the treatment strategy in terms of 6-month immune-related 
response (Wolchok et al. Clinical Cancer Research 2009) based on centrally reviewed 
radiological data. 
 
Assessment of the safety profile of the treatment strategy using the Common Terminology 
Criteria for Adverse Events (CTCAE) from the NCI v4.0. 
 
Growth modulation index (GMI), defined for each patient as the ratio of the PFS on the 
current treatment strategy to the PFS on the previous line of therapy (Von Hoff 1998), in 
patients with documented progression at inclusion. 
 
For each stratum 1 to 5: 
 
Translational research: pharmacodynamic (PD)/mechanism of action (MOA) biomarkers 
analysis as well as predictive biomarkers analysis (levels of angiogenic and immunologic 
biomarkers in blood at baseline and different study time points). 
 
Prospective determination of the proportion of STS that express PDL1. 
 
Identification of prognostic biomarkers of treatment response. 
 
 
 
 
 

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For strata 6 to 7: 
 
Translational research on blood and tumor tissue samples obtained at baseline and several 
time points during treatment for: 
- 
pharmacodynamic (PD)/mechanism of action (MOA) analysis assessing angiogenic and 
immunologic biomarkers, 
identification of biomarkers predictive of treatment response. 
3. STUDY DESIGN 
This is a phase II trial with seven independent strata: 
 
FOR TREATMENT STRATEGY A (STRATA 1 TO 6):  
 
 
Advanced leiomyosarcoma (stratum 1) 
o 
Single-arm phase 2 trial 
o 
Treatment: PEMBROLIZUMAB + Metronomic CP at standard doses. 
o 
2-stage dual endpoint design (72) 
 
Advanced undifferentiated sarcoma (stratum 2) 
o 
Same design/treatment as for leiomyosarcoma 
 
Advanced other sarcoma (stratum 3) 
o 
Same design/treatment as for leiomyosarcoma 
 
Advanced osteosarcoma (stratum 4) 
o 
Single-arm phase 2 trial 
o 
Treatment: PEMBROLIZUMAB + Metronomic CP at standard doses. 
o 
2-stage dual endpoint design (72) 
 
Advanced GIST (stratum 5) 
o 
Single-arm phase 2 trial 
o 
Treatment: PEMBROLIZUMAB + Metronomic CP at standard doses. 
o 
2-stage optimal Simon’s design (73) 
 
Advanced soft-tissue sarcomas with immune signature (stratum 6) 
o 
Single-arm phase 2 trial 
o 
Treatment: PEMBROLIZUMAB + Metronomic CP at standard doses. 
o 
2-stage optimal Simon’s design (73) 
 
FOR TREATMENT STRATEGY B (STRATUM 7): 
 
Metastatic soft-tissue sarcoma  
o 
Single-arm phase 2 trial 
o 
Treatment : PEMBROLIZUMAB + Metronomic CP at standard dose + G100 
o 
2-stage optimal Simon’s design (73) 
 
 

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4.  SELECTION OF PATIENTS 
4.1. INCLUSION CRITERIA 
4.1.1. 
For strata 1 to 5 
1. Histology: Leiomyosarcoma, or UPS (undifferentiated pleomorphic sarcoma), or other sarcoma, or 
GIST (gastro intestinal stromal tumor, or osteosarcoma, histologically confirmed by central review 
(Pr Coindre team), except if the diagnosis was already confirmed by the RRePS Network, 
2. Advanced non resectable / metastatic disease, 
3. Documented progression according to RECIST criteria. Progression on the last line of treatment 
should be confirmed by central review with two radiological assessments identical (CT scans or 
MRI) obtained at less from 6 months interval within the 12 months before inclusion, 
4. For strata 5, documented disease progression according to RECIST criteria after the first line 
imatinib and second line sunitinib, 
5. Have provided tissue from an archival tissue sample obtained on metastasis or on locally advanced 
disease, or newly obtained core or excisional biopsy of a tumor lesion 
6. For strata 1, 2 and 3: no more of four previous lines of systemic therapy for metastatic disease, 
7. Age ≥ 18 years, 
8. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1, 
9. Measurable disease according to RECIST v1.1 outside any previously irradiated field. At least one 
site of disease must be uni-dimensionally ≥ 10 mm, 
10. Life expectancy > 3 months, 
11. For strata 1, 2 and 3 at least 1 previous line(s) of chemotherapy in the palliative setting, 
12. No symptomatic central nervous system disease, 
13. No chronic use of glucocorticoids14. Adequate hematological, renal, metabolic and hepatic 
function: 
a. Hemoglobin > 9 g/dl (patients may have received prior red blood cell [RBC] transfusion, if 
clinically indicated); absolute neutrophil count (ANC) > 1.5 x 109/l and platelet count > 100 x 
109/l, 
b. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x upper limit of 
normality (ULN) (< 5 in case of liver metastasis). 
c. Total bilirubin < 1.5 x ULN OR Direct bilirubin < ULN for subjects with total bilirubin levels > 1.5 
x ULN. 
d. Albumin > 25g/l. 
e. Serum creatinine < 1.5 x ULN OR Calculated creatinine clearance (CrCl) > 60 ml/min 
(calculated per institutional standard) for subject with creatinine levels > 1.5 x ULN. 
f. Creatine phosphokinase (CPK) < 2.5 x ULN 
g. INR < 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within 
therapeutic range of intended use of anticoagulants 
h. aPTT ≤ 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is 
within therapeutic range of intended use of anticoagulants, 
i.  Thyroid function (T3, T4 and TSH) ≤ 1.5 x ULN and ≥ LLN. 
15. No prior or concurrent malignant disease diagnosed or treated in the last 2 years except for 
adequately treated in situ carcinoma of the cervix, basal or squamous skin cell carcinoma, or in situ 
transitional bladder cell carcinoma, 
16. At least three weeks since last chemotherapy, immunotherapy or any other pharmacological 
treatment and/or radiotherapy, 
17. Recovery to grade < 1 from any adverse event (AE) derived from previous treatment (excluding 
alopecia of any grade and non-painful peripheral neuropathy grade < 2 (according to the National 
Cancer Institute Common Terminology Criteria for Adverse Event (NCI-CTCAE, version 4.0), 
18. Women of childbearing potential must have a negative serum pregnancy test within 72 hours prior 
to receiving the first dose of study medication. Both women and men must agree to use a 
medically acceptable method of contraception throughout the treatment period days and for four 
months after discontinuation of treatment. Acceptable methods for contraception include 
intrauterine device (IUD), oral contraceptive, subdermal implant and double barrier. Subjects of 
childbearing potential are those who have not been surgically sterilized or have not been free from 
menses for > 1 year. 
19. Voluntary signed and dated written informed consents prior to any specific study procedure, 

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20. Patients with a French social security in compliance with the Law relating to biomedical research 
(Article 1121-11 of French Public Health Code). 
4.1.2. 
For stratum 6 
1. Histology : soft-tissue sarcoma histologically confirmed by central review (Pr Coindre team), 
except if the diagnosis was already confirmed by the RRePS Network, 
2. Advanced non resectable / metastatic disease 
3. Documented progression according to RECIST criteria. Progression on the last line of treatment 
should be confirmed by central review with two radiological assessments identical (CT scans or 
MRI) obtained at less than 6 months interval within the 12 months before inclusion, except for 
patients with metastatic disease diagnosed less than 6 months before inclusion. 
4. Have provided tissue of a tumor lesion from an archival tissue sample obtained on metastasis or 
on locally advanced disease, or newly obtained core or excisional biopsy. Tissue < 3 months old 
and with no subsequent treatment since or from a newly obtained core or excisional biopsy, 
5. Presence of tertiary lymphoid structures on freshly obtained tumor biopsy or archival tumor 
material collected before any systemic treatment or radiation therapy, 
6. No more of four previous lines of systemic therapy for metastatic disease 
7. Age ≥ 18 years, 
8. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1, 
9. Measurable disease according to RECIST v1.1 outside any previously irradiated field. At least one 
site of disease must be uni-dimensionally ≥ 10 mm, 
10. Life expectancy > 3 months, 
11. 
Participant must have advanced disease and must not be a candidate for other approved 
therapeutic regimen known to provide significant clinical benefit based on investigator judgement, 
12. No symptomatic central nervous system disease, 
13. No chronic use of glucocorticoids.  
14. Adequate hematological, renal, metabolic and hepatic function: 
a. Hemoglobin ≥ 9 g/dl (patients may have received prior red blood cell [RBC] transfusion, if 
clinically indicated); absolute neutrophil count (ANC) ≥ 1.5 x 109/l and platelet count ≥ 100 x 
109/l, 
b. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x upper limit of 
normality (ULN) (≤ 5 in case of liver metastasis). 
c. Total bilirubin ≤ 1.5 x ULN OR Direct bilirubin < ULN for subjects with total bilirubin levels ≥ 1.5 x 
ULN. 
d. Albumin ≥ 25g/l. 
e. Serum creatinine ≤ 1.5 x ULN OR Calculated creatinine clearance (CrCl) ≥ 60 ml/min (calculated 
per institutional standard) for subject with creatinine levels ≥ 1.5 x ULN. 
f. Creatine phosphokinase (CPK) ≤ 2.5 x ULN 
g. INR 
≤ 
1.5 
x 
ULN 
unless 
subject 
is 
receiving 
anticoagulant 
therapy 
as long as PT or PTT is within therapeutic range of intended use of anticoagulants 
h.  aPTT ≤ 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within 
therapeutic range of intended use of anticoagulants, 
i. Thyroid functions (T3, T4 and TSH) ≤ 1.5 x ULN and ≥ LLN. 
15. No prior or concurrent malignant disease diagnosed or treated in the last 2 years except for 
adequately treated in situ carcinoma of the cervix, basal or squamous skin cell carcinoma, or in 
situ transitional bladder cell carcinoma, 
16. At least three weeks since last chemotherapy, immunotherapyor any other pharmacological 
treatment and/or radiotherapy, 
17. Recovery to grade ≤ 1 from any adverse event (AE) derived from previous treatment (excluding 
alopecia of any grade and non-painful peripheral neuropathy grade ≤ 2 (according to the National 
Cancer Institute Common Terminology Criteria for Adverse Event (NCI-CTCAE, version 4.0), 
18. Women of childbearing potential must have a negative serum pregnancy test within 72 hours prior 
to receiving the first dose of study medication. Both women and men must agree to use 2 
medically acceptable methods of contraception throughout the treatment period and for 180 days 
after discontinuation of treatment. Subjects of childbearing potential are those who have not been 
surgically sterilized or have not been free from menses for ≥ 1 year, 
19. Voluntary signed and dated written informed consents prior to any specific study procedure, 
20. Patients with a social security in compliance with the french Law. 
 
 

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4.1.3. 
For stratum 7 
1. Histology: soft-tissue sarcoma histologically confirmed by central review (Pr Coindre team), except 
if the diagnosis was already confirmed by the RRePS Network, 
2. Locally advanced or metastatic disease with at least one injectable lesion. Note that lesion must be 
cutaneous, subcutaneous or intramuscular. Nethertheless, it would be allowed to inject deeper 
lesion, either if patient is not on anticoagulation or per the guidelines in the protocol, the lesion is 
compressible; either if patient is on ASA or anti-platelet agent and the lesion is not compressing or 
involving organs or vessels 
3. Documented progression according to RECIST criteria. Progression on the last line of treatment 
should be confirmed by central review with two radiological assessments identical (CT scans or 
MRI) obtained at less from 6 months interval within the 12 months before inclusion, except for 
patients with metastatic disease diagnosed less than 6 months before inclusion, 
4. Patients whose disease has progressed despite standard therapy and for whom no standard 
therapy exists, 
5. Have provided tissue of a tumor lesion from an archival tissue sample obtained on metastasis or on 
locally advanced disease, or newly obtained core or excisional biopsy. Tissue < 3 months old and 
with no subsequent treatment since or from a newly obtained core or excisional biopsy 
6. No more than 2 previous lines of systemic therapy in the palliative setting, 
7. Age ≥ 18 years, 
8. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1, 
9. Measurable disease according to RECIST v1.1 outside any previously irradiated field. At least one 
site of disease must be uni-dimensionally ≥ 10 mm, 
10. Life expectancy > 6 months, 
11. At least 1 previous line(s) of chemotherapy in the palliative setting, 
12. No symptomatic central nervous system disease, 
13. No chronic use of glucocorticoids 
14. Adequate hematological, renal, metabolic and hepatic function: 
a. Hemoglobin ≥ 9 g/dl (patients may have received prior red blood cell [RBC] transfusion, if 
clinically indicated); absolute neutrophil count (ANC) ≥ 1.5 x 109/l,  leukocyte count ≥ 2.5 x 
109/l and platelet count ≥ 100 x 109/l, and lymphocyte count ≥ 0.5 x 109/l. 
b. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x upper limit of 
normality (ULN) (≤ 5 in case of liver metastasis). 
c. Total bilirubin ≤ 1.5 x ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels ≥ 1.5 
x ULN. 
d. Albumin ≥ 25g/l. 
e. Serum creatinine ≤ 1.5 x ULN OR Calculated creatinine clearance (CrCl) ≥ 60 ml/min 
(calculated per institutional standard) for subject with creatinine levels ≥ 1.5 x ULN. 
f. Creatine phosphokinase (CPK) ≤ 2.5 x ULN 
g. INR ≤ 1.5 x ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use of anticoagulants 
h. aPTT ≤ 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is 
within therapeutic range of intended use of anticoagulants, 
i.  Thyroid function (T3, T4 and TSH) ≤ 1.5 x ULN and ≥ LLN. 
15. No prior or concurrent malignant disease diagnosed or treated in the last 2 years except for 
adequately treated in situ carcinoma of the cervix, basal or squamous skin cell carcinoma, or in situ 
transitional bladder cell carcinoma, 
16. At least three weeks since last chemotherapy, and 14 days since last immunotherapy or any other 
pharmacological treatment and/or radiotherapy, 
17. Recovery to grade < 1 from any adverse event (AE) derived from previous treatment (excluding 
alopecia of any grade and non-painful peripheral neuropathy grade ≤ 2 (according to the National 
Cancer Institute Common Terminology Criteria for Adverse Event (NCI-CTCAE, version 4.0), 
18. Women of childbearing potential must have a negative serum pregnancy test within 72 hours prior 
to receiving the first dose of study medication. Both women and men must agree to use 2 
medically acceptable methods of contraception throughout the treatment period and for 180 days 
after discontinuation of treatment. Subjects of childbearing potential are those who have not been 
surgically sterilized or have not been free from menses for ≥ 1 year. 
19. Voluntary signed and dated written informed consents prior to any specific study procedure, 
20. Patients with a social security in compliance with the French Law. 
 

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4.2. EXCLUSION CRITERIA 
4.2.1. 
For strata 1 to 5 
1. Previous treatment with PEMBROLIZUMAB or CP, 
2. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic 
T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumabor any other antibody 
or drug specifically targeting T-cell co-stimulation or checkpoint pathways), 
3. Evidence of progressive or symptomatic central nervous system (CNS) or leptomeningeal 
metastases, 
4. Men or women of childbearing potential who are not using an effective method of contraception as 
previously described; women who are pregnant or breast feeding, 
5. Participation to a study involving a medical or therapeutic intervention in the last 30 days, 
6. Previous enrolment in the present study, 
7. Patient unable to follow and comply with the study procedures because of any geographical, 
familial, social or psychological reasons, 
8. Known hypersensitivity to any involved study drug or of its formulation components, 
9. Has an active autoimmune disease requiring systemic treatment within the past 3 months or a 
documented history of clinically severe autoimmune disease, or a syndrome that requires systemic 
steroids or immunosuppressive agents.  Subjects with vitiligo or resolved childhood asthma/atopy 
would be an exception to this rule.  Subjects that require intermittent use of bronchodilators or 
local steroid injections would not be excluded from the study.  Subjects with hypothyroidism stable 
on hormone replacement or Sjorgen’s syndrome will not be excluded from the study, 
10. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of trial treatment, 
11. History of idiopathic pulmonary fibrosis, history of non-infectious pneumonitis that required 
steroids, drug-induced pneumonitis, organizing pneumonia, or evidence of active pneumonitis on 
screening chest CT scan. History of radiation pneumonitis in the radiation field (fibrosis) is 
permitted, 
12. Has known active hepatitis B or hepatitis C, 
13. Has a known history of Human Immunodeficiency Virus (HIV) (HIV1/2 antibodies), 
14. Has received a live vaccine within 30 days prior to the first dose of trial treatment. 
4.2.2. 
For stratum 6 
1. Previous treatment with PEMBROLIZUMAB 
2. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic 
T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumabor any other antibody 
or drug specifically targeting T-cell co-stimulation or checkpoint pathways), 
3. Evidence of progressive or symptomatic central nervous system (CNS) or leptomeningeal 
metastases, 
4. Men or women of childbearing potential who are not using an effective method of contraception; 
women who are pregnant or breast feeding, 
5. Participation to a study involving a medical or therapeutic intervention in the last 30 days, 
6. Previous enrolment in the present study, 
7. Patient unable to follow and comply with the study procedures because of any geographical, 
familial, social or psychological reasons, 
8. Known hypersensitivity to any involved study drug or of its formulation components, 
9. Has an active autoimmune disease requiring systemic treatment within the past 3 months or a 
documented history of clinically severe autoimmune disease, or a syndrome that requires systemic 
steroids or immunosuppressive agents.  Subjects with vitiligo or resolved childhood asthma/atopy 
would be an exception to this rule.  Subjects that require intermittent use of bronchodilators or 
local steroid injections would not be excluded from the study.  Subjects with hypothyroidism stable 
on hormone replacement or Sjorgen’s syndrome will not be excluded from the study, 
10. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of trial treatment, 
11. History of idiopathic pulmonary fibrosis, history of non-infectious pneumonitis that required 
steroids, drug-induced pneumonitis, organizing pneumonia, or evidence of active pneumonitis on 
screening chest CT scan. History of radiation pneumonitis in the radiation field (fibrosis) is 
permitted, 

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12. Has known history of or is positive for Hepatitis B (HBsAg reactive) or Hepatitis C.  
13. Has a known history of Human Immunodeficiency Virus (HIV) infection (HIV1/2 antibodies), 
14. Has received a live vaccine within 30 days prior to the first dose of trial treatment. 
15. Patients with oral anticoagulation therapy, 
16. Known urinary tract obstruction. 
17.Previous allogenic bone marrow transplant or solid organ transplantation, 
18.Has an active infection requiring systemic treatment within 14 days prior to study. 
 
4.2.3. 
For stratum 7 
1. Previous treatment with PEMBROLIZUMAB or G100, 
2. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic 
T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumabor any other antibody 
or drug specifically targeting T-cell co-stimulation or checkpoint pathways), 
3. Evidence of progressive or symptomatic central nervous system (CNS) or leptomeningeal 
metastases, 
4. Men or women of childbearing potential who are not using an effective method of contraception; 
women who are pregnant or breast feeding, 
5. Participation to a study involving a medical or therapeutic intervention in the last 30 days, 
6. Previous enrolment in the present study, 
7. Patient unable to follow and comply with the study procedures because of any geographical, 
familial, social or psychological reasons, 
8. Known hypersensitivity to any involved study drug or of its formulation components, 
9. Has an active autoimmune disease requiring systemic treatment within the past 3 months or a 
documented history of clinically severe autoimmune disease, or a syndrome that requires systemic 
steroids or immunosuppressive agents.  Subjects with vitiligo or resolved childhood asthma/atopy 
would be an exception to this rule.  Subjects that require intermittent use of bronchodilators or 
local steroid injections would not be excluded from the study.  Subjects with hypothyroidism stable 
on hormone replacement or Sjorgen’s syndrome will not be excluded from the study, 
10. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of trial treatment, 
11. History of idiopathic pulmonary fibrosis, history of non-infectious pneumonitis that required 
steroids, drug-induced pneumonitis, organizing pneumonia, or evidence of active pneumonitis on 
screening chest CT scan. History of radiation pneumonitis in the radiation field (fibrosis) is 
permitted, 
12. Has known history of or is positive for Hepatitis B (HBsAg reactive) or Hepatitis C.  
13. Has a known history of Human Immunodeficiency Virus (HIV) infection (HIV1/2 antibodies), 
14. Has received a live vaccine within 30 days prior to the first dose of trial treatment. 
15. Patients with oral anticoagulation therapy, 
16. Known urinary tract obstruction. 
17.Previous allogenic bone marrow transplant or solid organ transplantation, 
18.Has an active infection requiring systemic treatment within 14 days prior to study. 
 
5. STUDY PLAN 
5.1. DURATION OF STUDY (WHOLE POPULATION) 
The total duration of the study will be approximately 84 months, including about 72 months of active 
enrolment.  
Planned start date (first patient on study): 12/2014. 
Within each stratum, the date of planned stratum termination (clinical cutoff) corresponds to the date 
when each patient has been followed-up for 12 months or is deceased. 
End of study occurs when all the following criteria habe been satisfied: 
 
The trial is closed to recruitment 
And 
 
All patients have disease progression or are no longer on study medication 
And 

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 
The last included patient has been followed for 12 months, or if deceased, each patient has 
been followed-up for 12 months or is deceased. 
 
5.2. DEFINITIONS OF DURATION OF STUDY AND TREATMENT (PER PATIENT) 
Patients will receive study treatment as long as it is considered to be in their best interest for a 
maximum of 2 years. Patients will be evaluated at scheduled visits in up to three study periods:  
 Pre-treatment (PRE TT): from signature of informed consent to the first administration of study 
drugs. 
 Treatment (TT): from the first administration of study drugs to treatment discontinuation.  
 Follow-up (FUP): after treatment discontinuation, patients will be followed up four weeks (30 
days) for strata 1 to 5 and 90days for strata 6 to 7 later for toxicities except if the patient starts a 
new antitumor therapy before this period., and beyond if grade 3 or 4 toxicity, until resolution.  
Patients who discontinue treatment without progression will be followed clinically with 
radiological assessment (same method as used during treatment) every 12 weeks until: 
1. Disease progression, 
2. Initiation of other antitumor therapy,  
3. Death, or  
4. The end of the follow-up period, whichever occurs first.  
After documented progression or start of a new antitumor therapy, patients will be followed every 6 
months until: 
1. Death, or  
2. The end of the follow-up period, whichever occurs first. 
Patients will be considered to be on-study from the signature of the informed consent to the end of 
follow-up period. 
 
Patients will be considered to be on-treatment for the duration of their treatment until 30 days (4 
weeks) for stratum 1 to 5 and 90 days (12 weeks) for strata 6 to 7 after the last treatment 
administration, except if the patient starts a new antitumor therapy before this period. 
 
Patients may withdraw their consent at any time; no further study activities will be conducted on 
them. 
Treatment discontinuation occurs when an enrolled patient ceases to receive the study medication 
or starts a new antitumor therapy, regardless of the circumstances, and is defined as 30 days for 
stratum 1 to 5 and 90 days (12 weeks) for strata 6 to 7 after the day of the last treatment 
administration, unless the patient starts a new antitumor therapy, in which case the date of 
administration of this new antitumor therapy will be considered the date of treatment discontinuation. 
The primary reason for any discontinuation will be recorded on the patient’s Case Report Form (CRF). 
If a patient discontinues treatment, every effort should be made to complete the scheduled 
assessments.Administration of the study treatment should be discontinued if this is considered to be 
in the best interest of the patient. More specifically, treatment will be discontinued due to any of the 
following reasons: 
o Disease progression, 
o Unacceptable toxicity, 
o Intercurrent illness of sufficient magnitude to preclude safety continuation of the study, 
o Patient refusal and/or non compliance with study requirements, 
o Protocol deviation with an effect on the risk/benefit ratio of the clinical trial 

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Patients still experiencing a non-progression rate after 6 cycles will then be able to continue treatment 
off-study at the discretion of the investigator. Duration of treatment will be limited to a maximum of 2 
years.  
 
Study discontinuation occurs when an enrolled patient ceases to participate in the study, 
regardless of the reason (as detailed under “Follow-up” in Section 5.7). Patients have the right to 
withdraw consent at any time; if this is the case, no further follow-up should be performed. 
The date and reason for study discontinuation will be clearly documented on the patient’s CRF. 
 
 
5.3. PROTOCOL DEVIATION 
A protocol deviation is defined as any departure from what is described in the protocol of a clinical 
trial approved by an Independent Ethics Committee/Institutional Review Board (IEC/IRB) and 
Competent Authorities. Therefore, this applies to deviations related to patient inclusion and clinical 
procedures (e.g., assessments to be conducted or parameters to be determined), and also to other 
procedures described in the protocol that concern the Good Clinical Practice (GCP) guidelines or 
ethical issues (e.g., issues related to obtaining the patients’ Informed Consent, data reporting, the 
responsibilities of the investigator, etc.). 
Deviations with no effects on the risk/benefit ratio of the clinical trial (such as minimal delays in 
assessments or visits) will be distinguished from those that might have an effect on this risk/benefit 
ratio, such as: 
 Deviations that might affect the clinical trial objectives, such as those involving the 
inclusion/exclusion criteria (which could mean that the patient is not eligible for the trial) and 
those having an effect on patient evaluability. 
 Deviations that might affect the patient’s well-being and/or safety, such as an incorrect dosing 
of the investigational medicinal product due to not following dose adjustment specifications or 
an incorrect preparation of the medication. 
 Deviations related to the following of GCP guidelines as described in the protocol and 
regulations in force, such as deviations when obtaining the Informed Consent or not following 
the terms established for reporting serious adverse events, etc. 
As a general rule, NO deviations that may have an effect on the risk/benefit ratio of the clinical trial 
will be authorized.  Protocol deviations considered particularly relevant, which are related to ethical 
issues, fulfillment of GCP guidelines and trial procedures, will be notified to the pertinent IEC/IRB and, 
if pertinent, to the relevant authorities as established by local regulations. 
 
5.4. SCREENING EVALUATION 
During the pre-treatment period, and once the patient has signed the Informed Consent Form, the 
Investigator will confirm the patient’s eligibility for the study by conducting the assessments detailed 
below.  
Screening assessments. 
 
ASSESSMENT 
TIME 
1. History and 
clinical 
examination 
 Signed 
by 
the 
patient/legal 
representative 
Informed Consent Form 
Prior to any specific study procedures 
 
 
 Medical history and baseline condition 
 Complete physical examination 
 Performance status (ECOG PS; see Appendix 1) 
 Assessment of baseline signs and symptoms 
 Concomitant treatments 
Within two weeks prior to inclusion (+1 
week tolerance) 
 Vital signs: heart rate, blood pressure, body 
temperature, weight and height 
Within 7 days prior to inclusion (+1 day 
tolerance) 
 Demographic data 
Within four weeks prior to inclusion 

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ASSESSMENT 
TIME 
 Primary diagnostic and prior treatment/s data: 
- Date of diagnosis of the primary disease 
- Prior treatments (surgery, radiotherapy, 
chemotherapy, immunotherapy), specifying the 
date of best response and the time to 
progression 
 
2. Pathology 
 Central review to confirm sarcoma diagnosis, 
except in case of diagnosis confirmed by RRePS 
Network 
 Archived tumor tissue sample obtained on 
metastasis or on locally advanced disease, or a 
new obtained core or excisional biopsy of a tumor 
lesion. Tissue < 3 months old for strata 6 to 7 
 For stratum 6: central evaluation of presence of 
tertiary lymphoid structure on tumor sample 
Material sent within 7 days next to signed 
informed consent 
3. Laboratory 
tests 
 Hematology: differential WBC, haemoglobin and 
platelets, PT/INR, aPTT 
 Biochemistry: Serum electrolytes (Na+, Mg++, 
K+, Cl-, Ca++ and phosphorus), liver function tests 
(AST, ALT, AP, GGT and total bilirubin/direct 
bilirubin), LDH, creatinine, glucose, total proteins, 
urea, uric acid, CPK, albumin 
 Thyroid function: T3, T4 and TSH 
 Urinalysis: blood, glucose, protein, specific 
gravity (urinary strip) 
Within 7 days prior to inclusion (+3 days 
tolerance). In the event that the patient’s 
condition 
is 
deteriorating, 
laboratory 
evaluations should be repeated within 72 
hours prior to initiation of the treatment 
Within 7 days prior to inclusion (+3 days 
tolerance) 
4. Creatinine 
clearance 
 Calculated as per institutional standard 
Within 7 days prior to inclusion (+3 days 
tolerance) 
5. Pregnancy 
test, if 
applicable 
Measurement of serum human chorionic 
gonadotropin (HCG) 
Within 72 hours prior to inclusion (+1 day 
tolerance) 
6. ECG 
 If indicated 
Within 7 days prior to inclusion (+3 days 
tolerance) 
7. Tumor 
assessment 
 CT-scan or MRI of all measurable sites, as per 
RECIST (Appendix 2) 
 Centrally reviewing of two CT scan or MRI 
obtained at an interval less than 6 months in the 
period of 12 months prior to inclusion 
Within four weeks prior to inclusion (+1 
week tolerance) 
Sent within 7 days next to signed Informed 
Consent 
8. Biopsy 
 Only for consented patient (optional) for strata 1 
to 5 
 Mandatory for all patients for strata 6 to 7 
At baseline, within 7 days prior to C1D1 
9. Other tests 
 Intercurrent events, concomitant diseases and 
treatments. 
Within two weeks prior to inclusion. 
aPTT, activated partial thromboplastin time; ALT, alanine aminotransferase; AP, alkaline phosphatase, AST, aspartate 
aminotransferase; ECG, electrocardiogram; ECOG PS, Eastern Cooperative Oncology Group Performance Status; GGT, 
gamme glutyl-transferase; INR, internation, normalized ratio; LDH, lactate dehydrogenase; MRI, magnetic resonance 
imaging; PGx, pharmacogenomics; PT, prothrombin time; RECIST v1.1, Response Evaluation Criteria In Solid Tumors; 
WBC, white blood cells. 

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5.5. EVALUATIONS DURING TREATMENT 
The following assessments will be done while the patient is on treatment. 
5.5.1. 
For strata 1 to 6 
Evaluations during treatment 
 
ASSESSMENT 
TIME 
1. Clinical 
examination 
 Complete physical examination 
 Performance status (ECOG PS; see Appendix 1) 
 Vital signs: heart rate, blood pressure, body 
temperature and weight 
Repeat up to 48 hours before Day 1 of 
cycle 1 
Repeat on Days 8 and 15 of Cycle 1 
Repeat on Day 8 of cycle 2, 4, 6, etc… 
Repeat on Days 1 and 8 of cycle 3, 5, etc. 
 Assessment of baseline signs and symptoms 
Throughout the treatment period 
 Concomitant diseases and treatments 
Throughout the treatment period 
2. Laboratory 
tests* 
 Hematology: differential WBC, haemoglobin and 
platelets, PT/INR, aPTT 
 Biochemistry: Serum electrolytes (Na+, Mg++, 
K+, Cl-, Ca++ and phosphorus), liver function tests 
(AST, ALT, AP, GGT and total bilirubin), LDH, 
creatinine, glucose, total proteins, urea, uric acid, 
CPK, albumin 
 Thyroid function: T3, T4 and TSH 
 Urinalysis: blood, glucose, protein, specific 
gravity (urinary strip) 
Repeat up to 48 hours before Day 1 of 
cycle 1 
Repeat on Days 8 and 15 of Cycle 1 
Repeat on Day 8 of cycle 2, 4, 6, etc… 
Repeat on Days 1 and 8 of cycle 3, 5, etc. 
 
For thyroid function test: repeat on C2D8, 
C3D8 and every 3 cycles 
3. Creatinine 
clearance 
 Calculated as per institutional standard 
Repeat up to 48 hours before Day 1 of 
cycle 1 
Repeat on Days 8 and 15 of Cycle 1 
Repeat on Day 8 of cycle 2, 4, 6, etc… 
Repeat on Days 1 and 8 of cycle 3, 5, etc. 
4. Pregnancy 
test, if 
applicable 
 Measurement 
of 
serum 
human 
chorionic 
gonadotropin (HCG) 
While on study, pregnancy test will be 
repeated whenever clinically indicated in 
women with child bearing potential 
5. Tumor 
assessment 
 CT-scan or MRI of all measurable sites, as per 
RECIST (see Appendix 2) 
Tumor assessment must be repeated every 
six weeks (±7 days) and at least four 
weeks 
after 
first 
documentation 
of 
objective response even if there are 
treatment delays 
6. PD study 
 Predictive markers of treatment outcome from 
blood samples 
See section 17 
7. AEs 
As per NCI-CTCAE, version 4.0. 
Throughout the treatment period 
8. Biopsy 
 Only for consented patients (optional for strata 1 
to 5) 
 Mandatory for stratum 6 
On Day 8 of cycle 2 
*For all laboratory tests a window of 72 hours will be allowed. 
AE, adverse event; ALT, alanine aminotransferase; AP, alkaline phosphatase; aPTT, activated partial thromboplastin time; AST, 
aspartate aminotransferase; ECOG PS, Eastern Cooperative Oncology Group Performance Status; GGT, gamma glutyl-transferase; 
INR, internation, normalized ratio; LDH, lactate dehydrogenase; MRI, magnetic resonance imaging; NCI-CTCAE, National Cancer 
Institute Common Terminology Criteria for Adverse Events; PGx, pharmacogenomics; PT, prothrombin time; RECIST, Response 
Evaluation Criteria In Solid Tumors; WBC, white blood cells. 
 
 
 

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5.5.2. 
For stratum 7 
Evaluations during treatment 
 
ASSESSMENT 
TIME 
1. Clinical 
examination 
 Complete physical examination 
 Performance status (ECOG PS; see Appendix 1) 
 Vital signs: heart rate, blood pressure, body 
temperature and weight 
Repeat up to 48 hours before first G100 
injection (Day -7, impregnation phase) 
Repeat on Days 1, 8 and 15 of Cycle 1 
Repeat on Days 1 and 8 of Cycle 2  
Repeat on Day 8 of cycle 4, 6, etc… 
Repeat on Days 1 and 8 of cycle 3, 5, etc. 
Note: Must be repeated at each G100 
injection 
 Assessment of baseline signs and symptoms 
Throughout the treatment period 
 Concomitant diseases and treatments 
Throughout the treatment period 
2. Laboratory 
tests* 
 Hematology: differential WBC, haemoglobin and 
platelets, PT/INR, aPTT 
 Biochemistry: Serum electrolytes (Na+, Mg++, 
K+, Cl-, Ca++ and phosphorus), liver function tests 
(AST, ALT, AP, GGT and total bilirubin), LDH, 
creatinine, glucose, total proteins, urea, uric acid, 
CPK, albumin 
 Thyroid function: T3, T4 and TSH 
 Urinalysis: blood, glucose, protein, specific 
gravity (urinary strip) 
Repeat up to 48 hours before first G100 
injection (Day -7, impregnation phase) 
Repeat on Days 1, 8 and 15 of Cycle 1 
Repeat on Day 8 of cycle 2, 4, 6, etc… 
Repeat on Days 1 and 8 of cycle 3, 5, etc. 
 
For thyroid function test: repeat up to 48 
hours before first G100 injection (Day -7, 
impregnation phase) and on C2D8, C3D8 
and every 3 cycles 
3. Creatinine 
clearance 
 Calculated as per institutional standard 
Repeat up to 48 hours before first G100 
injection (Day -7, impregnation phase) 
Repeat on Days 1, 8 and 15 of Cycle 1 
Repeat on Day 8 of cycle 2, 4, 6, etc… 
Repeat on Days 1 and 8 of cycle 3, 5, etc. 
4. Pregnancy 
test, if 
applicable 
 Measurement 
of 
serum 
human 
chorionic 
gonadotropin (HCG) 
While on study, pregnancy test will be 
repeated whenever clinically indicated in 
women with child bearing potential 
5. Tumor 
assessment 
 CT-scan or MRI of all measurable sites, as per 
RECIST (see Appendix 2) 
Tumor assessment must be repeated at 
week 9, week 18, week 24 and every six 
weeks (±7 days) and at least four weeks 
after first documentation of objective 
response even if there are treatment 
delays 
6. PD study 
 Predictive markers of treatment outcome from 
blood samples 
See section 17 
7. AEs 
As per NCI-CTCAE, version 4.0. 
Throughout the treatment period 
8. Biopsy 
 Mandatory for all patients 
On Day 8 of cycle 2 but in case of 
radiotherapy, biopsy must be performed 
before RT initiation and a second biopsy 
must be performed within 3-4 weeks after 
RT termination. 
*For all laboratory tests a window of 72 hours will be allowed. 
AE, adverse event; ALT, alanine aminotransferase; AP, alkaline phosphatase; aPTT, activated partial thromboplastin time; AST, 
aspartate aminotransferase; ECOG PS, Eastern Cooperative Oncology Group Performance Status; GGT, gamma glutyl-transferase; 
INR, internation, normalized ratio; LDH, lactate dehydrogenase; MRI, magnetic resonance imaging; NCI-CTCAE, National Cancer 
Institute Common Terminology Criteria for Adverse Events; PGx, pharmacogenomics; PT, prothrombin time; RECIST, Response 
Evaluation Criteria In Solid Tumors; WBC, white blood cells. 
 
 
 
 

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5.6. EVALUATION AT THE END OF TREATMENT 
The end-of-treatment visit will be scheduled 30 days (4 weeks) for stratum 1 to 5 and 90 days (12 
weeks) for strata 6 to 7 after the last treatment administration (a window of ±1 week is allowed). 
Regardless of the reason for discontinuation, the complete workup has to be done at the end-of-
treatment visit. This will include the following assessments: 
 
Assessment of signs and symptoms. 
 
Complete physical examination. 
 
ECOG performance status. 
 
Vital signs [heart rate, blood pressure and temperature]. 
 
Hematology. 
 
Biochemistry. 
 
Urinalysis, urinary strip. 
 
Clinical and radiological tumor assessment (CT-scan/MRI) (except for patients with confirmed 
PD at discontinuation or who had started a new treatment).  
 
Intercurrent events and concomitant disease and treatments. 
 
Safety assessment (AEs). 
Adverse events must be reported for 90 days after the last treatment administration or until the start 
of a new antitumor therapy, whichever occurs first. All SAEs occurring within 90 days of the last 
treatment administration or until the start of a new antitumor therapy, whichever occurs first, will be 
reported. Beyond this period of time, only those SAEs suspected to be treatment-related will be 
reported (see Section 11). 
 
5.7. FOLLOW-UP AFTER END-OF-TREATMENT VISIT 
- 
Each patient will be followed-up for 12 months 
- 
The date and reason of the study discontinuation will be recorded on the patient’s CRF (see 
Section 5.2).  
- 
After treatment discontinuation, patients will be followed four weeks after until resolution of 
toxicities, if any.  
- 
Patients who discontinue treatment without PD will be followed every 12 weeks until disease 
progression, other antitumor therapy or death or until the end of the follow-up period, 
whichever occurs first. 
- 
 After disease progression, patients will be followed every 6 months until death or until the 
end of the follow-up period, whichever occurs first. 
- 
Patients who withdraw consent will not be followed with any study procedures.  
All AEs (including SAEs) suspected to be treatment-related will be followed-up until the events or their 
sequelae resolve or stabilize at a level acceptable to the Investigator and the Sponsor. 
 
6. REGISTRATION PROCEDURES 
6.1. SCREENING 
Upon signature of consent, screened patient will be entered on study centrally at the Institut Bergonié 
Coordinating Center by the Study Coordinator as described in a specific SOP provided by the Sponsor.  
 
 
If applicable, site will send to Bergonie Institute within 7 days after the signature of informed consent: 
 
Pathology request form completed  
 
10 unstained slides and/or preferable FFPE (Formalin-Fixed Paraffin-Embedded) block of specimen 
tumor sampling, obtained anytime during disease development 
 
Initial pathology report with patient code and date of birth (including macroscopic description) 
and pathology report of molecular biology if any. 
 
Each site will send to Bergonie Institute for central review before registration: 

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 
Anonymized CD of CT-scan or MRI of two radiological assessments identical obtained at less 
than 6 months interval within the 12 months before inclusion 
 
Baseline Clinical Subject Profile with the first shipment 
 
Radiological Referral Form  
 
For stratum 6, each site will centrally send within 7 days after the signature of 
informed consent, archived or newly obtained FFPE (Formalin-Fiwed Paraffin-
Embedded) block, in order to assess the presence of tertiary lymphoid structures. 
Details will be available in a specific SOP provided by the Sponsor. 
To complete the registration process, the Coordinator will assign a patient screening number. 
Upon results of pathological and radiological review will be available, the CRA at Institut Bergonie 
should inform site by e-mail and return results by fax. 
 
6.2. INCLUSION  
With screening results, all eligible patients will be entered in the study centrally at the Institut 
Bergonié Coordinating Center by the Study Coordinator as described in a specific SOP provided by the 
Sponsor. 
This must be done before the start of the protocol treatment which should begin within one 
week (7 days) following registration. 
To complete the registration process, the Coordinator will: 
- 
Assign a patient study number 
- 
Register the patient on the study 
- 
Fax or e-mail the patient study number 
The patient study number attributed at the end of the registration procedure identifies the patient 
and must be reported on all case report forms. 
 
Issues that would cause treatment delays should be discussed with the Principal Investigator.  If a 
patient does not receive the protocol therapy following registration, the patient’s registration on the 
study may be cancelled.  The Study Coordinator should be notified of cancellations as soon as 
possible. 
 
 

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7. STUDY TREATMENT 
Sponsor will provide cyclophosphamide for all patients, with identifying labels that will include all the 
information required by local regulations.  
Merck will provide PEMBROLIZUMAB for all patients, with identifying labels that will include all the 
information required by local regulations. 
Immune Design will provide G100 for patients treated by strategy B with identifying labels that will 
include all the information required by local regulations. 
IMPs will have to be requested using appropriate forms provided by the Sponsor.  
The study sites will have to ensure drug traceability at all times. 
 
7.1. DESCRIPTION OF TREATMENT 
For instructions regarding drug inventory, handling, reconstitution, dilution, storage, accountability 
and disposal, please refer to the IMP Investigator’s Brochure and/or the more updated Summary of 
Product Characteristics (SPC), all provided as separate documents. 
 
7.2. PHARMACEUTICAL INFORMATIONS  
Product description 
Galenic 
Dosage 
Route 
of 
administration 
Storage 
Supply 
PEMBROLIZUMAB 
Infusion 
200mg 
Intraveinous 
2°C < temp < 8°C 
Yes 
Cyclophosphamide 
Pill 
50mg 
Orally 
< 25°C 
Yes 
G100 
Oil-in-
water 
1 
vial 
(0,6ml) = 
80µg/ml  
Intra-tumoral 
2°C < temp < 8°C 
Yes 
GLA-SE, a formulation of glucopyranosyl lipid A (GLA), is a synthetic toll-like receptor 4 (TLR4) agonist 
that activates specific cells of the immune system. TLR4 agonists activate DCs and induce acute 
inflammatory responses including production of chemokines and cytokines that mediate leukocyte 
infiltration, stimulation of DC maturation and induction of adaptive immune responses. Several 
completed clinical studies with vaccines containing GLA administered to healthy subjects have shown 
that GLA is generally well tolerated and is associated with heightened immune responses. When GLA-
SE is administered as a monotherapy, IMDZ designates the product as G100. 
G100 (GLA-SE) is a stable oil-in-water emulsion and will be used in this study in NHL. G100 is 
formulated in a high-pressure microfluidizer followed by filter-sterilization. It is composed of GLA with 
the SE (stable emulsion) vehicle which includes excipients squalene (oil), glycerol, tocopherol (vitamin 
E), dimyristoyl-phosphatidylcholine (DMPC), surfactant (polaxamer) and buffer (ammonium 
phosphate). G100 is filter sterilized and the emulsion is filled aseptically into each vial and appears as 
a milky white liquid. 
 
7.3. ADMINISTRATION OF TREATMENT 
Drugs will be prescribed after validation by the physician. 
The patient will be requested to maintain a medication diary (Appendix 6 to 7  ) of each dose of 
medication.  The medication diary will be returned to clinic staff at the end of each course. 
Reported adverse events and potential risks are described in Section 11. 
 
Regimen Description 
Agent 
Dose 
Route 
Schedule 
Cycle 
Length 
PEMBROLIZUMAB 
200mg 
I.V. 
On day 8 of each cycle 
21 days  
(3 
weeks) 
Cyclophosphamide 
50mg b.i.d. 
oral 
Twice a day  
In the morning and evening 
One week on / one week off 

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G100 
20µg 
I.Tum 
One week before Cyclophosphamide 
start, ie. On Day -7 (“Impregnation 
phase”) 
Weekly for at least 6 injections and for a 
maximum of 12 injections. 
Only one lesion can be injected 
7.3.1. 
Cyclophosphamide 
CP should be taken fasting but may be given with food to improve digestive tolerance as no significant 
PK variation has been demonstrated in this regard. . In case of vomiting or missed dose, the patient 
should not take additional tablet. 
7.3.2. 
Pembrolizumab 
PEMBROLIZUMAB should be administered as a 30 minutes IV infusion. Sites should make every effort 
to target infusion timing to be as close to 30 minutes as possible. However, given the variability of 
infusion pumps from site to site, a window of -5 minutes and +10 minutes is permitted (i.e., infusion 
time is 30 minutes: -5 min/+10 min). 
7.3.3. 
G100 
G100 will be given by direct injection into a tumor to treat. This injection must be performed during 
hospitalization. Note that only one lesion can be injected. Lesion must be cutaneous, 
subcutaneous or intramuscular. Nethertheless, it would be allowed to inject deeper lesion, either 
if patient is not on anticoagulation or per the guidelines in the protocol the lesion is compressible; 
either if patient is on ASA or anti-platelet agent and the lesion is not compressing or involving organs 
or vessels. 
7.3.3.1. 
G100 PREPARATION 
To prepare G100 for injection, the GLA-SE is diluted with an equal volume of 0.9% saline. The vial 
should be gently inverted 5 – 10 times to mix the GLA-SE with the saline diluent. The GLA SE vial is 
single use. 
For intratumoral administration the dose of G100 will be fixed at the 20 µg/dose. Details on the 
handling, preparation of the study agent and dose concentration and volume will be provided in the 
dose preparation manual (separate document).  
G100 should be used within 4 hours of dilution. 
G100 must not be frozen. 
7.3.3.2. 
G100 PLANNING OF INJECTION SITES 
Before injection, physician should: 
- 
Assess depth 
- 
Confirm ability to palpate 
- 
Imaging is not needed to inject tumor 
- 
Prepare supplies for injection 
- 
Adjust patient for comfort 
- 
Mark site 
- 
Clean and drap site 
7.3.3.3. 
 G100 ADMINISTRATION 
Appropriate sized needle should be used based on tumor location.  No pre-meds are required. 
The injection site should be prepped and sterilized using standard methods; 
G100 is injected in a relatively short amount of time directly into the tumor mass 
For injection, physician should: 
- 
Palpate tumor to hold its position for injection 
- 
Insert needle into tumor and pull back on plunger to verify location is not vascular 
- 
Inject slowly into tumor 
- 
Needle/syringe may be repositioned to inject into different portions of the tumor 
- 
Inject in different directions 
- 
Distribute evenly 
- 
Upon completion, check for bleeding and use pressure as needed 

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- 
Cover with dressing and observe patient in clinic for any post-injection reactions for 20 to 30 
minutes and then discharge if stable. 
 
7.4. GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during the 
ongoing trial.  If there is a clinical indication for one of these or other medications or vaccinations 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may be 
required.  The investigator should discuss any questions regarding this with the Sponsor.  The final 
decision on any supportive therapy or vaccination rests with the investigator and/or the subject's 
primary physician.  However, the decision to continue the subject on trial therapy or vaccination 
schedule requires the mutual agreement of the Investigator, the Sponsor, and the subject. 
7.4.1. 
Acceptable concomitant medication 
All treatments that the investigator considers necessary for a subject’s welfare may be administered at 
the discretion of the investigator in keeping with the community standards of medical care.  All 
concomitant medication will be recorded on the case report form (CRF) including all prescription, over-
the-counter (OTC), herbal supplements, and IV medications and fluids.  If changes occur during the 
trial period, documentation of drug dosage, frequency, route, and date may also be included on the 
CRF. 
All concomitant medications received within 28 days before the first dose of trial treatment and 30 
days after the last dose of trial treatment should be recorded.  Concomitant medications administered 
after 90 days after the last dose of trial treatment should be recorded for SAEs. 
7.4.2. 
Prohibited concomitant medication 
Subjects are prohibited from receiving the following therapies during the Screening and Treatment 
Phase (including retreatment for post-complete response relapse) of this trial: 
• 
Anti-cancer systemic chemotherapy or biological therapy  
• 
Immunotherapy not specified in this protocol 
• 
Chemotherapy not specified in this protocol 
• 
Investigational agents other than PEMBROLIZUMAB and CP and G100  
• 
Radiation therapy and other surgical or radiological local treatment of targeted lesions 
o Note:  Palliative radiation therapy to a symptomatic lesion or to the brain may be allowed 
after consultation with Sponsor. For stratum 7, palliative radiotherapy is allowed after week#3. Dose 
and schedule is at the discretion of the investigator. 
• 
Live vaccines within 30 days prior to the first dose of trial treatment, during the study 
treatment and 6 months after the last dose.  Examples of live vaccines include, but are not limited to, 
the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral) 
vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; 
however intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated vaccines, and are not 
allowed.  
• 
Glucocorticoids for any purpose other than to modulate symptoms from an event of clinical 
interest of suspected immunologic etiology.  The use of physiologic doses of corticosteroids may be 
approved after consultation with the Sponsor.  
 
For patients treated with G100: oral anticoagulation:  
o Potential of bleeding during treatment by G100 
 
Note for G100:  Aspirin, anti-platelet agents (clopidogrel), NSAIDs may be used. It depends on 
the tumor injected (superficial / deeper mass) and the risk of bleeding.  
 
Based on the consensus guidelines from the Cardiovascular and Interventional Radiology Society 
of Europe, if a patient is to have a superficial lymph node or subcutaneous mass injected, NSAIDs, 
aspirin, or clopidogrel may be used and do not have to be withheld.  For procedures with 
moderate or significant risk of bleeding, the decision for long-acting agents such as aspirin or 
clopidogrel is at the discretion of the investigator and may need to be discontinued before 

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beginning G100 therapy. (Higher risk would include deeper lesions or those within organs or with 
the potential for bleeding without the possibility of simple compression to help stop the bleeding). 
Subjects who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the trial.  Subjects may receive other 
medications that the investigator deems to be medically necessary. 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
7.4.3. 
Restriction during the study 
7.4.3.1. 
CONTRACEPTION (ALL STRATA) 
Women may only be enrolled if they are willing to use 2 methods of birth control or are considered 
highly unlikely to conceive.  
Highly unlikely to conceive is defined as  
1) surgically sterilized,  
2) or postmenopausal (a woman who is ≥ 45 years of age and has not had menses for greater 
than 1 year will be considered postmenopausal),  
3) or not heterosexually active for the duration of the study. Abstinence is only acceptable as 
“true abstinence” when it is in line with the preferred and usual lifestyle of the patient and not 
a periodic occurrence.  
The two birth control methods can be either two barrier methods or a barrier method plus a hormonal 
method to prevent pregnancy. Subjects should start using birth control 4 weeks before starting study 
treatments, throughout the study period and up to 180 days after the last dose of study treatments. 
The following are considered adequate barrier methods of contraception: diaphragm, condom (by the 
partner) and copper intrauterine device. Appropriate hormonal contraceptives will include any 
registered and marketed contraceptive agent that contains an estrogen and/or a progestational agent 
(including oral, SC, intrauterine, or IM agents).  
For male patients, acceptable contraception includes use of male condom. Subjects should start using 
birth control throughout the study period up to 180 days after the last dose of study treatments. 
If the partner is a woman of childbearing potential, supplemental contraception with hormonal or 
barrier methods should be considered.  
Subjects should be informed that taking the study medication may involve unknown risks to the fetus 
(unborn baby) if pregnancy were to occur during the study. 
7.4.4. 
Supportive care guideline for pembrolizumab 
Subjects should receive appropriate supportive care measures as deemed necessary by the treating 
investigator including but not limited to the items outlined below. Where appropriate, these guidelines 
include the use of oral or intravenous treatment with corticosteroids as well as additional anti-
inflammatory agents if symptoms do not improve with administration of corticosteroids.   Note that 
several courses of steroid tapering may be necessary as symptoms may worsen when the steroid dose 
is decreased. For each disorder, attempts should be made to rule out other causes such as metastatic 
disease or bacterial or viral infection, which might require additional supportive care. The treatment 
guidelines are intended to be applied when the investigator determines the events to be related to 
pembrolizumab. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event. 
 
For Immune-related adverse events (ir-AE): Please see Section 7.5.2 regarding diagnosis and 
management of adverse experiences of a potential immunologic etiology. 
• 
Nausea/vomiting: Nausea and vomiting should be treated aggressively, and consideration 
should be given in subsequent cycles to the administration of prophylactic antiemetic therapy 

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according to standard institutional practice.  Subjects should be strongly encouraged to maintain 
liberal oral fluid intake. 
• 
Anti-infectives: Subjects with a documented infectious complication should receive oral or IV 
antibiotics or other anti-infective agents as considered appropriate by the treating investigator for a 
given infectious condition, according to standard institutional practice. 
• 
Management of Infusion Reactions (table 2):  Acute infusion reactions (which can include 
cytokine release syndrome, angioedema, or anaphylaxis) are different from allergic/hypersensitive 
reactions, although some of the manifestations are common to both AEs.  Signs and symptoms 
usually develop during or shortly after drug infusion and generally resolve completely within 24 hours 
of completion of infusion. Signs/symptoms may include: Allergic reaction/hypersensitivity (including 
drug fever); Arthralgia (joint pain); Bronchospasm; Cough; Dizziness; Dyspnea (shortness of breath); 
Fatigue (asthenia, lethargy, malaise); Headache; Hypertension; Hypotension; Myalgia (muscle pain); 
Nausea; Pruritis/itching; Rash/desquamation; Rigors/chills; Sweating (diaphoresis); Tachycardia; 
Tumor pain (onset or exacerbation of tumor pain due to treatment); Urticaria (hives, welts, wheals); 
Vomiting. 
Table 2 Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion 
of the investigator. 
None 
Grade 2 
Requires therapy or  infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications 
indicated for < =24 hrs 
Stop 
Infusion 
and 
monitor 
symptoms. 
Additional appropriate medical therapy 
may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion 
of the investigator. 
If symptoms resolve within one hour of 
stopping drug infusion, the infusion 
may be restarted at 50% of the original 
infusion rate (e.g. from 100 mL/hr to 50 
mL/hr).  Otherwise dosing will be held 
until symptoms resolve and the subject 
should be premedicated for the next 
scheduled dose. 
Subjects who develop Grade 2 
toxicity despite adequate 
premedication should be 
permanently discontinued from 
further trial treatment 
administration. 
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of PEMBROLIZUMAB 
with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of 
antihistamine). 
 
Acetaminophen 500-1000 mg po 
(or equivalent dose of analgesic). 
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: 
Stop Infusion. 
Additional appropriate medical therapy 
may include but is not limited to: 
    IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine** 
 
**In 
cases 
of 
anaphylaxis, 
No subsequent dosing 

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NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Life-threatening; pressor or 
ventilatory support indicated 
epinephrine 
should 
be 
used 
immediately  
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion 
of the investigator. 
Hospitalization may be indicated. 
Subject is permanently 
discontinued from further trial 
treatment administration. 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the 
period of drug administration. 
For Further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov 

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7.5. DOSING DELAYS/DOSE MODIFICATIONS AND ADVERSE EVENT MANAGEMENT 
7.5.1. 
General rules for dose modification 
Once a dose has been reduced, dose re-increased is not allowed for all IMP. 
 
Doses will be reduced for haematological and other adverse events.  Dose adjustments are to be 
made according to the greatest degree of toxicity.  Adverse events will be graded using the NCI 
Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE). 
 
Main reported toxicities in published series and clinical trials assessing metronomic CP are 
myelosuppression, nausea and vomiting - which are generally mild - and asthenia which appears more 
as a cumulative toxicity [19, 20]. 
 
Patient who permanently discontinue one IMP should go off protocol therapy. 
7.5.1.1. 
FOR TREATMENT STRATEGY A 
Adverse events of clinical interest related to PEMBROLIZUMAB are of an inflammatory or autoimmune 
nature.  
The following guidelines outline dose adjustments for the most frequent of these toxic effects. As no 
severe toxicity is expected, if any other occurs it should be referred to the principal investigator in 
order to decide management in the best interest of the patient according to Investigator Brochure. If 
a patient experiences several adverse events with conflicting recommendations, please use the dose 
modification recommendation that reduces the dose to the lowest level. 
 
Dose Level 
CP  Dose 
1 
50mg b.i.d 
-1 
50mg/d 
 
Nausea 
Management/Next Dose for CP 
Management/Next Dose for 
PEMBROLIZUMAB  
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
No change but give appropriate medication 
systematically 
No change in dose but give appropriate 
medication systematically 
Grade 3 
Hold until < Grade 2, give appropriate 
medication systematically and resume at 
same level, pursuing systemic antiemetic. 
If recurrent: same  
If second recurrent: same and resume at 
lower level dose (level dose -1) 
No change in dose but give appropriate 
medication systematically 
Grade 4 
- 
- 
Patients requiring a delay of >4 weeks should go off protocol therapy. 
Patients requiring > one dose reduction should go off protocol therapy. 
Patient requiring 2 or more consecutive cancellation of PEMBROLIZUMAB injection should go off 
protocol therapy 
Recommended management:  1) domperidone or metoclopramide 

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Vomiting* 
Management/Next Dose for CP 
Management/Next Dose for 
PEMBROLIZUMAB 
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
No change but give appropriate medication 
systematically 
No change but give appropriate 
medication systematically 
Grade 3 
Hold until < Grade 2, give appropriate 
medication systematically and resume at 
same level, pursuing systematic antiemetic 
If recurrent: same and resume at lower 
level dose (level dose -1) 
No change but give appropriate 
medication systematically 
Grade 4 
Hold until < Grade 2, give appropriate 
medication systematically and resume at 
same level, pursuing systematic antiemetic 
If recurrent: same and resume lower level 
dose (level dose -1) If recurrent: off study 
No change but give appropriate 
medication systematically 
If recurrent : add setrons 
If recurrent: off study 
*Management depending on cause of vomiting (CP or MK). 
Patients requiring a delay of >4 weeks or > 1 dose reduction should go off protocol therapy. 
Patient requiring 2 or more consecutive cancellation of PEMBROLIZUMAB injection should go off 
protocol therapy 
Recommended management:  1) domperidone or metoclopramide 2) setrons 
 
Neutropenia 
Management/Next Dose for CP 
Management/Next Dose for 
PEMBROLIZUMAB 
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
No change in dose 
No change in dose 
Grade 3 
Hold until ≤ Grade 2 and resume at 
lower level dose (level dose -1) 
Skip injection until ≤ Grade 2 
Grade 4 
Hold until ≤ Grade 2 and resume at 
lower level dose (level dose -1) 
If recurrent: off study 
Skip injection until ≤ Grade 2 
If recurrent: off study 
Patients requiring a delay of >4 weeks should go off protocol therapy. 
Patients requiring > one dose reduction should go off protocol therapy. 
Patient requiring 2 or more consecutive cancellation of PEMBROLIZUMAB injection should go off 
protocol therapy 
 
Lymphopenia 
Management/Next Dose for CP 
Management/Next Dose for 
PEMBROLIZUMAB 
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
No change in dose 
No change in dose 
Grade 3 
Hold until ≤ Grade 2 and resume 
If recurrent: same and resume at 
lower level dose (level dose -1) 
No change in dose 
Grade 4 
Hold until ≤ Grade 2 and resume at 
lower level dose (level dose -1) 
If recurrent: off study 
Skip injection until ≤ Grade 3 
If recurrent: off study 
Patients requiring a delay of >4 weeks should go off protocol therapy. 
Patients requiring > one dose reduction should go off protocol therapy. 
Patient requiring 2 or more consecutive cancellation of PEMBROLIZUMAB injection should go off 
protocol therapy 
 
 
 
 
 

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Thrombocytopenia 
Management/Next Dose for CP 
Management/Next Dose for 
PEMBROLIZUMAB 
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
Hold until ≤ Grade 1 and resume at 
same dose level. 
If recurrent: same and resume at 
lower level dose (level dose -1) 
No change in dose 
Grade 3 
Hold until ≤ Grade 1 and resume at 
lower level dose (level dose -1) 
Skip injection until ≤ Grade 2 
Grade 4 
Hold until ≤ Grade 1 and resume at 
lower level dose (level dose -1) 
If recurrent: off study 
Skip injection until ≤ Grade 2 
If recurrent: off study 
Patients requiring a delay of >4 weeks should go off protocol therapy. 
Patients requiring > one dose reduction should go off protocol therapy. 
Patient requiring 2 or more consecutive cancellation of PEMBROLIZUMAB injection should go off 
protocol therapy 
 
Fatigue/Asthenia 
Management/Next Dose for CP 
Management/Next Dose for 
PEMBROLIZUMAB 
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
No change in dose 
No change in dose 
Grade 3 
Hold until ≤ Grade 2 and resume at 
same level 
If recurrent: same and resume at lower 
level dose (level dose -1) 
No change in dose 
Grade 4 
Hold until ≤ Grade 2 
If recurrent: same and resume at lower 
level dose (level dose -1) If recurrent: 
off study 
Skip injection until ≤ Grade 2 
If recurrent: off study 
Patients requiring a delay of > 4 weeks should go off protocol therapy. 
Patients requiring > one dose reduction should go off protocol therapy. 
Patient requiring 2 or more consecutive cancellation of PEMBROLIZUMAB injection should go off 
protocol therapy 
 
7.5.1.2. 
FOR TREATMENT STRATEGY B 
Adverse events of clinical interest related to Pembrolizumab are of an inflammatory or autoimmune 
nature.  
Please refer to the guidelines of strategy A for dose adjustments for the most frequent of adverse 
effects. For other adverse effects, please refer to the most updated Investigator Brochure 
(Pembrolizumab and G100)/Summary of Product Characteristics (CP). 
 
As no severe toxicity is expected, if any other occurs it should be referred to the principal investigator 
in order to decide management in the best interest of the patient. If a patient experiences several 
adverse events with conflicting recommendations, please use the dose modification recommendation 
that reduces the dose to the lowest level. 
 
7.5.2. 
Immune related adverse event (irAE) 
7.5.2.1. 
IMMUNE RELATED ADVERSE EVENT (IRAE) 
Immune-Related Adverse Events (irAE)may be defined as an adverse event, associated with drug 
exposure and is consistent with an immune phenomenon.  irAEs may be predicted based on the drug’s 
mechanism of action, and reported experience with immunotherapies that have a similar mechanism 
of action.  Special attention should be paid to potential irAEs.  An irAE can occur between shortly after 
the first dose to several months after the last dose of treatment.   
If an irAE is suspected, efforts should be made to rule out neoplastic, infectious, metabolic, toxin or 
other etiologic causes prior to labeling an adverse event as an irAE.  All irAE should be reported to 

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sponsor (see section 11.5) but more specially subjects who develop a Grade 2 or higher irAE should 
be discussed immediately with the Sponsor.  
When a second episode of the same serious adverse reaction occurs (including colitis grade 3), 
permanently discontinue all IMP immediately  
Patient requiring 2 or more consecutive cancellation of PEMBROLIZUMAB injection should be 
withdrawn from the study. 
Patient who permanently discontinue one IMP should be withdrawn from the study. 
For G100, no dose reduction is required in case of occurrence of irAE. 
The management of ir-AE is described in annexe 9. For more details, refer to the most updated 
Investigator’s Brochure of each IMP. 
As of this day, no irAE has been reported with G100. However, as with any immune stimulatory 
approach, irAEs resulting from cross-reactivity of the immune response with normal patient tissues 
could potentially occur (such as autoimmune colitis, hypophysitis, etc. observed with anti-PD-1 
therapeutics). 
 
Based on limited data from clinical studies if immune-related adverse reactions could not be controlled 
with corticosteroid use, administration of other systemic immunosuppressants can be considered. 
.  
7.5.2.2. 
SEVERE SKIN REACTIONS 
 
Cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some with fatal 
outcome, have been reported in patients treated with PEMBROLIZUMAB. When SJS or TEN is 
suspected, withhold PEMBROLIZUMAB and refer the patient for specialized care for assessment and 
treatment. 
When SJS or TEN is confirmed, permanently discontinue  PEMBROLIZUMAB immediately.  
 
7.5.2.3. 
IMMUNE-MEDIATED MYOCARDITIS 
For suspected immune-mediated myocarditis, ensure adequate evaluation to exclude other etiologies, 
and administer corticosteroids as appropriate. 
In all the cases of myocarditis, pembrolizumab must be permanently discontinued.  
Besides, the administration of high-dose steroids, the following recommendations must 
be followed:  
 
 
Haemodynamically unstable patients 
Patients with haemodynamically unstable heart failure should be managed promptly for heart failure in 
intensive care units with respiratory and mechanical cardio-pulmonary support facilities. In 
acute/fulminant cases with cardiogenic shock and severe ventricular dysfunction, ventricular assist 
devices or extracorporeal membrane oxygenation (ECMO) may be needed to provide a bridge to 
transplant or to recovery. Because of its simplicity and effectiveness, ECMO therapy can rescue this 
group of patients. 
 
Haemodynamically stable patients 
When myocarditis is suspected in asymptomatic or mildly symptomatic patients, admission to hospital 
and clinical monitoring are recommended until a deﬁnite diagnosis is established, since the situation 
can evolve rapidly and a cardiopulmonary emergency (e.g. severe heart block or life-threatening 
arrhythmia) is possible and unpredictable, even if systolic function is initially preserved. Exercise 
testing is contraindicated in the acute stage as it can precipitate arrhythmia. 
Patients with haemodynamically stable heart failure should be treated with diuretics, angiotensin-
converting enzyme inhibitor, or angiotensin receptor blockade and beta-adrenergic blockade. In 
patients who have persistent heart failure symptoms despite optimal management, additional 
treatment with aldosterone antago-nists should be considered. 
 
 

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7.5.2.4. 
IMMUNE-MEDIATED NEUROPATHIES 
Immune-mediated neuropathies have been reported in patients treated with Pembrolizumab. 
Monitor subjects for symptoms of motor or sensory neuropathy such as unilateral or bilateral 
weakness, sensory alterations, or paresthesia. 
Permanently discontinue Pembrolizumab in subjects with severe neuropathy (interfering with daily 
activities) such as Guillain-Barré-like syndromes; institute medical intervention as appropriate for 
management of severe neuropathy. Consider initiation of systemic corticosteroids at a dose of 1 to 2 
mg/kg per day prednisone or equivalent for severe neuropathies.  
Withhold Pembrolizumab doses in subjects with moderate neuropathy (not interfering with daily 
activities). 
 
7.5.2.5. 
ENCEPHALITIS 
Encephalitis has been reported in patients treated with Pembrolizumab. 
Permanently discontinue Pembrolizumab in subjects with encephalitis and patients must be 
hospitalized in neurological intensive care unit for appropriate management. 
 
7.6. PACKAGING AND LABELING 
The following information will appear on the labels: 
 
Name of the Sponsor. 
 
Dosage and route of administration. 
 
Quantity or contents of container. 
 
Batch number/packaging number. 
 
Expiration date and storage conditions. 
 
Local legal information, as appropriate. 
 
7.7. SUPPLIES AND DRUG ACCOUNTABILITY 
PEMBROLIZUMAB is an investigational agent supplied by Merck.  
Cyclophosphamide will be supplied by the Sponsor. 
G100 is an investigational agent supplied by Immune Design. 
Each participating institution will order study drugs according to the process describe in the manual 
pharmacy. 
Proper drug accountability will be done by the clinical trial monitor. Each study site will keep records 
to allow a comparison of quantities of drug received and used at each site. The Investigator at each 
study site will be the person ultimately responsible for drug accountability at the site.    
During or at the end of the study, all unused drug supplied by the Sponsor will be properly destroyed 
at the study site or returned to the distribution depot for destruction, at the end of the study. 
Documentation of this procedure must be provided to the clinical trial monitor. 
 
7.8. TREATMENT COMPLIANCE 
The Investigator is responsible for supervising compliance with the instructions described in this study 
protocol. 
 

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8. STUDY EVALUATIONS 
Study evaluations aim to assess:  
 
Diagnosis  
 
Efficacy 
 
Safety 
 
8.1. CENTRAL REVIEW FOR DIAGNOSIS OF SARCOMA/GIST AND PROGRESSIVE 
DISEASE 
8.1.1. 
Diagnosis 
8.1.1.1. 
DIAGNOSIS OF SARCOMA/GIST 
If diagnosis of sarcoma was not confirmed by the RRePS Network, pathological central review will be 
performed to confirm histological diagnosis of sarcoma/GIST by Pr. Coindre and collaborators, 
Department of Pathology, Institut Bergonié, Bordeaux, France. The reviewer will assess pathological 
diagnosis; document the results on the ‘Pathological request form’ response completed and sign this 
form. 
Every discrepancy will be discussed between referral investigator, Pr Coindre or collaborators and the 
Sponsor, until a final decision is reached. Patients with diagnosis different from sarcoma/GIST will be 
considered ineligible and will not be included in the study. 
8.1.1.2. 
PATHOLOGICAL SPECIMEN SAMPLING NECESSARY FOR CENTRAL REVIEW 
For a gross description and diagnostic information concerning pathological specimens, reference to 
“Recommendations for reporting soft tissue sarcomas” is strongly advised (Recommendations, 1999). 
Available tumor samples obtained at diagnosis or at relapse, as unstained slides (10), and/or 
preferable paraffin-embedded tumor blocks (one or two) is mandatory for central review. 
8.1.1.3. 
PATHOLOGICAL PROCESS SCHEDULE AND IMPLEMENTATION (NOT APPLICABLE IF 
DIAGNOSIS REVIEWED IN RREPS NETWORK) 
Each site will send to Institut Bergonié within 7 days after the signature of informed consent: 
- 
Pathology request form completed  
- 
10 unstained slides and/or preferable FFPE (Formalin-Fixed Paraffin-Embedded) block of 
specimen tumor sampling, obtained anytime during disease development 
- 
Initial pathology report with patient code and date of birth (including macroscopic description) 
and pathology report of molecular biology if any. 
 
All material must be sent as described in specific guidelines provided by the Sponsor: 
 
8.1.2. 
Diagnosis of progressive disease – Central review before 
registration 
8.1.2.1. 
CENTRALIZED PATHOLOGICAL REVIEW TO CONFIRM DIAGNOSIS OF PROGRESSIVE 
DISEASE FOR SARCOMA/GIST 
Centralized radiological review will be performed to confirm progressive disease status at inclusion 
time. This will be performed by centrally reviewing two CT scans or MRI obtained prior to inclusion 
(obtained at an interval less than 6 months in the period of 12 months prior to inclusion). 
8.1.2.2. 
GENERAL PROCEDURE 
Review process will be centralized at Institut Bergonié and will be performed by one radiologist expert 
in sarcomas/GIST. 
The results of the centralized review will be used for the diagnosis for progressive disease. 
 
 
 

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8.1.2.3. 
REVIEW PROCESS SCHEDULE AND PRACTICAL IMPLEMENTATION 
With regards to inclusion scan, the progressive disease status at baseline must be confirmed by 
central review. Within 7 Days after the signature of informed consent: 
- 
Each site will send two-imaging CD (two radiological assessments identical, CT-scans or MRI) 
obtained at less from 6 months interval within 12 months before inclusion) to Bergonie 
Institute  
- 
Each site must send the completed "Baseline Radiological Form" with the first shipment 
- 
For each shipment, each media should be accompanied by the completed "Radiological 
Referral Form" 
Patient's information must be recorded on an imaging CD. 
All CDs must be sent as described in specific guidelines provided by the Sponsor 
 
8.2. BIOPATHOLOGICAL CONFIRMATION FOR STRATUM 6 
Centralized pathologival review will be performed to confirm the presence of tertiary lymphoid 
structures on tumor sample. 
8.2.1. 
General procedure 
Review process will be centralized. 
The results of the centralized pathological review will be used to confirm patient eligibility. 
8.2.2. 
Review process schedule and practical implementation 
Each site will send within 7 days after the signature of informed consent, archived or newly obtained 
FFPE (Formalin-Fixed Paraffin-Embedded) block. 
 
All material must be sent as described in specific guidelines provided by the Sponsor. 
 
8.3. EFFICACY  
The antitumor activity of the treatment strategy will be evaluated in terms of 6-month objective 
response, 6-month non-progression, best overall response, Growth modulation index (GMI), 1-year 
progression-free survival (PFS) and 1-year overall survival (OS). Objective response, non-progression 
and best overall response are defined as per the Response Evaluation Criteria in Solid Tumors 
(RECIST v1.1, 75 – Appendix 2).  
 
8.3.1. 
Assessing Tumor Response (RECIST v1.1) 
 
A comprehensive workup will be performed at baseline and every six weeks. 
 
Whenever response criteria are met, the appropriate imaging tests will be repeated at least four 
weeks later in order to confirm the response.  
 
The same method will be used to evaluate each identified lesion both at baseline and throughout 
the study. 
 
Treatment will be administered as long as no disease progression or unacceptable toxicity is 
found, or as long as no other reasons for treatment discontinuation are met.  
 
Assessment of efficacy will be essentially based on a set of measurable lesions identified at 
baseline as target lesions and followed until disease progression and following the RECIST v1.1 
criteria (RECIST v1.1, 75 – Appendix 2). 
 
8.3.2. 
Centralized Radiological Review (Institut Bergonié)  
8.3.2.1. 
GENERAL PROCEDURE 
Centralized radiological review will be performed to review all disease status at 6 months in 
comparison with baseline. 
Review process will be centralized at Institut Bergonié and then will be performed by an independant 
radiologist expert in soft tissue sarcomas and/or GISTs. 
In case of discordance between the local radiologist and the expert reviewer, the judgment provided 

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by the expert reviewer will be retained and used in statistical analyses. 
8.3.2.2. 
REVIEW PROCESS SCHEDULE  
All tumor evaluations will be sent as soon as there were available. 
Patient’s information must be recorded on a provided imaging CD. 
8.3.2.3. 
PRACTICAL IMPLEMENTATION 
For each shipment, each media should be accompanied by the Radiological Forms provided by the 
sponsor. 
All CDs must be sent as described in specific guidelines provided by the Sponsor 
 
8.3.3. 
Assessing 
immune-related 
response 
by 
centralized 
Radiological Review (Institut Bergonié)  
Centralized radiological review will be performed to evaluate 6-months immune-related response 
(Wolchok et al. Clinical Cancer Research 2009) in comparison with baseline (all imaging available at 6 
months). 
Review process will be centralized at Institut Bergonié and then will be performed by a radiologist 
expert in soft tissue sarcomas and/or GISTs, and will be based on media previously sent. 
 
8.4. SAFETY 
Patients will be evaluable for safety if they have received at least one treatment administration. Safety 
will be evaluated using clinical examinations, which will comprise vital signs analysis, clinical 
assessment of AEs, changes in laboratory parameters (hematological and biochemical, including liver 
function tests) and any other analyses that may be considered necessary. Safety profile will be 
continuously followed during treatment up to 90 days after the last treatment administration or until 
the start of a new antitumor therapy, whichever occurs first. All AEs will be classified according to the 
NCI-CTCAE, version 4.0 (81). 
 
9. STUDY ENDPOINTS 
9.1. PRIMARY ENDPOINT 
9.1.1. 
Advanced leiomyosarcoma (stratum 1) 
 
The primary efficacy endpoint is a dual endpoint encompassing non-progression and objective 
response at 6 months. 
o 
Non-progression is defined as complete response, partial response or stable disease 
more than 24 weeks as defined as per RECIST evaluation criteria v1.1 (RECIST v1.1, 
75 – Appendix 2). 
o 
Objective response is defined as complete response or partial response as defined as 
per RECIST evaluation criteria v1.1 (RECIST v1.1, 75 – Appendix 2)  
o 
The rates of objective response and non-progression at 6 months will be reported. 
 
All eligible and assessable patients (section 10.2) will be included in the 
denominator for the calculation of the response rate or non-progression rate. 
 
The rate of non-progression will be calculated as the number of patients 
remaining alive and progression-free at 6 months from the start of the 
treatment divided by the number of patients eligible and assessable (section 
10.2). 
 
The rate of objective response will be calculated as the number of patients 
alive with complete or partial response at 6 months divided by the number of 
patients eligible and assessable (section 10.2). 
 
The 95% two-sided confidence limits will be provided for the calculated rates 
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 
Trial conclusions will be based on these rates for all eligible and assessable 
patients (section 10.2). 
 
Tumor measurements will be repeated every 6 weeks. Documentation (radiologic) will be provided 
for patients removed from study for progressive disease. 
 
Following RECIST v1.1 recommendations:  
o 
Claimed (complete or partial) responses will have to be confirmed at least 4 weeks 
later to ensure responses identified are not the result of measurement errors. 
o 
6-month radiological data will be reviewed by an independent expert radiologist.  
o 
Primary efficacy analysis will be based on the central radiological review data. 
9.1.2. 
Advanced undifferentiated sarcoma (stratum 2) 
 
The primary efficacy endpoint is a dual endpoint encompassing non-progression and objective 
response at 6 months. 
 
See section 9.1.1. 
9.1.3. 
Advanced other sarcoma (stratum 3) 
 
The primary efficacy endpoint is a dual endpoint encompassing non-progression and objective 
response at 6 months. 
 
See section 9.1.1. 
9.1.4. 
Advanced osteosarcoma (stratum 4) 
 
The primary efficacy endpoint is a dual endpoint encompassing non-progression and objective 
response at 6 months. 
 
See section 9.1.1. 
9.1.5. 
Advanced GIST (stratum 5) 
 
The primary efficacy endpoint is non-progression at 6 months. 
 
See section 9.1.1. 
9.1.6. 
Advanced soft tissue sarcomas with immune signature 
(stratum 6) 
 
The primary efficacy endpoint is non-progression at 6 months. 
 
See section 9.1.1. 
9.1.7. 
Metastatic STS (stratum 7) 
 
The primary efficacy endpoint is non-progression at 6 months. 
 
See section 9.1.1. 
 
9.2. SECONDARY ENDPOINTS 
For each stratum: 
 
Efficacy of the association of the treatment strategy in terms of: 
o 
Best overall response is defined as the best response recorded from the start of the 
study treatment until the end of treatment taking into account any requirement for 
confirmation as per RECIST v1.1 criteria (appendix 2) :  
 
 The rate of best overall response will be reported. 
 
All eligible and assessable patients (section 10.2) will be included in the 
denominator for the calculation of the rate. 
 
The rate of best overall response will be calculated as the number of patients 
alive with the best response (recorded from the start of the treatment) 
divided by the number of patients eligible and assessable (section 10.2).   

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 
The 95% two-sided confidence limits will be provided for the calculated rate 
(binomial law). 
Following RECIST v1.1 recommendations:  
 
The best overall response is determined once all the data for the patient is 
known. 
 
Complete or partial responses may be claimed only if the criteria for each are 
met at a subsequent time point (>= 4 weeks later).  
o 
1-year progression-free survival (PFS): PFS is defined as the time from study 
treatment initiation to the first occurrence of disease progression or death (of any 
cause), whichever occurs first. 
o 
1-year overall survival (OS): OS is defined as the time from study treatment initiation 
to death (of any cause). 
o 
Immune-related response is defined following Wolchok et al. (Clinical Cancer Research 
2009, Appendix 5). Analysis of Immune-related response will be based on central 
radiological review data. 
o 
Growth modulation index (GMI), defined for each patient as the ratio of the PFS on 
the current treatment strategyto the PFS on the previous line of therapy (61), in 
patients with documented progression at inclusion. 
 
Assessment of the safety profile of the treatment strategy. Toxicity will be graded using the 
common toxicity criteria from the NCI v4.0.  
For each stratum 1 to 5:  
 
Performance of pharmacodynamic (PD)/mechanism of action (MOA) biomarkers analysis as 
well as predictive biomarkers analysis (levels of angiogenic and immunologic biomarkers in 
blood at baseline and different study time points. Blood samples will be collected at predefined 
time points: 
o 
 Serum/plasma cytokines levels (TNFγ, TNFα, TGFβ, IL2, 4, 6, 10) (ELISA) 
o 
Serum/plasma VEGF and TPS-1 levels (ELISA)  
o 
Treg, CD4+ CD8+ and DR lymphocytes subpopulations monitoring, CD8+/Treg ratio 
(flow cytometry)  
o 
Plasma levels of Kynurenine and Kynurenine to Tryptophan ratio (ELISA and LC/MS). 
o 
Additional details are provided in section 17. 
 
Fresh pre-treatment (or archival material obtained from less than 12 weeks before inclusion) will 
be collected in consenting patients to assess pharmacodynamics biomarkers.  Formalin-fixed, 
paraffin-embedded biopsy samples will be analysed for (but not limited to) PDL1, CSF-1R, 
CD68/CD163, CD68/MHC class II, CD31 (microvessel density), Ki67 and other exploratory 
markers. Additional details are provided in section 17. 
 
Prospective determination of the proportion of STS that express PDL1 will be assessed as detailed 
in section 17.  
For each stratum 6 to 7:  
 
Pharmacodynamic (PD)/mechanism of action (MOA) biomarkers analysis as well as predictive 
biomarkers analysis (levels of angiogenic and immunologic biomarkers in blood and tumor 
tissue at baseline and different study time points. 
o 
Blood samples will be mandatory collected at predefined timepoints for assessment of: 
o 
Serum/plasma cytokines levels (TNFγ, TNFα, TGFβ, IL2, 4, 6, 10) (ELISA) 
o 
Treg, CD4+ CD8+ and DR lymphocytes subpopulations monitoring, 
CD8+/Treg ratio (flow cytometry) 
o 
Plasma levels of Kynurenine and Kynurenine to Tryptophan ratio (ELISA and 
LC/MS). 
o 
Additional details are provided in section 17. 
 
Fresh tumor samples will be mandatorily collected at baseline and during treatment. Formalin-
fixed, paraffin-embedded biopsy samples will be analysed for (but not limited to) CD8+ effectors, 
CD68 and 163 Macrophages and FOXP3+ cells infiltrates as well as PDL1, IDO1, CD31 
(microvessel density), Ki67 expression by IHC. Frozen samples will be analysed by (but not limited 
to) RNA sequencing in search for a predictive signature for response. Additional details are 

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provided in section 17.  
 
10. STATISTICAL CONSIDERATIONS 
10.1. 
HYPOTHESES AND NUMBER OF SUBJECTS NEEDED  
6-month non-progression is a worldwide recognized endpoint for STS phase 2 trials based on the 
EORTC results (European Organization for Research and Treatment of Cancer) who demonstrated 
that, in case of progressive disease following a first-line chemotherapy, a drug can be considered 
active in soft-tissue sarcoma patients if the 6-month non-progression rate is at least ≥ 20% (4). In 
STS patients refractory to fist-line chemotherapy, pazopanib was associated with a 6-months non-
progression rate of 40% and a response rate of 6% (60). The data from the literature about outcome 
of patients with advanced osteosarcomas are limited. Objective response as a single endpoint may not 
be an appropriate surrogate marker for therapeutic activity in osteosarcoma. Indeed, due to the 
abundant bone matrix, substantial anti-tumor activity may not result in a marked decrease in overall 
tumor volume. Median progression-free survival of relapsed osteosarcomas patients with unresectable 
disease and rechallenged with chemotherapy is about 2 months (76).  GIST patients refractory to 
first-line imatinib and 2nd line sunitinib have a 6-months non progression rate of about 40% on third 
line treatment (24, 77).   
 
10.1.1. 
Advanced leiomyosarcoma (stratum 1) 
 
We rely on a single-arm phase 2 trial based on 2-stage dual endpoint design (72).  
 
PEMBROLIZUMAB + metronomic CP will be considered promising if either tumour response 
rate or 6-month non-progression rate is promising 
 
Hypotheses under PEMBROLIZUMAB + metronomic CP are the following:  
o 
 Hypotheses for non-progression at 6 months: 
 
40% non-progression rate (null hypothesis),  
 
60% non-progression rate (alternative hypothesis),  
o 
Hypotheses for objective response at 6 months: 
 
5% objective response rate (null hypothesis),  
 
20% objective response rate (alternative hypothesis),  
o 
Maximal type I error of 5% rate and 80% minimum power  
 
 
Assuming 30 eligible and assessable patients: 
o 
Stage 1 (15 eligible and assessable patients): Inclusions will continue if either 
objective response is observed in at least 3 or non-progression is observed for 
9patients or more. Otherwise, the stratum will be terminated early and declared 
negative. 
o 
Stage 2 (15 additional eligible and assessable patients): PEMBROLIZUMAB + 
metronomic CP will be considered worthy of further testing in this indication if at least 
8 objective responses, or at least 20 non-progression at six months are observed 
among the 30 evaluable patients.  
 
Inclusions will be suspended after the recruitment of the first 15 patients while data are being 
analysed for the first stage of inclusion. 
 
In order to account for not evaluable patients (+/- 10%), 33 patients with 
advanced leiomyosarcoma will be recruited. 
 
10.1.2. 
Advanced undifferentiated sarcoma (stratum 2) 
 
Same hypotheses as for leiomyosarcoma 
 
Assuming 30 eligible and assessable patients: 
o 
Stage 1 (15 eligible and assessable patients): Inclusions will continue if either 
objective response is observed in at least 3 or non-progression is observed for 9 

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patients or more. Otherwise, the stratum will be terminated early and declared 
negative. 
o 
Stage 2 (15 additional eligible and assessable patients): PEMBROLIZUMAB + 
metronomic CP will be considered worthy of further testing in this indication if at least 
8 objective responses, or at least 20 non-progression at six months are observed 
among the 30 evaluable patients.  
 
Inclusions will be suspended after the recruitment of the first 15 patients while data are being 
analysed for the first stage of inclusion. 
 
In order to account for not evaluable patients (+/- 10%), 33 patients with 
advanced undifferentiated sarcoma will be recruited. 
 
10.1.3. 
Advanced other sarcoma (stratum 3) 
 
Same hypotheses as for leiomyosarcoma 
 
Assuming 30 eligible and assessable patients: 
o 
Stage 1 (15 eligible and assessable patients): Inclusions will continue if either 
objective response is observed in at least 3 or non-progression is observed for 9 
patients or more. Otherwise, the stratum will be terminated early and declared 
negative. 
o 
Stage 2 (15 additional eligible and assessable patients): PEMBROLIZUMAB + 
metronomic CP will be considered worthy of further testing in this indication if at least 
8 objective responses, or at least 20 non-progression at six months are observed 
among the 30 evaluable patients.  
 
Inclusions will be suspended after the recruitment of the first 15 patients while data are being 
analysed for the first stage of inclusion. 
 
In order to account for not evaluable patients (+/- 10%), 33 patients with 
advanced other sarcoma will be recruited. 
 
10.1.4. 
Advanced osteosarcoma (stratum 4) 
 
Same hypotheses as for leiomyosarcoma 
 
Assuming 30 eligible and assessable patients: 
o 
Stage 1 (15 eligible and assessable patients): Inclusions will continue if either 
objective response is observed in at least 3 or non-progression is observed for 9 
patients or more. Otherwise, the stratum will be terminated early and declared 
negative. 
o 
Stage 2 (15 additional eligible and assessable patients): PEMBROLIZUMAB + 
metronomic CP will be considered worthy of further testing in this indication if at least 
8 objective responses, or at least 20 non-progression at six months are  observed 
among the 30 evaluable patients.  
 
Inclusions will be suspended after the recruitment of the first 15 patients while data are being 
analysed for the first stage of inclusion. 
 
In order to account for not evaluable patients (+/- 10%), 33 patients with 
advanced osteosarcoma will be recruited. 
 
10.1.5. 
Advanced GIST (stratum 5) 
 
We rely on a single-arm phase 2 trial based on an optimal two-stage Simon’s design (73)  
 
PEMBROLIZUMAB + metronomic CP will be considered promising if 6-month non-progression 
rate is promising 
 
Hypotheses under PEMBROLIZUMAB + metronomic CP treatment are the following (78)  
o 
Hypotheses for non-progression at 6 months: 
 
 30% non-progression rate (null hypothesis),  
 
60% acceptable non-progression rate (alternative hypothesis),  
o 
5% type I error rate,   

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o 
90% power, 
 
A total of 28 assessable subjects will be necessary, with 10 assessable subjects recruited to 
the first stage.  
o 
Stage 1: Following the inclusion of the first 10 assessable patients, if 3 or less patients 
are progression-free (complete response, partial response or stable disease), the 
study will be terminated early. Otherwise, the second group of 18 subjects will be 
recruited.  
o 
 Stage 2: If at the end of recruitment, 13 patients or more are progression-free (out of 
the 28 evaluable patients), PEMBROLIZUMAB + metronomic CP will be considered 
worthy of further testing in this disease. 
 
Inclusions will be suspended after the recruitment of the first 10 patients while data are being 
analysed for the first stage of inclusion. 
 
In order to account for not evaluable patients (+/- 10%), 31 patients with 
advanced GIST will be recruited. 
 
10.1.6. 
Advanced soft tissue sarcomas with immune signature 
(stratum 6) 
 
We rely on a single-arm phase 2 trial based on an optimal two-stage Simon’s design (73).  
 
PEMBROLIZUMAB + metronomic CP will be considered promising if 6-month non-progression 
rate is promising (>=15%). 
 
Hypotheses under PEMBROLIZUMAB + metronomic CP treatment are the following (92):  
o 
Hypotheses for non-progression at 6 months: 
 
 15% non-progression rate (null hypothesis),  
 
40% acceptable non-progression rate (alternative hypothesis),  
o 
5% 1-sided type I error rate,   
o 
90% power, 
 
A total of 29 eligible and assessable subjects will be necessary, with 13 assessable subjects 
recruited to the first stage.  
o 
Stage 1: Following the inclusion of the first 13 assessable patients, if 2 or less patients 
are progression-free at 6 months (complete response, partial response or stable 
disease), the study will be terminated early. Otherwise, the second group of 16 
subjects will be recruited.  
o 
 Stage 2: If at the end of recruitment, 8 patients or more are progression-free at 6 
months (out of the 29 eligible and evaluable patients), PEMBROLIZUMAB + 
metronomic CP will be considered worthy of further testing in this disease (efficacy 
rate >=15%). 
 
Inclusions will not be suspended after the recruitment of the first 13 patients while data are 
being analysed for the first stage of inclusion. 
 
In order to account for not evaluable patients (+/- 10%), 32 patients with 
sarcoma with immune signature will be recruited. 
 
10.1.7. 
Metastatic STS (stratum 7) 
 
We rely on a single-arm phase 2 trial based on an optimal two-stage Simon’s design (73).  
 
PEMBROLIZUMAB + metronomic CP + G100 will be considered promising if 6-month non-
progression rate is promising (>=15%). 
 
Hypotheses under PEMBROLIZUMAB + metronomic CP + G100 treatment are the following 
(92):  
o 
Hypotheses for non-progression at 6 months: 
 
 15% non-progression rate (null hypothesis),  
 
40% acceptable non-progression rate (alternative hypothesis),  
o 
5% 1-sided type I error rate,   

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o 
90% power, 
 
A total of 29 eligible and assessable subjects will be necessary, with 13 assessable subjects 
recruited to the first stage.  
o 
Stage 1: Following the inclusion of the first 13 assessable patients, if 2 or less patients 
are progression-free at 6 months (complete response, partial response or stable 
disease), the study will be terminated early. Otherwise, the second group of 16 
subjects will be recruited.  
o 
 Stage 2: If at the end of recruitment, 8 patients or more are progression-free at 6 
months (out of the 29 eligible and evaluable patients), PEMBROLIZUMAB + 
metronomic CP + G100 will be considered worthy of further testing in this disease 
(efficacy rate >=15%). 
 
Inclusions will be suspended after the recruitment of the first 13 patients while data are being 
analysed for the first stage of inclusion. 
 
In order to account for not evaluable patients (+/- 10%), 32 patients with 
metastatic soft-tissue sarcoma will be recruited. 
 
10.2. 
DEFINITION OF STUDY POPULATIONS 
10.2.1. 
Advanced leiomyosarcoma (stratum 1) 
 Eligible population: All patients included without major violation of eligibility criteria. 
 Population eligible and assessable for the primary endpoint : eligible patients who received at least 
one administration of PEMBROLIZUMAB and one administration of Metronomic CP 
 Safety population: All patients with at least one treatment (any) administration. 
Replacement of patients: patients who do not comply with the definition of the population “eligible 
and assessable for the primary endpoint” will be replaced. 
10.2.2. 
Advanced undifferentiated sarcoma (stratum 2) 
Same definitions as for leiomyosarcoma 
10.2.3. 
Advanced other sarcoma (stratum 3) 
Same definitions as for leiomyosarcoma 
10.2.4. 
Advanced osteosarcoma (stratum 4) 
Same definitions as for leiomyosarcoma 
10.2.5. 
Advanced GIST (stratum 5) 
Same definitions as for leiomyosarcoma 
10.2.6. 
Advanced soft tissue sarcomas with immune signature 
(stratum 6) 
Same definitions as for leiomyosarcoma 
10.2.7. 
Metastatic STS (stratum 7) 
 Eligible population: All patients included without major violation of eligibility criteria. 
 Population eligible and assessable for the primary endpoint: eligible patients who received at least 
one administration of PEMBROLIZUMAB and one administration of Metronomic CP and one 
administration of G100. 
 Safety population: All patients with at least one treatment (any) administration. 
 
Replacement of patients: patients who do not comply with the definition of the population “eligible 
and assessable for the primary endpoint” will be replaced. 
 
 
 
 
 

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10.3. 
STATISTICAL ANALYSIS 
 Each stratum will be analysed independently. No statistical comparison will be performed between 
strata. 
 For each stratum, two statistical analysis plans (SAP) will be produced by the statistician and 
validated by the steering committee before the first database extraction for analysis (version n°1): 
one for the interim statistical analysis and one for the final statistical analysis. The SAP may be 
revised during the course of the study in case of substantial modification of the protocol or 
following recommendations of the Independent Data Monitoring Committee.  
10.3.1. 
Endpoint analysis 
 
Patients entered into the study will be described according to the following characteristics:  
o 
Compliance with eligibility criteria, 
o 
Sociodemographic characteristics, 
o 
Clinical and laboratory characteristics, 
o 
Treatment characteristics. 
 
 
Primary efficacy endpoint analysis 
o 
The primary efficacy endpoint will be analysed based on the eligible and assessable 
population (see chapter 10.2 for definition). 
 
Efficacy of the treatment strategy will be assessed in terms of : 
 
6-month objective response (complete response and partial response) 
and 6-month non-progression (complete response and partial 
response, stable disease more than 24 weeks) for leiomyosarcoma 
(stratum 1), undifferentiated sarcoma (stratum 2), other sarcoma 
(stratum 3), osteosarcoma (stratum 4) (dual endpoint)  
 
6-month non-progression for GIST (stratum 5), advanced soft-tissue 
sarcoma with immune signature (stratum 6) and metastatic STS 
(stratum 7) (single endpoint) 
 
Objective response and non-progression are defined based on radiological 
and clinical data as defined as per RECIST v1.1 criteria. 
 
Primary efficacy analysis will be based on the central radiological review data. 
 
Each patient will be assigned one of the following categories:  
 
Complete response 
 
Partial response 
 
Stable disease 
 
Progression 
 
Not evaluated for response. 
 
The rates of objective response and non-progression at 6 months will be 
reported for strata 1 to 4. 
 
The rates of non-progression at 6 months will be reported for strata 5 to 7. 
 
All eligible and assessable patients (section 10.2) will be included in the 
denominator for the calculation of the response rate. 
 
The 95% two-sided confidence limits will be provided for the calculated 
response rate (binomial law). 
 
Trial conclusions will be based on the response rates for all eligible and 
assessable patients (section 10.2). 
 
As regards to the other efficacy endpoints, the analyses will be carried out in the eligible   and 
assessable population.  
 
The safety analysis will be performed on the safety population.  
 
Quantitative variables will be described using means and standard errors if the normality 
assumption is satisfied, else other descriptive statistics (median, range, quartiles) will be used. 
 
Qualitative variables will be described using frequency, percentage and 95% confidence interval 
(binomial law). 
 
Survival endpoints will be analysed using the Kaplan-Meier method. The median survival rates will 
be reported with a 95% confidence interval. Median follow-up will be calculated using the reverse 
Kaplan-Meier method. Multivariate analyses can also be carried out based on Cox’s proportional 
risk method and after checking the risk proportionality hypothesis.  
 
Prognostic role of biomarkers will be assessed using logistic or survival models depending on the 
nature of the outcome variable (time-to-event or binary endpoint). Multivariate models will be 

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constructed following a backward selection approach based on candidates variables selected 
following univariate analyses. 
 
10.3.2. 
Interim Statistical Analyses 
 
For each stratum, an interim statistical analysis will be performed at the end of the 1st stage of 
recruitment. Results of these interim statistical analyses will be presented to the IDMC members 
(section 12.1.2). 
10.3.2.1. 
EARLY REVIEWS OF SAFETY DATA 
10.3.2.1.1. 
STRATA 1 TO 5 
 
Inclusions will be suspended after inclusion of the first 10 patients. 
 
The first review of safety data will take place once 2-month follow-up data are available for the 
first 3 treated patients (independently of the stratum).  
o 
The steering committee (section 12.1.1) will review the safety data for these patients. 
o 
The steering committee will then decide if inclusions can continue and/or, if needed, 
whether treatment surveillance should be modified.  
10.3.2.1.2. 
STRATUM 6 
 
As safety data are already available for strata 1 to 5, no additional review will be performed for 
this stratum. 
10.3.2.1.3. 
STRATUM 7 
 
For each therapeutic strategy, the first review of safety data will take place once 2-month follow-
up data are available for the first 3 treated patients (independently of the stratum).  
o 
Inclusion will not be suspended 
o 
The steering committee (section 12.1.1) will review the safety data for these patients. 
o 
The steering committee will then decide if inclusions can continue and/or, if needed, 
whether treatment surveillance should be modified.  
o 
Conclusions of the steering committee and safety data will be submitted to an 
independent data monitoring committee (IDMC). 
o 
Sponsor is then responsive for sending IDMC recommandations and safety review reports 
to ANSM. 
 
The second review of safety data will take place once 2-month follow-up data are available for the 
first 6 treated patients (independently of the stratum).  
o 
Inclusions will not be suspended 
o 
The steering committee (section 12.1.1) will review the safety data for these patients. 
o 
The steering committee will then decide if inclusions should be stopped and/or, if needed, 
whether treatment surveillance should be modified 
o 
Conclusions of the steering committee and safety data will be submitted to an 
independent data monitoring committee (IDMC). 
o 
Sponsor is then responsive for sending IDMC recommandations and safety review reports 
to ANSM. 
 
The third review of safety data will take place once 2-month follow-up data are available for the 
first 10 treated patients (independently of the stratum).  
o 
Inclusions will not be suspended 
o 
The steering committee (section 12.1.1) will review the safety data for these patients. 

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o 
The steering committee will then decide if inclusions should be stopped and/or, if needed, 
whether treatment surveillance should be modified.  
 
The next reviews of safety data by the steering committee (section 12.1.1) will take place every 
year and during the interim statistical analyse of each strata. Inclusions will not be suspended 
except for the interim analyse of each strata. 
10.3.2.2. 
ADVANCED LEIOMYOSARCOMA (STRATUM 1) 
 
An interim statistical analysis will be carried out once inclusions for the first stage of the dual 
endpoint design (15 eligible and assessable patients) will be completed in the experimental arm 
(PEMBROLIZUMAB + metronomic CP).  
 
Inclusions will continue if either objective response is observed in at least 3 patients or non-
progression is observed for 9 patients or more. Otherwise, the stratum will be terminated early 
and declared negative. 
 
A statistical report will be produced by the statistician of the study. Inclusion will be suspended 
during this interim analysis. Results of the interim statistical analyses will be presented to the 
IDMC members. 
10.3.2.3. 
ADVANCED UNDIFFERENTIATED SARCOMA (STRATUM 2) 
Same as for leiomyosarcoma 
10.3.2.4. 
ADVANCED OTHER SARCOMA (STRATUM 3) 
Same as for leiomyosarcoma. 
10.3.2.5. 
ADVANCED OSTEOSARCOMA (STRATUM 4) 
 
An interim statistical analysis will be carried out once inclusion for the first stage of the dual 
endpoint design (15 eligible and assessable patients) will be completed.  
 
Inclusions will continue if either objective response is observed in at least 3 patients or non-
progression is observed for 9 patients or more. Otherwise, the stratum will be terminated early 
and declared negative.  
 
A statistical report will be produced by the statistician of the study. Inclusion will be suspended 
during this interim analysis. Results of the interim statistical analyses will be presented to the 
IDMC members. 
10.3.2.6. 
ADVANCED GIST (STRATUM 5) 
 
An interim statistical analysis will be carried out once inclusion for the first stage of the 2-stage 
Simon’s design (10 eligible and assessable patients). 
 
Inclusions will continue if non-progression is observed for 4 patients or more. Otherwise, the 
stratum will be terminated early and declared negative.  
 
A statistical report will be produced by the statistician of the study. Inclusion will be suspended 
during this interim analysis. Results of the interim statistical analyses will be presented to the 
IDMC members. 
10.3.2.7. 
ADVANCED SOFT TISSUE SARCOMAS WITH IMMUNE SIGNATURE  (STRATUM 6) 
 
An interim statistical analysis will be carried out once inclusion for the first stage of the 2-stage 
Simon’s design (13 eligible and assessable patients). 
 
Inclusions will continue if non-progression at 6 months is observed for 3 patients or more. 
Otherwise, the stratum will be terminated early and declared negative.  
 
A statistical report will be produced by the statistician of the study. Inclusion will not be 
suspended during this interim analysis. Results of the interim statistical analyses will be presented 
to the IDMC members. 
 
 
 
 
 

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10.3.2.8. 
METASTATIC STS (STRATUM 7) 
 
An interim statistical analysis will be carried out once inclusion for the first stage of the 2-stage 
Simon’s design (13 eligible and assessable patients). 
 
Inclusions will continue if non-progression at 6 months is observed for 3 patients or more. 
Otherwise, the stratum will be terminated early and declared negative.  
 
A statistical report will be produced by the statistician of the study. Inclusion will be suspended 
during this interim analysis. Results of the interim statistical analyses will be presented to the 
IDMC members. 
 
11. ADVERSE EVENTS 
11.1. 
DESCRIPTION OF SAFETY EVALUATION CRITERIA 
The safety evaluation will comprise an evaluation of the patient’s general condition (ECOG Appendix 
1), a physical exam, regular blood tests and the recording of adverse events occurring throughout the 
study. Toxicity will be evaluated using the NCI-CTCAE scale, version 4 available on website: 
http://ctep.info.nih.gov. All appropriate treatment areas should have access to a copy of the CTCAE 
version 4.   
In an emergency situation, the patient, his/her friends/family or treating physician will contact the 
investigator to report an event and/or to discuss the treatments to be implemented. 
 
11.2. 
DEFINITION 
11.2.1. 
Adverse event 
An adverse event is defined as any untoward medical occurrence which occurs in a patient, a clinical 
investigation subject. Adverse events include, but are not limited to: 
• Abnormal test findings, 
• Clinical symptoms and signs,  
• Changes in physical examination findings,  
• Hypersensitivity, 
• Drug abuse, 
• Drug dependency, 
• Any suspected transmission of an infectious agent via a medicinal product. 
 
As well as signs and symptoms resulting from: 
• Drug overdose, 
• Drug withdrawal, 
• Drug misuse, 
• Drug interactions, 
• Extravasation, 
• Exposure during pregnancy, 
• Exposure during breastfeeding, 
• Medication error, 
• Occupational exposure. 
11.2.2. 
Serious adverse event 
A Serious Adverse Event (SAE) is defined as an adverse event regardless of the dose and that: 
• results in death (fatal) and/or, 
• is life-threatening and/or, 
• requires inpatient hospitalization or prolongation of existing hospitalization and/or, 
• results in persistent or significant disability/incapacity and/or, 
• results in congenital anomaly/birth defect and/or, 
• is medically significant. 
Pregnancy and overdose will be also considered as a SAE whatever the clinical consequences. 
Medical and scientific judgment is exercised in determining whether an event is an important medical 
event. An important medical event may not be immediately life-threatening and/or result in death or 

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hospitalization. However, if it is determined that the event may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed in the definition above, the important medical 
event should be reported as serious. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not 
result in hospitalization, or development of drug dependency or drug abuse. 
 
Any suspected transmission via a medicinal product of an infectious agent, pathogenic or non-
pathogenic, is assessed as a serious adverse event with the seriousness criterion important medical 
event. The event may be suspected from clinical symptoms or laboratory findings indicating an 
infection in a patient exposed to a medicinal product. The terms “suspected transmission” and 
“transmission” are considered synonymous. 
Any abnormal laboratory’s result resulting as a grade 4 in the CTCAE version 4 will be considered as 
serious adverse event even if this event is not clinically relevant. 
Whether or not corresponding to the above-mentioned criteria, any other adverse event considered as 
serious by any IMP, any healthcare professional or any investigator should be handled as a serious 
adverse event. 
11.2.2.1. 
DEATH 
Death as such is the outcome of a SAE or the seriousness criteria and should not be used as the SAE 
term itself. Instead the cause of death should be recorded as the SAE term. When available, the 
autopsy report will be provided to the Sponsor. 
11.2.2.2. 
LIFE-THREATENING EVENT 
Any event in which the patient 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 were more severe. 
11.2.2.3. 
HOSPITALIZATION OR PROLONGATION OF HOSPITALIZATION 
Any AE requiring hospitalization (or prolongation of hospitalization) that occurs or worsens during the 
course of a patient’s participation in a clinical trial must be reported as a SAE. Prolongation of 
hospitalization is defined as any extension of an inpatient hospitalization beyond the stay 
anticipated/required for the initial admission, as determined by the Investigator or treating physician. 
Hospitalizations that do not meet criteria for SAE reporting are:  
 Reasons described in protocol [e.g., investigational medicinal product (IMP) administration, 
protocol-required intervention/investigations, etc]. However, events requiring hospitalizations or 
prolongation of hospitalization as a result of a complication of therapy administration or clinical trial 
procedures will be reported as SAEs. 
 Hospitalization or prolonged hospitalization for technical, practical or social reasons, in absence of 
an AE. 
 Pre-planned hospitalizations: Any pre-planned surgery or procedure must be documented in the 
source documentation. Only if the pre-planned surgery needs to be performed earlier due to a 
worsening of the condition, should this event (worsened condition) be reported as a SAE.  
11.2.3. 
Non serious adverse event 
A non-serious adverse event is an adverse event whose characteristics do not meet the criteria of a 
serious adverse event. 
 
11.2.4. 
Adverse reaction 
An adverse reaction is any untoward and unintended responses to an experimental drug regardless of 
the dose. 
11.2.5. 
Expected/Unexpected character 
An unexpected adverse event is an event whose nature, severity/intensity, frequency or outcome does 
not correspond to the information shown within the reference document for the study. The Sponsor 
will use as the reference safety information for the evaluation of listedness/expectedness the most 
updated Investigator’s Brochure (IB) and/or Summary Product Characteristic (SmPC) for the studied 
IMP. 

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In practice, the term “new effect” is sometimes used as a synonymous of “unexpected adverse 
effect”. 
11.2.6. 
Intensity criterion 
The CTEP Active Version of the NCI Common Terminology Criteria for Adverse Event (CTCAE) will be 
utilized for AE reporting.  
The intensity of adverse events not listed in this classification will be assessed using the following 
descriptors: 
- 
Mild (grade 1): does not affect the patient’s usual daily activities, 
- 
Moderate (grade 2): disturbs the patient’s usual daily activities, 
- 
Severe (grade 3): prevents the patient’s usual daily activities, 
- 
Very severe (grade 4): requires critical care/life-threatening, 
- 
Death (grade 5). 
11.2.7. 
New information 
A new information is any new safety data that could lead to reevaluate the ratio between the benefits 
and risks of the research or the investigational product, to modify the use of the investigational 
product, the research management or the research documents or to suspend or interrupt or modify 
the protocol of research or similar research. 
11.2.8. 
For trials of first administration or use of a health product in 
persons without any conditions: any serious adverse reactions. 
The study PEMBROSARC is not concerned by this situation.Causal 
relationship 
Medical judgment should be used to determine the relationship, considering all relevant factors, 
including pattern of reaction, temporal relationship, de-challenge or re-challenge, confounding factors 
such as concomitant medication, concomitant diseases and relevant history. Assessment of causal 
relationship should be recorded in the case report forms. 
- 
Yes: There is a reasonable causal relationship between the investigational drug administered 
and the AE. 
- 
No: There is no reasonable causal relationship between the investigational drug administered 
and the AE. 
In case of multiples drugs, the causal relationship must be provided by the investigator for all 
potential trial drugs, i.e. for all other trial drugs. 
11.2.9. 
Special considerations 
Certain product safety monitoring reports should be forwarded even if there is no associated adverse 
event. These reports involve circumstances that may increase the patient/consumer’s risk of 
developing adverse events.  
These circumstances include: 
 medication errors, 
 exposure during pregnancy, 
 exposure during breastfeeding, 
 overdose, 
 misuse, 
 extravasation, 
 occupational exposure. 
Some of these special circumstances are considered in more details below. 
Medications errors: a medication error is any preventable event that may cause or lead to 
inappropriate medication use or patient harm while the medication is in the control of the healthcare 
professional, patient, or consumer. Such events may be related to professional practice, healthcare 
products, procedures, and systems, including: prescribing; order communication; product labeling, 
packaging, and nomenclature; compounding; dispensing; distribution; administration; education; 
monitoring; and use. 
A medication error does not necessarily involve the administration of the product (e.g. the error may 
have been corrected prior to administration of the product). 
Potential medication errors or “near-misses,” which are individual reports of information or complaints 
about product name, labeling, or packaging similarities that do not involve a patient, are also 
reportable. 

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 
Exposure during pregnancy: exposure during pregnancy refers to pregnancies where the fetus 
(from pre-embryo to birth) may have been exposed at a given time during pregnancy to a medicinal 
product (or a blinded treatment). Even if there is no associated adverse event, exposure during 
pregnancy must always be reported. It can indeed provide the opportunity to obtain pregnancy 
outcome important information where appropriate. 
Exposure during pregnancy may occur either: 
 
- Through maternal exposure  
 A female becomes, or is found to be, pregnant either: 
• While receiving a medicinal product 
• After discontinuing a medicinal product 
• During or following environmental exposure to a medicinal product (eg, a 
nurse reports she is pregnant and that she was exposed to chemotherapy 
drugs via inhalation or after accidentally overturning a bottle) 
or 
 
-Through paternal exposure 
 
A male has been exposed to a medicinal product (either due to treatment or 
environmental circumstances) prior to or around the time of conception and/or is 
exposed during the partner pregnancy. 
 
Exposure during breastfeeding: exposure during breastfeeding occurs where an infant or child 
may have been exposed through breast milk to a medicinal product during breastfeeding by a female 
taking the product. 
All drug exposure during breastfeeding cases are reported, whether or not there is an associated 
adverse event. 
 
11.3. 
SERIOUS ADVERSE EVENT AND NEW INFORMATION NOTIFICATION 
(RESPONSIBILITY OF THE INVESTIGATOR) 
The investigator will notify the Vigilance Unit without delay about any serious adverse events or new 
events occurring: 
- From the date of the informed consent is signed, 
- During the whole patient treatment period as defined by the research, 
- Until 90 days after the last dose of the IMP/studied treatments or the initiation of new anti-cancer 
therapy, whichever is earlier, 
- Beyond this period of time, only those SAEs suspected to be related to the IMP will be collected. 
Nonetheless, the Sponsor will evaluate any safety information related to the clinical trial that is 
spontaneously reported by an Investigator beyond the time frame specified in the protocol. 
Type of Event 
Reporting procedure 
Deadline for reporting to the 
sponsor 
SAE 
SAE Notification form + written 
report form if necessary 
To be reported immediately to the 
sponsor 
New information 
Written report form 
To be reported immediately to the 
sponsor 
Pregnancy 
Pregnancy Notification form +  
Written report form if necessary 
As soon as pregnancy is confirmed 
The investigator must complete the “Serious Adverse Event Notification Form” (Appendix 3) 
immediately, in English, and assess the relationship with the study treatment. The form must then be 
dated, signed and sent by fax to the following address without delay to: 
CELLULE DE VIGILANCE (VIGILANCE UNIT) – Institut Bergonié 
 
Fax: +33 5 56 33 04 85 
Or Contact : Sabrina SELLAN-ALBERT (AEC) Tél : 05.56.33.78.05 – Mail : s.albert@bordeaux.unicancer.fr 
Emilie Toulza (pharmacien) Tél : 05 47 30 60 53 – Mail : e.toulza @bordeaux.unicancer.fr or vigilance-
promotion-essaiscliniques@bordeaux.unicancer.fr  
Responsable : Emilie TOULZA Tél : 05.56.33.78.90 – Mail : e.toulza @bordeaux.unicancer.fr 

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The sponsor (Institut Bergonié) will forward the “Serious Adverse Event Notification Form” to MSD 
immediately. 
For each event, the investigator will record: 
 - A description of the event that is as clearly as possible, using medical terminology, 
 - The date the event started and ended, 
 - The patient’s relevant medical history, 
 - The steps taken and whether or not corrective treatment was required, whether or not the 
investigational treatment was discontinued, etc. 
 - Concomitant medications / therapies 
 - The causal link between this event and the trial treatment, disease treated or an intercurrent 
disease or treatment, or any obligation imposed by the research (a treatment-free period, additional 
examinations requested as part of the research etc.), 
 - Clinical course. If the event was not fatal, it should be monitored until recovery, until the patient 
has returned to his/her previous condition, or until any sequelae have stabilized, 
 - Whenever possible, the investigator must also attach the following with the serious adverse event 
report: 
- 
A copy of the hospitalization or extended hospitalization report, 
- 
A copy of the autopsy report, if required, 
- 
A copy of all the results of any additional tests performed, including relevant negative results, 
along with the normal laboratory values, 
- 
Any other document he or she considers useful and relevant. 
All these documents must be anonymized. Additional information may be requested (by fax, by 
telephone or during a visit) by the CRA and/or by the Vigilance Unit using a follow-up request form. 
SAE will be monitored until they have resolved, returned to baseline, or they are not clinically 
significant, stable, or do not require any additional follow-up as judged by investigator. Sometimes 
this may mean that follow-up will extend beyond the patient’s withdrawal from the trial. 
The investigator keeps the documents about the presumed adverse effect so that the information 
previously sent can be added to if necessary. 
The investigator responds to requests for additional information from the Vigilance Unit in order to 
document the original observation. 
 
11.4. 
REPORTING PREGNANCY CASES OCCURRED WITHIN THE CLINICAL TRIAL 
Pregnancy and suspected pregnancy (including a positive pregnancy test regardless of age or disease 
state) of a female patient or the female partner of a male patient occurring while the patient is on 
study drug, or 180 days after the last dose of  
IMP/studied treatments or 30 days in case of initiation of new anti-cancer therapy, are considered 
immediately reportable events. 
The Investigator will report the following events immediately and always within 24 hours from first 
knowledge: 
 Any occurrence of a pregnancy where any kind of exposure to the IMP is suspected, 
 Possible exposure of a pregnant woman (this could involve a partner of a male patient or a 
pregnant female who came in contact with the clinical trial IMP), 
 All reports of elevated/questionable or indeterminate beta human chorionic gonadotropins (β-
hCGs). 
Immediately after detecting a case of suspected pregnancy in a female clinical trial patient, the 
decision on her continued participation in the clinical trial will be jointly taken by the trial patient, the 
Investigator and the Sponsor, with the patient’s best interest in mind. A decision to continue the 
pregnancy will require immediate withdrawal from the trial.  
Any pregnancy, suspected pregnancy, or positive pregnancy test must be reported to the Vigilance 
Unit immediately by facsimile using the Pregnancy Report form (appendix 54). In the case of 
pregnancy of the female partner of a trial patient, the Investigator will obtain her consent to provide 
the information in these situations. 
The Investigator will follow the pregnancy until its outcome, and must notify the Vigilance Unit the 
outcome of the pregnancy within 24 hours of first knowledge as a follow-up to the initial report. 

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For any event during the pregnancy which meets a seriousness criterion (including fetal or neonatal 
death or congenital anomaly) the Investigator will also follow the procedures for reporting SAEs 
(complete and send the SAE form to the Vigilance Unit by facsimile within 24 hours of the 
Investigator’s knowledge of the event).  
All neonatal deaths that occur within 30 days of birth should be reported, without regard to causality, 
as SAEs. In addition, any infant death at any time thereafter that the Investigator suspects is related 
to the exposure to the study drug/IMP should also be reported to the Vigilance Unit by facsimile within 
24 hours of the Investigators’ knowledge of the event. 
Whenever possible, the investigator must also attach the following with the serious adverse event 
report: 
- A copy of the hospitalization or extended hospitalization report, 
- A copy of the autopsy report, if required, 
- A copy of all the results of any additional tests performed, including relevant negative results, along 
with the normal laboratory values, 
- Any other document he or she considers useful and relevant. 
All these documents must be anonymized. 
Additional information may be requested (by fax, by telephone or during a visit) by the Vigilance Unit. 
 
11.5. 
REPORTING EVENTS OF CLINICAL INTEREST AND IMMUNE-RELATED 
ADVERSE EVENTS 
The investigator will notify the Vigilance Unit without delay about any events of clinical interest and 
immune-related adverse event.  
The investigator must complete the specific form (Appendix 8) immediately, in English The form must 
then be dated, signed and sent by fax to the following address without delay to: 
CELLULE DE VIGILANCE (VIGILANCE UNIT) – Institut Bergonié 
Fax: +33 5 56 33 04 85 
 
Contact : Sabrina SELLAN-ALBERT (AEC) Tél : 05.56.33.78.05 – Mail : s.albert@bordeaux.unicancer.fr 
Emilie Toulza (pharmacien) Tél : 05 47 30 60 53 – Mail : e.toulza @bordeaux.unicancer.fr or vigilance-
promotion-essaiscliniques@bordeaux.unicancer.fr  
Responsable : Emilie TOULZA Tél : 05.56.33.78.90 – Mail : e.toulza @bordeaux.unicancer.fr 
 
Adverse events that are both an SAE and an irAE should be reported one time as an SAE only, 
however the event should be appropriately identified as an irAE as well in the database. 
 
11.5.1. 
 Cases of mediastinal lymph nodes 
The Steering Committee (SC) has discussed about several cases of mediastinal lymph nodes related to 
sarcoidosis. It is a new immune related adverse event of pembrolizumab that has been already 
described with other immunotherapy which blocks the cytotoxic T-lymphocyte-associated antigen-4 
(ipilimumab).  
Three cases of mediastinal lymph nodes have been observed. This effect appeared after 6 weeks of 
pembrolizumab treatment and disappeared spontaneously after the end of treatment. This effect 
should be known to avoid misdiagnosis of disease progression due to mediastinal lymph node 
involvement (84).  
  
The SC has decided that all investigators should be informed about this effect and the risk of 
misdiagnosis of disease progression and that all mediastinal lymph node and related to sarcoidosis 
should be declared immediately to the sponsor as events of clinical interest. 
 
 
 
 
 
 

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11.6. 
NON SERIOUS ADVERSE EVENT 
TYPE OF EVENT 
REPORTING PROCEDURES 
DEADLINE FOR REPORTING 
TO THE SPONSOR 
Non-serious AE 
Case report/record form 
Does not need to be reported 
immediately 
Non-serious adverse events will be reported by the investigator in the patient’s CRF and will be 
followed up until complete resolution.  
If an adverse event becomes serious, it should be reported and followed-up as mentioned in the 
previous reporting procedures. 
If the investigator would like to decrease trial treatment dose or temporarily stop study management 
without respecting protocol procedures, he/she should have previously discussed with the coordinator. 
However, symptomatic treatment can be prescribed to manage the adverse event. 
Any definitive interruption of the procedure has to be immediately notified to the sponsor. The patient 
remains in the study and is followed-up according to the procedures described in the protocol. 
 
11.7. 
RESPONSIBILITY OF VIGILANCE UNIT AND SAE REPORTING  
The Vigilance Unit will analyze each SAE to define: 
-  The relationship with the study treatment, 
-  The listedness/expectedness according to the most updated reference safety information of the 
studied IMP Investigator’s Brochure (IB) and/or Summary Product Characteristic (SmPC).  
SAEs will be reported by the Sponsor to the different laboratories according to the contracts’ 
requirements. 
 
11.8. 
REPORTING OF SAFETY DATA TO NATIONAL COMPETENT AUTHORITY AND 
ETHICS COMMITTEE (RESPONSIBILITY OF THE SPONSOR) 
The sponsor notifies unexpected serious adverse events and new information to the Regulatory 
Authorities (in person, or through an organization which has received allowances for this task) 
according to the usual notification procedures.  
 
Once a year throughout the clinical trial, the Sponsor should submit to the national competent 
authority and the Ethics Committee, a DSUR (Development Safety Update Report). The annual safety 
report should be submitted no later than 60 calendar days from the date of authorization of the 
research. 
 
 
12. QUALITY ASSURANCE AND TRIAL MONITORING 
12.1. 
MONITORING OF THE TRIAL 
12.1.1. 
Steering Committee 
The study will be supervised and monitored by a Steering Committee comprising members participating 
in the study: 
 
Pr A. Italiano, Co-ordinating Investigator and Chairman of the Commitee,  
 
Dr M. Toulmonde, Investigator and medical oncologist, 
 
A representative of the sponsor (Pr S. Mathoulin-Pélissier or Dr Hoppe), 
 
The biostatistician of the trial (Ms M. Pulido or a substitute), 
 
The pharmacist of the trial (Ms E.Toulza or a substitute) 
 
The co-ordinating Clinical research manager (S Sellan-Albert or a substitute) 
This committee must ensure the following:  
 
Implementation and regular follow-up of the study 
 
Review of the safety data following the inclusion of the first 10 treated patients in each treatment 
strategy (except for stratum 6) (section 10.3.2).  

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 
Patient protection, 
 
That the trial is conducted ethically, in accordance with the protocol, 
 
That the trial benefit/risk ratio is evaluated and the scientific results are checked during or at the 
end of the trial.  
 
It decides on any relevant amendment to the protocol that is required in order to continue the trial 
(protocol amendments prior to submission to the EC and the relevant Health Authorities, decisions on 
whether to open or close research sites, discussion of results and the strategy for the publication of 
these results). It must inform the sponsor of any decisions taken. Decisions concerning a major 
amendment or a change to the budget must be approved by the sponsor. 
12.1.2. 
Independent Data Monitoring Committee 
An independent Data Monitoring Committee (IDMC) will be created at the request of the relevant 
Authority, the sponsor or the Steering Committee. The IDMC plays an advisory role for the Sponsor, 
who has the final decision regarding the implementation of recommendations put forward by the 
IDMC. 
Composition of the IDMC 
 
This Committee must comprise at least one qualified oncologist, one pharmacologist and one 
statistican: 
o 
Qualified oncologist (Dr Christophe Perrin) 
o 
Pharmacologist (Dr Driss Berdaï) 
o 
Statistician (Mme Sophie Gourgou-Bourgade) 
All of whom will have experience in the monitoring and analysis of clinical trials. One of these 
members will be appointed as the Trial Rapporteur.  
 
Each of these members must be unconnected with the trial and cannot, therefore, be one of the 
trial investigators.  
 
These members are appointed by the Sponsor in consultation with the trial co-ordinator and the 
Steering Committee.  
Responsibilities of the IDMC 
The IDMC is responsible for the following: 
 
Analyzing preliminary efficacy and safety data, 
 
Making recommendations on the continuation, early discontinuation (in the case of toxicity or lack 
of efficacy) or publication of the trial results, 
 
Drafting the minutes after each meeting and monitoring their confidentiality. 
Any recommendation from the IDMC that can be made public will be announced by the Sponsor and 
not by the Steering Committee. The Sponsor is responsible for sending IDMC recommendations to the 
regulatory authorities [ANSM (French Agency for the Safety of Health Care Products) and EMEA 
(European Medicines Evaluation Agency)].  
 
12.2. 
QUALITY ASSURANCE 
12.2.1. 
Data collection 
The data will be collected on an electronic case report form and directly input via the Internet. Only 
the investigators and the Investigator’s Clinical Research Assistants (CRAs) appointed by the later and 
duly authorized by the sponsor will be authorized to enter the data. 
Data will be handled by an online trial management software on the Internet (Macro v4, Infermed 
Company); it will be transferred and monitored remotely in real time. 
The study CRA and/or any other person appointed by the sponsor will be available to assist the 
investigators in carrying out the study and to ensure that the trial is carried out in accordance with the 
protocol. 

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The study CRA will contact the investigators regarding the study implementation visit.  
All of the necessary data will be collected on an electronic case report form provided by the sponsor. 
The generic names of the concomitant medication will be given in French. 
Corrections made to the original data must be justified. These corrections will be automatically dated 
and signed by the authorized member of staff via the personalized password allocated at the start of 
the study. 
The case report form will be validated by the investigator or the CRA at the authorized center 
whenever data is entered. 
Laboratory data exceeding normal limit values will be commented upon if they are considered clinically 
significant. Data other than that requested within the scope of the protocol can be collected as 
additional data; their interest will be specified. 
12.2.2. 
Monitoring 
In order to guarantee the authenticity and credibility of the data in accordance with the principles of 
GCP (Good Clinical Practice) dated 24 November 2006, the sponsor shall implement a quality 
assurance system comprising: 
 
the management and monitoring of the trial in accordance with the procedures stipulated by the 
Institut Bergonié, 
 
the quality control of the research site data by the CRA whose role is to: 
o 
check compliance with the protocol, GCP and current legislation and regulations, 
o 
check the consent and eligibility of each patient taking part in the trial, 
o 
check the consistency and coherence of case report form date against the source 
documents. 
o 
check that each serious adverse event is reported, 
o 
monitor the traceability of the study medication (dispensation, storage and drug 
accountability), 
o 
check, where applicable, that the persons likely to take part in the trial are not 
already participating in another trial that could prevent them from being included in 
the clinical trial proposed. The CRA shall also ensure that the patients have not 
participated in a trial for which an exclusion period currently applies. 
 
The possible audit of study centers 
 
The centralized review of certain protocol criteria. 
The check procedures will include: 
 
Study progression, 
 
Protocol compliance, 
 
The updating of information on the Internet site. 
The checking of data by comparing the information on the electronic case report form and the original 
clinical or laboratory data is one of the monitoring procedures. 
The following will be checked, in particular, for each patient (100% level): patient identification, 
informed consent (procedure and signature), selection criteria, therapeutic procedure, adverse events, 
principal response variables. The personal data relating to each patient shall remain confidential. On 
the electronic case report form or any other form dispatched, the patients will be identified solely by 
their initials (1/name – 1/surname) and an inclusion number. However, the investigators must keep a 
list identifying the patients in their folders. 
The CRAs responsible for the quality control of this clinical trial are duly appointed by the sponsor for 
this particular purpose and must have access, with the consent of those involved, to individual trial 
participant data required strictly in accordance with this control procedure. The CRAs are subject to 
professional secrecy under the conditions defined by Articles 226-13 and 226-14 of the French penal 
code. The traceability of monitoring visits is guaranteed by a written monitoring report. 

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The investigators shall undertake to give CRAs direct access to the medical records of each patient in 
order to allow the CRAs to ensure optimal quality control of the trial. The same applies to health 
authority representatives. 
12.2.3. 
Handling of missing data 
The monitoring of data for adverse events will be carried out regularly in order to effectively limit the 
amount of missing data likely to prevent or hamper trial implementation and analysis. 
12.2.4. 
Audits 
The sponsor, the local authorities or the authorities to which information about this study has been 
submitted can decide to have an audit.  
All the documents relating to this study must be available for such an inspection after prior 
notification. 

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13. REGULATORY ASPECTS AND ETHICAL CONSIDERATIONS 
 
Clinical Research Management Unit – Institut Bergonié 
Contacts: Marie-Laure Marty–  Tel.: +33 5 47 30 60 79 – e-mail: m.marty@bordeaux.unicancer.fr  
 
The study will be carried out in accordance with: 
 
Law no. 2012-300 dated 5 March 2012 relating to researchs involving the human person 
 
The ethical principles of the current version of the “Declaration of Helsinki” (available on its full 
version on the site http://www.wma.net). 
 
Good Clinical Practice (GCP): I.C.H. version 4 of 9 November 2016 and decision dated 24 
November 2006 (Official Bulletin of 30 November 2006, text 64). 
 
European Directive (2001/20/EC) on clinical trial procedures. 
 
Huriet’s law (No. 88-1138) dated 20 December 1988, concerning the protection of persons taking 
part in Biomedical Research with the provisions of the Public Health law (No. 2004-806) of 9 
August 2004 and implementating decree No. 2006-477 of 26 April 2006 relating to biomedical 
research. 
 
The French law on Data Protection and Civil Liberties, No. 78-17 of 6 January 1978 amended by 
law No. 2004-801, dated 6 August 2004, concerning the protection of persons with regards to the 
processing of personal data. 
 
The application of Circular DHOS/INCA/MOPRC/2006/475 of 7 November 2006: the Sponsor shall 
undertake to register the Trial and thus make it accessible to the general public, in the INCa 
(French Cancer Institute) register via the Internet site: www.e-cancer.fr. Each trial published in 
the INCa register will be sent to the NCI for registering on the following site: 
www.clinicaltrials.gov. The trial will be registered before the first patient is entered into the study. 
The Sponsor is responsible for updating the study data in order to guarantee the reliability of the 
information available on-line. 
 
Law no. 2004-800 dated 6 August 2004, concerning bioethics, amended by law No. 2012-387, 
dated 22 March 2012. 
 
13.1. 
CLINICAL TRIAL AUTHORIZATION 
This trial is registered under Eudract N° 2014-004568-39. 
The protocol has been approved by the South West and Overseas Territories III Ethics Committee, 
Bordeaux.  Approval was given on 22/12/2014. 
The Relevant Authority, the “Agence Nationale de Sécurité du Médicament et des Produits de Santé” 
(ANSM - French Agency for the Safety of Health Care Products) authorized the clinical trial on 
18/02/2015. 
Any amendments to the protocol concerning study objectives, patient population and principal 
methods will require an amendment, which must be approved by the EC and l'ANSM.  The sponsor 
will inform the EC and ANSM of expected and/or unexpected serious adverse events in accordance 
with current regulations and within 30 days after of completion of the trial. 
The sponsor will send the summary of the final report to the relevant Authority within one year of 
completion of the trial. 
The sponsor has made a commitment to compliance the Reference methodology for the processing of 
personal data carried out in biomedical research: Référence methodology MR-001. This commitment 
of compliance is registred under No 118019 of the 07/11/2006. 
 
 
 
 

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13.2. 
INSURANCE POLICY  
The Institut Bergonié has taken out an insurance policy (policy No.0100871914011-140005-10998) 
with société HDI-Gerling, Tour opus12, 77, Esplanade de la défense, 92914 PARIS LA DEFENSE 
through an insurance broker, namely Biomédic Insure (Parc d'Innovation Bretagne Sud, CP 142, 
56038 Vannes, tel. 02 97 69 19 19) in case compensation is payable to investigators or patients taking 
part in the study. 
 
13.3. 
INFORMING AND OBTAINING CONSENT FROM PATIENTS 
The investigator in charge of the patient will provide the latter with relevant information relating to 
the study objectives, potential benefits and possible adverse events. The study methods will be 
outlined. The patient can refuse treatment before or at any time during the study, without 
experiencing any adverse repercussions in terms of his/her subsequent care. 
The patient’s written consent will be obtained prior to entry into the study by using the Patient 
Information Leaflet and Informed Consent Form. These forms must be combined in the same 
document in order to ensure that all of the information is given to the trial participant. 
The consent form must be personally dated and signed by the trial participant and the investigator. 
The original will be given to the patient and the second, archived in the investigator’s folder. Upon 
request, a copy will be sent to the sponsor in a sealed envelope. 
 
13.4. 
SPONSOR’S RESPONSIBILITIES  
The sponsor of the clinical trial, the Institut Bergonié, will take the initiative for this clinical trial. The 
Institute will manage the trial and ensure that finance is provided. 
The sponsor’s main responsibilities are to: 
 
Take out civil liability insurance, 
 
Obtain the Eudract No. and register the trial in the European database (European Drug Regulatory 
Authorities Clinical Trials), 
 
Obtain clinical trial authorization for the initial project and any amendments from the EC and 
ANSM; approval by the EC and decision taken by ANSM.  
 
Notify the relevant authority any suspected unexpected serious adverse reaction (SUSAR), 
 
Give trial-related information to the site directors, pharmacists and investigators, 
 
Notify the relevant authority of the trial start and end dates, 
 
Draft the final trial report and sent the summary to ANSM, 
 
Send the trial results to the relevant authority, EC and investigators, 
 
Archive essential trial documents in the sponsor’s folder for a minimum period of 15 years after 
the trial has ended. 
 
13.5. 
 INVESTIGATORS’ RESPONSIBILITIES 
The principal investigator of each establishment concerned undertakes to conduct the clinical trial in 
accordance with the protocol that was approved by the ethics committee and the relevant authority 
(ANSM). 
The investigator must not make any changes to the protocol without the written consent of the 
sponsor or without the ethics committee and the relevant authority having authorized the proposed 
changes. 
It is the responsibility of the principal investigator is: 
 
to provide the sponsor with his/her curriculum vitae as well as those of his/her co-investigators, 
 
to identify the members of his/her team who are participating in the trial and to define their 
responsibilities, 

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 
to start patient recruitment after authorization has been obtained from the sponsor, 
 
to ensure that he/she is available for investigators’s meeting anf for “monitoring”. 
 
It is the responsibility of each investigator: 
 
to comply with the confidential nature of the trial, 
 
to obtain informed consent, signed and dated personally by each trial participant, before any 
screening procedures specific to the trial are carried out, 
 
to regularly complete the case report forms (CRFs or e-CRFs) for each of the patients enrolled in 
the trial and to allow the Clinical Research Assistant (CRA) duly authorised by the Sponsor a direct 
access to source documents so that the latter can validate the data on the CRF or e-CRF, 
 
to promptly notify the sponsor of any serious adverse event and/or new information occurring 
during the trial, 
 
to date, correct and validate corrections on the case report forms (CRFs or e-CRFs) and the Data 
Query Forms (DQFs), 
 
to accept regular visits CRA and eventually visits of auditors duly authorised by the Sponsor or 
inspectors of regulatory authorities, 
 
to inform trial participants of the overall results of the research on first demand. 
 
13.6. 
AUTHORITY TO EXECUTE THE TRIAL  
The investigator shall certify that he/she is authorized to enter into this agreement and that the terms 
and conditions of the protocol and agreement do not conflict with other agreements that the 
investigator may have entered into with any other party, or any other arrangement agreed by the 
Institution where the investigator is employed. 
 
13.7. 
REGULATIONS GOVERNING THE COLLECTION OF HUMAN BIOLOGICAL 
SAMPLES 
During the medical procedures to be carried out, samples will be collected for medical purposes. A 
fraction of these samples will be kept and used for scientific research purposes.  
The patient will be informed of this research and provided that he/she approves by signing an 
informed consent, these samples intended for research will be: 
 
Initially prepared and stored using a specific technique to preserve them under excellent 
conditions. 
 
and secondly, used within the scope of this research.   
The preparation, storage and use of these samples will not in any way affect current or future medical 
care administered to the patient for the purpose of diagnosis or treatment. 
The results of this research may, in future, appear in scientific publications.  All of the data shall 
remain anonymous. 
Obtaining and using additional samples 
This biomarker study is made up of exploratory research that is described in the section 17. 
On completion of the trial, provided that the patient agrees and provided that not all of the samples 
have been used, the said samples can be used for subsequent scientific research purposes without the 
approval of the Ethics Committee (EC) and the signing of a new consent form by the patients 
included. 
 
 
 
 

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13.8. 
 FEDERATION DES COMITES DE PATIENTS POUR LA RECHERCHE CLINIQUE 
EN CANCEROLOGIE (FCPRCC) (FEDERATION OF PATIENT COMMITTEES FOR 
CLINICAL RESEARCH IN ONCOLOGY) 
The Fédération des Comités de Patients pour la Recherche Clinique en Cancérologie (FCPRCC) 
(Federation of Patient Committees for Clinical Research in Oncology) was created on the initiative of 
the Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) (Federation of Anti-Cancer 
Centers) and the Ligue Nationale Contre le Cancer (National Anti-Cancer League) in order to review 
clinical trial protocols in oncology. This Federation of Patient Committees is co-ordinated by the Office 
for Clinical and Therapeutic Trials and groups together the League patient committees as well as other 
health care establishments. The Sponsor undertakes to transmit the protocol to the Federation for 
review. The Federation undertakes to propose improvements focusing primarily on the quality of the 
information leaflet, the availability of a treatment and monitoring plan and the suggestion of measures 
aimed at improving patient comfort. 
 
13.9. 
DATA PROCESSING  
In accordance with the French Law on Data Protection and Civil Liberties of 06 August 2004 and its 
implementing decrees, the Sponsor shall follow the methodology of reference MR001 of the 
“Commission Nationale de l’Informatique et des Libertés” (French National Commission for Data 
Protection and Liberties). 
Furthermore, if the biomedical research data is computer processed or managed by computerized 
systems, each Center: 
 
shall check and document the fact that the computerized systems used in the research comply 
with requirements drawn up in relation to data integrity, accuracy and reliability, as well as 
compliance with expected performances (i.e. validation); 
 
shall implement and ensure the monitoring of standard operating procedures relating to the use of 
these systems; 
 
shall ensure that the design of these systems allows for data to be amended such that the 
amendments are documented and that any item of data input cannot be deleted (i.e. maintaining 
data and amendment audit trail) ; 
 
shall implement and ensure the monitoring of a secure system that prevents any unauthorized 
data access; 
 
shall update the list of persons authorized to amend the data; 
 
shall keep appropriate back-up copies of the data; 
 
shall maintain blind status, where applicable (e.g. during data entry and processing); 
 
shall ensure that personal data used within the scope of the trial is processed in accordance with 
the conditions defined by law No. 78-17 dated 6 January 1978 relating to data processing, files 
and liberties modified by law No. 2004-801 of 6 August 2004 and its implementing regulations. 
If the data is converted during processing, it must always be possible to compare the original data 
and observations with the data after conversion. 
The system used to identify subjects taking part in the trial must not present with any ambiguity and 
must allow all of the data collected for each of these subjects to be identified whilst maintaining the 
confidentiality of the personal data, in accordance with law No. 78-17, duly amended. 
The archiving data is performed according to the applicable regulations and under the responsibility of 
investigator. All data and the patient indentification codes will be kept for at least 15 years after the 
completion or discontinuation of the trial. 
 

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14. CONFIDENTIALITY AND OWNERSHIP OF DATA  
All of the information communicated or obtained and the data and results generated by the trial 
legally belong to as their obtaining the Institut Bergonié, which can use this data at its own discretion.  
According to article R 5121-13 of the French Public Health Code, investigators and people who will 
have  to collaborate in the trial shall be bound by professional secrecy with regard to the particular 
nature of the products studied, trial, trial participants, and results. In particularly, all documentation 
relating to the trial sent to the investigator should be considered confidential information. 
Without the consent of the sponsor, the investigator cannot,give information about trials at anyone, 
except the Minister in charge of Public Health, public health medical inspectors, public health 
pharmacists inspectors, the General Director and inspectors of ANSM.  
The trial cannot be the subject of any written or verbal comments without the sponsor’s consent. 
 
15. PUBLICATION AND VALORISATION 
15.1. 
SCIENTIFIC COMMUNICATION 
All of the information arising from this study shall be considered confidential (cf. section 14). 
All forms of publication must be submitted to the Steering Committee for review and approval prior to 
publication (allowing at least 15 working days for abstracts and oral presentations, and 45 working 
days for written publications). The Steering Committee shall check the accuracy of the information 
submitted (in order to avoid any inconsistency with that submitted to the Health Authorities), and 
ensure that confidential information is not inadvertently disclosed.  It will also provide additional 
information as required. In any case, the sponsor will control the first publication. 
Furthermore, all memos, manuscripts or presentations must comprise a heading referring without fail 
to the Institut Bergonié, all of the institutions, investigations, co-operating groups and learned 
societies that have contributed to the implementation of the trial, and listing any organizations that 
have provided financial support. 
 
the study coordinator 
 
the investigators will be listed on a pro rata basis according to the number of patients recruited 
 
a representative of the trial statistics unit (in the first 3 positions according to degree of 
involvement in the preparation of publications) 
 
15.2. 
INFORMATION TO PATIENTS 
According to Article L.1122-1 of the Fench Code of Public Health Investigator undertakes to inform 
trial participants of the overall results of the research on first demand. 

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51. Thompson RH, Dong H, Lohse CM, Leibovich BC, Blute ML, Cheville JC, et al. PD-1 expressed 
by tumor-infiltrating immune cells and is associated with poor outcome for patients with renal 
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52. Talmadge JE, Donkor M, Scholar E. Inflammatory cell infiltration of tumors: Jekyll or Hyde. 
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53. Usubütün A, Ayhan A, Uygur MC, zen H, klu C, acan S. Prognostic factors in renal cell 
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54. Al-Shibli KI, Donnem T, Al-Saad S, Persson M, Bremnes RM, Busund L-T. Prognostic effect of 
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55. Deschoolmeester V, Baay M, Van Marck E, Weyler J, Vermeulen p, Lardon F, et al. Tumor 
infiltrating lymphocytes: an intriguing player in the survival of colorectal cancer patients. BMC 
Immunol 2010;11:19. 

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prognostic score in colorectal adenocarcinomas. Anticancer Res 1998;18:689-94.   
57. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, et al. Type, 
density, and location of immune cells within human colorectal tumors predict clinical outcome. 
Science 2006;313:1960-4.   
58. Hiraoka N. Tumor-infiltrating lymphocytes and hepatocellular carcinoma: molecular biology. 
Int J Clin Oncol 2010;15:544-51.   
59. Nobili C, Degrate L, Caprotti R, Franciosi C, Leone BE, Trezzi R, et al. Prolonged survival of a 
patient affected by pancreatic adenocarcinoma with massive lymphocyte and dendritic cell 
infiltration after interleukin-2 immunotherapy. Report of a case. Tumori 2008;94:426-30.   
60. Hodi FS, Dranoff G. The biologic importance of tumor-infiltrating lymphocytes. J Cutan Pathol 
2010;37(Suppl 1):48-53.   
61. Kloor M. Lymphocyte infiltration and prognosis in colorectal cancer. Lancet 2009;10(840):841.   
62. Hillen F, Baeten CIM, van de Winkel A, Creytens D, van der Schaft DWJ, Winnepenninckx V, et 
al. Leukocyte infiltration and tumor cell plasticity are parameters of aggressiveness in primary 
cutaneous melanoma. Cancer Immunol Immunother 2008;57:97-106.   
63. Lee HE, Chae SW, Lee YJ, Kim MA, Lee HS, Lee BL, et al. Prognostic implications of type and 
density of tumour-infiltrating lymphocytes in gastric cancer. Br J Cancer 2008;99(10):1704-11.   
64. Leffers N, Gooden MJM, de Jong RA, Hoogeboom B-N, ten Hoor KA, Hollema H, et al. 
Prognostic significance of tumor-infiltrating T-lymphocytes in primary and metastatic lesions of 
advanced stage ovarian cancer. Cancer Immunol Immunother 2009;58:449-59.   
65. Nishimura H, Honjo T, Minato N. Facilitation of β selection and modification of positive 
selection in the thymus of PD-1-deficient mice. J Exp Med 2000;191(5):891-7.   
66. Liotta F, Gacci M, Frosali F, Querci V, Vittori G, Lapini A, et al. Frequency of regulatory T cells 
in peripheral blood and in tumour-infiltrating lymphocytes correlates with poor prognosis in 
renal cell carcinoma. BJU Intern 2010;107:1500-6.   
67. Kim, J. R., Y. J. Moon, et al. (2013). "Tumor Infiltrating PD1-Positive Lymphocytes and the 
Expression of PD-L1 Predict Poor Prognosis of Soft Tissue Sarcomas." PLoS One 8(12): 
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68. D'Angelo SP et al. (2014). “PD-L1 expression and immune infiltrates in sarcoma”. J Clin Oncol 
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Immunol Res.;2:690-8.  
70. Lussier et al. (2011). “Enhancement of T cell immunity to osteosarcoma through modulation 
of PD-1/PD-L1 interactions”. Journal for ImmunoTherapy of Cancer, 1(Suppl 1):P162 
71. Mkrtichyan, M., Y. G. Najjar, et al. (2011). "Anti-PD-1 synergizes with cyclophosphamide to 
induce potent anti-tumor vaccine effects through novel mechanisms." Eur J Immunol 41(10): 
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72. Goffin JR, Tu D (2008). Phase II stopping rules that employ response rates and early 
progression. J Clin Oncol. Aug 1;26(22):3715-20. 
73. Simon R.(1989). Designs for efficient clinical trials. Oncology (Williston Park). 1989 
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(2009). New response evaluation criteria in solid tumours: revised RECIST guideline (version 
1.1). Eur J Cancer. Jan;45(2):228-47 
76. Leary SE, Wozniak AW, Billups CA, Wu J, McPherson V, Neel MD, Rao BN, Daw NC. (2013) 
Survival of pediatric patients after relapsed osteosarcoma: the St. Jude Children's Research 
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77. Italiano A, Cioffi A, Coco P, Maki RG, Schöffski P, Rutkowski P, Le Cesne A, Duffaud F, Adenis 
A, Isambert N, Bompas E, Blay JY, Casali P, Keohan ML, Toulmonde M, Antonescu CR, Debiec-
Rychter M, Coindre JM, Bui B (2012). Patterns of care, prognosis, and survival in patients with 
metastatic gastrointestinal stromal tumors (GIST) refractory to first-line imatinib and second-
line sunitinib. Ann Surg Oncol. May;19(5):1551-9 
78. Demetri GD1, Reichardt P, Kang YK, Blay JY, et al. (2013). Efficacy and safety of regorafenib 
for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): 
an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. Jan 
26;381(9863):295-302. doi: 10.1016/S0140-6736(12)61857-1. Epub 2012 Nov 22 
79. Goldberg JM (2013). Immunotherapy of sarcomas. Curr Opin Oncol;25:390-7. 
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82. Cousin S, Toulmonde M, Kind M, Cazeau A, Béchade D, Coindre JM, Italiano A (2016). 
Pulmonary sarcoidosis induced by the anti-PD1 monoclonal antibody Pembrolizumab. Ann 
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83.  Li 
J, 
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glucopyranosyl lipid adjuvant system as a vaccine adjuvant. PloS one 2011;6:e16333. 
85.  Kim YH, Gratzinger D, Harrison C, et al. In situ vaccination against mycosis fungoides by 
intratumoral injection of a TLR9 agonist combined with radiation: a phase 1/2 study. Blood 
2012;119:355-63. 
86.  Brody JD, Ai WZ, Czerwinski DK, et al. In situ vaccination with a TLR9 agonist induces 
systemic lymphoma regression: a phase I/II study. Journal of clinical oncology : official 
journal of the American Society of Clinical Oncology 2010;28:4324-32. 
87.  Lugade AA, Moran JP, Gerber SA, Rose RC, Frelinger JG, Lord EM. Local radiation therapy of 
B16 melanoma tumors increases the generation of tumor antigen-specific effector cells that 
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88. Chiappinelli KB, Zahnow CA, Ahuja N, Baylin SB. Combining Epigenetic and Immunotherapy to 
Combat Cancer. Cancer Res. 2016 Apr 1;76(7):1683-9. doi: 10.1158/0008-5472.CAN-15-2125. 
Epub 2016 Mar 17. 
89. Lim J, Poulin NM, Nielsen TO. New Strategies in Sarcoma: Linking Genomic and 
Immunotherapy Approaches to Molecular Subtype. Clin Cancer Res. 2015 Nov 1;21(21):4753-
9. doi: 10.1158/1078-0432.CCR-15-0831. Epub 2015 Sep 1. 
90. DuPage M, Chopra G, Quiros J, Rosenthal WL, Morar MM, Holohan D, Zhang R, Turka L, 
Marson A, Bluestone JA. The chromatin-modifying enzyme Ezh2 is critical for the maintenance 
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10.1016/j.immuni.2015.01.007. Epub 2015 Feb 10. 
91. Rodriguez RM, Suarez-Alvarez B, Lavín JL, Mosén-Ansorena D, Baragaño Raneros A, 
Márquez-Kisinousky L, Aransay AM, Lopez-Larrea C. Epigenetic Networks Regulate the 
Transcriptional Program in Memory and Terminally Differentiated CD8+ T Cells. J Immunol. 
2017 Jan 15;198(2):937-949. doi: 10.4049/jimmunol.1601102. Epub 2016 Dec 14. 

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92. Van Glabbeke M, Verweij J, Judson I, Nielsen OS; EORTC Soft Tissue and Bone Sarcoma 
Group. Progression-free rate as the principal end-point for phase II trials in soft-tissue 
sarcomas. Eur J Cancer. 2002 Mar;38(4):543-9. 
93. PetitPrez et al, A novel transcriptomic-based immune classification of soft-tissue sarcomas 
and its association with molecular characteristics, clinical outcome and response to therapy. 
AACR Annual Meeting 2018, abstract number 4045 
94. PetitPrez et al. Immune sub-classes in sarcoma predict survival and immunotherapy 
response. Nature 2018, submitted for publication 
 

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17. TRANSLATIONAL STUDIES 
17.1. 
BIOMARKER STUDY 
17.1.1. 
Collection of available specimen 
The main objective of this biomarker study is to explore pharmacodynamics and mechanisms of action 
of PEMBROLIZUMAB + CP +/- G100 as well as potential predictive biomarkers. 
For each patient, blood samples will be collected at predefined time points. Note that patients must be 
fasten since at least 3 hours. 
 
Schedule of blood sampling for BM Study 
 
EDTA 
CITRATE 
HEPARIN 
C1D1 (Day-7 for 
stratum 7 
XXX 
XX 
X 
C1D8 
XXX 
 
 
C2D8 
XXX 
XX 
X 
C3D8 
XXX 
XX 
X 
C4D8 
XXX 
XX 
X 
C6D8 
XXX 
XX 
X 
Progression 
XXX 
XX 
X 
 
For plasma study, one 5ml EDTA and one 5ml citrate blood tube will be taken at each timepoint. 
Samples will be centrifugated for 10min at 1900g and 4°C. The aliquoted samples will be annotated 
with study name (PEMBROSARC), center study ID number (1,2,3), Patients study ID number, date 
(../../..) and identification (marker ID: TNFγ, TNFα, TGFβ, IL2, 4, 6, 10, VEGF, TPS-1,… and time 
point) and stored at < -20° until day of shipping.  
For lymphocytes subpopulations monitoring study, a 15 ml sample of peripheral blood will be collected 
on heparin at each timepoint, annotated with study name (PEMBROSARC), center study ID number 
(1,2,3), Patients study ID number, date (../../..) and identification (marker ID: Ly and timepoint).  
For Kynurenine pathway assessment, one 5ml citrate blood tube will be taken at each timepoint. 
A separate document includes a protocol for sample collection (Pharmacodynamics Methods 
Guidelines will be provided by the sponsor as a separate document) and will be the reference. 
17.1.2. 
BM analysis 
Altogether, both angiogenic and immune markers will be explored in this translational study in order 
to explore potential surrogate biomarkers for activity or efficacy.  
- Plasma cytokines levels (TNFγ, TNFα, TGFβ, IL2, 4, 6, 10) (ELISA) 
- Plasma VEGF, Svegfr2 and TPS-1 levels (ELISA) for strata 1 to 5 only. 
- CD8+, CD4+, Treg, and DR lymphocytes subpopulations monitoring, CD8+/Treg ratio (flow 
cytometry) 
- Plasma levels of Kynurenine and Kynurenine to Tryptophan ratio (ELISA and LC/MS) 
A separate document includes a protocol for methods of analysis. (Pharmacodynamics Methods 
Guidelines will be provided by the sponsor as a separate document) 
17.1.2.1. 
SITE PERFORMING BM STUDY 
Plasma studies and flow cytometry will be performed at Centre Georges-Francois Leclerc, Dijon. 

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17.1.2.2. 
SHIPPING OF SPECIMENS 
The containers containing the samples will be labelled with coded numbers to ensure full compliance 
with privacy policy. Samples will be grouped in each institution and sent frozen for centralized 
processing to: 
Docteur GHIRINGHELLI 
Centre Georges-Francois LECLERC 
Laboratoire de Biologie 
1, rue Professeur Marion – BP 77980 
21079 DIJON cedex 
Tel: 03.80.73.75.28 – Fax: 03.80.73.77.74 
Shipping will only be performed by a promoter authorized transporter with respect to good practice. 
 
17.2. 
PDL-1 EXPRESSION FOR STRATA 1 TO 5 
17.2.1. 
Collection of specimen 
For all patients, available tumor tissue sample: 
- 
Either archived FFPE (Formalin-Fixed Parrafin-Embedded) block of specimen tumor sampling 
obtained on metastasis or on locally advanced disease 
- 
Either newly obtained fresh tumor biopsies FFPE before inclusion. 
17.2.2. 
Handling and shipping of specimen 
The samples will be labelled with coded numbers to ensure full compliance with privacy policies. 
Samples will be grouped in each institution and sent for centralized processing with the documents. 
All samples will be stored before they are analyzed. 
The sample collection information must be captured on the appropriate CRF page(s). 
17.2.3. 
Site performing PDL-1 expression research 
All pathological specimens sampling with documents must be sent as described in a specific SOP 
provided by the Sponsor. 
17.2.4. 
PDL-1 expression analysis 
Archived tumor sample or fresh pre-treatment tumor biopsies will be collected in all patients to assess 
PDL-1 expression. Formalin-fixed, paraffin-embedded tumor samples will be analyzed for (but not 
limited to) PDL1, CSF-1R, CD68/CD163, CD68/MHC class II, CD31 (microvessel density), Ki67 and 
other exploratory markers.  
 
17.3. 
OPTIONAL BIOPSY FOR STRATA 1 TO 5 
17.3.1. 
Collection of samples 
Tumor biopsies will be performed in consented patien at baseline and at Day 8 of cycle 2 postdose. 
 
17.3.2. 
Handling and shipping of specimen 
One half of the specimen will be formalin fixed and paraffin embedded [FFPE (Formalin-Fixed Paraffin-
Embedded)] and the second half will be fresh frozen at -80°C. 
The samples will be labelled with coded numbers to ensure full compliance with privacy policies. 
Samples will be grouped in each institution and sent for centralized processing with the documents. 
All samples will be stored before they are analyzed. 
The sample collection information must be captured on the appropriate CRF page(s). 
17.3.3. 
Site performing PDL-1 expression research 
All pathological specimens sampling with documents must be sent as described in a specific SOP 
provided by the Sponsor. 
 

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17.4. 
MANDATORY BIOPSY FOR STRATA 6 TO 7 
17.4.1. 
Collection of samples 
Tumor biopsies will be performed in all patients included in strata 6 to 7 at baseline and during 
treatment: 
- 
Baseline 
- 
Cycle 2 Day 8. Note that for stratum 7, in case of radiotherapy, biopsy must be performed 
before RT initiation and an additional biopsy must be performed within 3-4 weeks after RT 
termination. 
17.4.2. 
Handling and shipping of specimen 
One half of the specimen will be formalin fixed and paraffin embedded [FFPE (Formalin-Fixed Paraffin-
Embedded)] and the second half will be fresh frozen at -80°C. 
The samples will be labelled with coded numbers to ensure full compliance with privacy policies. 
Samples will be grouped in each institution and sent for centralized processing with the documents. 
All samples will be stored before they are analyzed. 
The sample collection information must be captured on the appropriate CRF page(s). 
17.4.3. 
Site performing analysis 
All pathological specimens sampling with documents must be sent as described in a specific SOP 
provided by the Sponsor. 
17.4.4. 
Biomarkers expression analysis 
Formalin-fixed, paraffin-embedded biopsy samples will be analysed for (but not limited to) CD8+ 
effectors, CD68 and 163 Macrophages and FOXP3+ cells infiltrates as well as PDL1, IDO1, CD31 
(microvessel density), Ki67 expression by IHC. Frozen samples will be analysed by (but not limited to) 
RNA sequencing in search for a predictive signature for response. 
 

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APPENDIX 1: ECOG PERFORMANCE STATUS ASSESSMENT SCALE 
 
Grade 
Activity 
0 
Able to carry on all normal activities without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out light work.  
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed 
or chair. 
 
 
 

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APPENDIX 2: EVALUATION OF RESPONSE. THE RECIST 
 
Response and progression will be evaluated in this study using the new international criteria proposed 
by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) [Eur J Ca 
45:228-247, 2009]. Changes in only the largest diameter (unidimensional measurement) of the tumor 
lesions are used in the RECIST criteria. 
DEFINITIONS 
Evaluable for toxicity:  All patients will be evaluable for toxicity from the time of their first treatment 
with study drugs. 
Evaluable for objective response:  Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be 
considered evaluable for response.  These patients will have their response classified according to the 
definitions stated below.  (Note:  Patients who exhibit objective disease progression prior to the end 
of cycle 1 will also be considered evaluable.) 
DISEASE PARAMETERS  
Measurable disease.  Measurable lesions are defined as those that can be accurately measured in at 
least one dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 mm with 
CT scan, or >10 mm with calipers by clinical exam.  All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). 
Note:  Tumor lesions that are situated in a previously irradiated area are not considered 
measurable. 
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 disease.  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered non-
measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by 
CT or MRI), are considered as non-measurable. 
Note:  Cystic 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. 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline.  Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, but in addition should be those that lend 
themselves to reproducible repeated measurements.  It may be the case that, on occasion, the largest 
lesion does not lend itself to reproducible measurement in which circumstance the next largest lesion 
which can be measured reproducibly should be selected.  A sum of the diameters (longest for non-
nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters.  If lymph nodes are to be included in the sum, then only the short axis is 
added into the sum.  The baseline sum diameters will be used as reference to further characterize any 
objective tumor regression in the measurable dimension of the disease. 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions over and 
above the 5 target lesions should be identified as non-target lesions and should also be recorded at 
baseline. Measurements of these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up.  
 

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METHODS FOR EVALUATION OF MEASURABLE DISEASE 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred 
to evaluation by clinical examination unless the lesion(s) being followed cannot be imaged but are 
assessable by clinical exam. 
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based on the 
assumption that CT slice thickness is 5 mm or less.  If CT scans have slice thickness greater than 5 
mm, the minimum size for a measurable lesion should be twice the slice thickness.  MRI is also 
acceptable in certain situations (e.g. for body scans).   
 
RESPONSE CRITERIA 
 Evaluation of 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. 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking 
as reference the baseline sum diameters. 
Progressive Disease (PD): 
At least a 20% increase in the sum of the diameters of target lesions, 
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 
progressions). 
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 study 
 
Evaluation of Non-Target Lesions 
Complete Response (CR): 
Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis) 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a patient to 
be considered in complete clinical response. 
Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or unequivocal progression 
of existing non-target lesions.  
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and the progression status should be confirmed at a 
later time by the review panel (or Principal Investigator). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Definition of the Best Response 
The best response determination in trial where confirmation of complete or partial response is 
required: 
Complete or partial responses may be claimed only if the criteria for each are met at a subsequent 
time point as specified in the protocol (generally 4 weeks later). In this circumstance, the best 
overall response can be interpreted as in Table below. 
 
 
 
Special notes on response assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to ‘normal’ size 
(<10 mm), they may still have a measurement reported on scans. This measurement should be 
recorded even though the nodes are normal in order not to overstate progression should it be based 
on increase in size of the nodes. As noted earlier, this means that patients with CR (complete 
response) may not have a total sum of ‘zero’ on the case report form (CRF). 
 
In trials where confirmation of response is required, repeated ‘NE’ time point assessments may 
complicate best response determination. The analysis plan for the trial must address how missing 
data/assessments will be addressed in determination of response and progression. For example, in 
most trials it is reasonable to consider a patient with time point responses of PR-NE-PR as a confirmed 
response. 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as ‘symptomatic 
detioration’. Every effort should be made to document objective progression even after 
discontinuation of treatment. Symptomatic deterioration is not a descriptor of an objective response: it 
is a reason for stopping study therapy. The objective response status of such patients is to be 
determined by evaluation of target and non-target disease as shown in Tables belows. 
 

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APPENDIX 3: SERIOUS ADVERSE EVENT FORM 
 

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Appendix 4: PREGNANCY REPORT FORM 
 
 
 

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APPENDIX 5: IMMUNE RELATED RESPONSE CRITERIA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX 6: PATIENT MEDICATION DIARY STRATEGY A 
 
 
 
 
 
 
 
 

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APPENDIX 7: PATIENT MEDICATION DIARY STRATEGY B 
 

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APPENDIX 8: EVENT OF CLINICAL INTEREST NOTIFICATION FORM 
 

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APPENDIX 9: D O S E  M O D I F I C A T I O N  A N D  T O X I C I T Y  M A N A G E M E N T  G U I D E L I N E S  
F O R  I M M U N E - R E L A T E D  A E S  A S S O C I A T E D  W I T H  P E M B R O L I Z U M A B   
Immune-
related AEs 
Toxicity Grade or 
Conditions 
(CTCAEv4.0) 
Action Taken with 
Study Medication 
irAE Management with 
Corticosteroid and/or Other 
Therapies 
Monitor and Follow-up 
Pneumonitis  
Grade 2 
Withhold until Grade 
0-1  
 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 until Grade 
0-1 
 Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper 
 
 
Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, blood or 
mucus in stool with or without fever) and of bowel 
perforation (ie, peritoneal signs and ileus). 
 
Participants with ≥Grade 2 diarrhea suspecting colitis 
should consider GI consultation and performing 
endoscopy to rule out colitis.  
 
Participants with diarrhea/colitis should be advised to 
drink liberal quantities of clear fluids. If sufficient oral 
fluid intake is not feasible, fluid and electrolytes should 
be substituted via IV infusion. 
Grade 4, or 
recurrent Grade 3 
Permanently 
discontinue 
AST / ALT 
Elevation or 
Increased 
Bilirubin 
Grade 2 a 
Withhold until Grade 
0-1 
 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 returns to 
baseline or is stable 
Grade 3 b or 4 c  
Permanently 
discontinue 
 Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper 

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Immune-
related AEs 
Toxicity Grade or 
Conditions 
(CTCAEv4.0) 
Action Taken with 
Study Medication 
irAE Management with 
Corticosteroid and/or Other 
Therapies 
Monitor and Follow-up 
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia1 
Newly onset T1DM 
or Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure 
Withhold until Grade 
0-1 d 
 Initiate insulin replacement 
therapy for participants with 
T1DM  
 Administer anti-hyperglycemic 
in participants with 
hyperglycemia  
 
Monitor participants for hyperglycemia or other signs 
and symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold until Grade 
0-1 
 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 until Grade 
0- 1 or permanently 
discontinued 
Hyperthyroidism1 
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 until Grade 
0- 1 or permanently 
discontinue d  
Hypothyroidism1 
Grade 2-4 
Continue 
 Initiate thyroid replacement 
hormones (eg, levothyroxine 
or liothyronine) per standard 
of care 
 
Monitor for signs and symptoms of thyroid disorders.  
 
Nephritis and 
Renal Dysfunction 
grading according 
to increased 
creatinine or 
acute kidney 
injury 
Grade 2 
Withhold until Grade 
0- 1 
 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  
Withhold 
 
Based on severity of AE 
administer corticosteroids 
 
Ensure adequate evaluation to confirm etiology or 
exclude other causes 
Grade 2, 3 or 4 
Permanently 
discontinue 

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Immune-
related AEs 
Toxicity Grade or 
Conditions 
(CTCAEv4.0) 
Action Taken with 
Study Medication 
irAE Management with 
Corticosteroid and/or Other 
Therapies 
Monitor and Follow-up 
Neurological 
Toxicities 
Grade 2 
 
 
Withhold  
 
 
 Based on severity of AE 
administer corticosteroids 
 
Ensur adequate evaluation to confirm etiology and/or 
exclude other causes 
Grade 3 or 4 
Permanently 
discontinue 
Exfoliative 
Dermatological 
Conditions 
Suspected SJS, 
TEN, or DRESS 
 
 
Withhold 
 
 
 
 Based on severity of AE 
administer corticosteroids 
 
Ensur adequate evaluation to confirm etiology or 
exclude other causes 
Confirmed SJS, 
TEN, or DRESS 
Permanently 
discontinue 
All Other 
Immune-related 
AEs 
Persistent Grade 2 
Withhold until Grade 
0- 1 
 Based on severity of AE 
administer corticosteroids  
 
Ensure adequate evaluation to confirm etiology or 
exclude other causes 
 
Grade 3 
Withhold or 
discontinue based on 
the type of event e.  
Events that require 
discontinuation 
include but are not 
limited to:  
encephalitis and 
other clinically 
important irAEs (eg 
vasculitis and 
sclerosing 
cholangitis) 

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Immune-
related AEs 
Toxicity Grade or 
Conditions 
(CTCAEv4.0) 
Action Taken with 
Study Medication 
irAE Management with 
Corticosteroid and/or Other 
Therapies 
Monitor and Follow-up 
Grade 4 or 
recurrent Grade 3  
Permanently 
discontinue 
 
General Instructions: 
1. Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should begin if the 
irAEs are not controlled by corticosteroids. 
2. Study intervention must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not ≤10 mg/day within 12 weeks of the last study 
intervention treatment.  
3. The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks. 
4. If study intervention has been withheld, study intervention may resume after the irAE decreased to ≤ Grade 1 after corticosteroid taper. 
 
NOTES:  
1. For participants with Grade 3 or 4 immune-related endocrinopathy where withholding 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)  
 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 
a AST/ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal;  bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if 
baseline abnormal 
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if baseline normal; >3.0 to 10.0 x baseline 
if baseline abnormal 
c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal;  bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal 
d The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. If control achieved or ≤ Grade 2, 
pembrolizumab may be resumed. 
e Events that require discontinuation include, but are not limited to: encephalitis and other clinically important irAEs (eg, vasculitis and sclerosing cholangitis). 
 
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug 
Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; 
T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.