Trabectedin Combined With Durvalumab (MEDI4736) in Patients With Advanced Pretreated Soft-tissue Sarcomas and Ovarian Carcinomas. A Phase Ib Study.
Phase: PHASE1
Conditions: Ovarian Carcinoma, Soft Tissue Sarcoma
Sponsor: Institut Bergonié

 
 
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TRABECTEDIN COMBINED WITH DURVALUMAB (MEDI4736) IN PATIENTS 
WITH ADVANCED PRETREATED SOFT-TISSUE SARCOMAS AND OVARIAN 
CARCINOMAS 
A PHASE IB STUDY  
 
Protocol TRAMUNE 
 
VERSION N°8.0 of |16|11|2021|- N° : IB 2016- 02 
 
EudraCT n° 2016-004720-33 
 
 
 
Coordinating Investigator 
Maud TOULMONDE, 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 : m.toulmonde@bordeaux.unicancer.fr  
 
 
Scientific responsive  
Anne FLOQUET, MD                                                                        Department of Medical Oncology 
Medical Oncologist 
Institut Bergonié 
 
229, cours de l’Argonne – 33076 BORDEAUX Cedex, France 
 
Tél : 05.56.33.33.46 – Fax : 05.56.33.04.85 – E-mail : a.floquet@bordeaux.unicancer.fr  
 
 
Clinical Research Unit 
Simone MATHOULIN-PÉLISSIER, MD, PhD  
Institut Bergonié, Bordeaux 
Head of the Unit 
Marina PULIDO, MSc 
Institut Bergonié, Bordeaux 
Biostatistician 
Sabrina SELLAN-ALBERT, MsC  
Institut Bergonié, Bordeaux 
Clinical Research Manager 
 
 
Pharmacist 
Ludivine POIGNIE, PharmD 
Institut Bergonié, Bordeaux 
 
 
Pharmacovigilance 
 
UNICANCER 
 
 
 
 
 
SPONSOR 
INSTITUT BERGONIE 
 

Institut Bergonié 
Protocol TRAMUNE 
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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 ......................................................... 16 
1. RATIONALE OF THE TRIAL ............................................................................................... 18 
1.1. 
MANAGEMENT OF SOFT-TISSUE SARCOMA IN ADVANCED SETTING ....................................... 18 
1.2. 
MANAGEMENT OF PLATINUM-SENSITIVE RELAPSED OVARIAN CARCINOMA ........................... 18 
1.3. 
TRABECTEDIN .................................................................................................................... 19 
1.3.1. Chemical structure .............................................................................................................. 19 
1.3.2. Preclinical and mechanism of action .................................................................................... 19 
1.3.3. Clinical data ....................................................................................................................... 21 
1.4. 
DURVALUMAB (MEDI4736) ...................................................................................................... 21 
1.4.1. Chemical structure .............................................................................................................. 21 
1.4.2. Preclinical data and mechanism of action ............................................................................. 21 
1.4.3. Clinical data ....................................................................................................................... 22 
1.4.4. Fixed dosing rationale ......................................................................................................... 23 
1.5. 
STUDY RATIONALE ............................................................................................................. 23 
2. OBJECTIVES ...................................................................................................................... 24 
2.1. 
PRIMARY OBJECTIVE ................................................................................................................ 24 
2.2. 
SECONDARY OBJECTIVES ........................................................................................................... 24 
3. STUDY DESIGN ................................................................................................................. 24 
3.1. 
OVERALL STUDY DESIGN ..................................................................................................... 24 
3.2. 
DEFINITIONS ...................................................................................................................... 24 
3.3. 
DOSE ESCALATION PART ........................................................................................................... 25 
3.3.1. Treatment scheme ............................................................................................................. 25 
3.3.2. Dose levels ........................................................................................................................ 25 
3.4. 
EXPANSION COHORTS ............................................................................................................ 26 
3.5. 
PATIENT’S REPLACEMENT .......................................................................................................... 26 
4. SELECTION OF PATIENTS ................................................................................................. 26 
4.1. 
INCLUSION CRITERIA ............................................................................................................... 26 
4.2. 
EXCLUSION  CRITERIA .............................................................................................................. 27 
STUDY PLAN ............................................................................................................................ 28 
4.3. 
DURATION OF STUDY (WHOLE POPULATION) ................................................................................. 28 
4.3.1. Dose escalation part ........................................................................................................... 28 
4.3.2. Expansion cohort ................................................................................................................ 28 
4.4. 
DEFINITIONS OF DURATION OF STUDY AND TREATMENT (PER PATIENT) ................................................ 28 
4.5. 
PROTOCOL DEVIATION ....................................................................................................... 29 
4.6. 
SCREENING EVALUATION .................................................................................................... 30 
4.7. 
EVALUATIONS DURING TREATMENT .................................................................................... 31 
4.8. 
EVALUATION AT THE END OF TREATMENT............................................................................. 32 
4.9. 
FOLLOW-UP AFTER THE END-OF-TREATMENT VISIT .............................................................. 33 
5. REGISTRATION PROCEDURES .......................................................................................... 33 
5.1. 
SCREENING ........................................................................................................................... 33 
5.2. 
INCLUSION ............................................................................................................................ 33 
6. STUDY TREATMENT .......................................................................................................... 33 
6.1. 
DESCRIPTION OF TREATMENT ..................................................................................................... 33 

 
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6.2. 
PHARMACEUTICAL INFORMATIONS ............................................................................................... 34 
6.3. 
ADMINISTRATION OF TREATMENT ................................................................................................ 34 
6.4. 
DURVALUMAB ......................................................................................................................... 34 
6.4.1. Formulation/packaging/storage ........................................................................................... 34 
6.4.2. Study drug preparation ....................................................................................................... 34 
6.4.3. Monitoring of dose administration ........................................................................................ 35 
6.5. 
TRABECTEDIN ........................................................................................................................ 35 
6.6. 
GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES ............................................ 35 
6.6.1. Acceptable concomitant medication ..................................................................................... 35 
6.6.2. Prohibited concomitant medication ...................................................................................... 36 
6.6.3. Restrictions during study ..................................................................................................... 36 
6.6.4. Potential drug interaction .................................................................................................... 37 
6.7. 
DOSING DELAYS/DOSE MODIFICATIONS AND ADVERSE EVENT MANAGEMENT ............................................ 38 
6.7.1. General rules for dose modification ...................................................................................... 38 
6.7.2. Events of clinical interest and immune mediated adverse event (imeics) ................................ 39 
6.8. 
PACKAGING AND LABELING ........................................................................................................ 41 
6.9. 
SUPPLIES AND DRUG ACCOUNTABILITY ......................................................................................... 42 
6.10. 
TREATMENT COMPLIANCE ...................................................................................................... 42 
7. STUDY EVALUATIONS ....................................................................................................... 43 
7.1. 
CENTRAL REVIEW FOR DIAGNOSIS OF SOFT-TISSUE SARCOMA .............................................................. 43 
7.1.1. Diagnosis of soft-tissue sarcoma ......................................................................................... 43 
7.1.2. Pathological specimen sampling necessary for central review ................................................ 43 
7.1.3. Pathological process schedule and implementation (not applicable if diagnosis reviewed in the 
RRePS Network) ........................................................................................................................ 43 
7.2. 
EFFICACY – EXPANSION COHORT ONLY ......................................................................................... 43 
7.2.1. Assessing Objective Tumor Response (RECIST v1.1) ............................................................ 43 
7.2.2. Centralized Radiological Review (Institut Bergonié)............................................................... 44 
7.3. 
SAFETY ................................................................................................................................ 44 
8. STUDY ENDPOINTS .......................................................................................................... 44 
8.1. 
PRIMARY ENDPOINT ................................................................................................................. 44 
8.2. 
SECONDARY ENDPOINTS............................................................................................................ 45 
9. STATISTICAL CONSIDERATIONS ..................................................................................... 46 
9.1. 
HYPOTHESES AND NUMBER OF SUBJECTS NEEDED............................................................................. 46 
9.1.1. Phase I (Dose escalation part) ............................................................................................ 46 
9.1.1. Phase I (Expansion cohorts) ................................................................................................ 46 
9.2. 
DEFINITION OF STUDY POPULATIONS ............................................................................................ 46 
9.2.1. Phase I (Dose escalation part) ............................................................................................ 46 
9.2.2. Phase I (Expansion cohorts) ................................................................................................ 46 
9.3. 
STATISTICAL ANALYSIS ............................................................................................................. 47 
9.3.1. Patient characteristics at baseline ........................................................................................ 47 
9.3.2. Endpoint analyses .............................................................................................................. 47 
10. 
ADVERSE EVENTS .......................................................................................................... 49 
10.1. 
DESCRIPTION OF SAFETY EVALUATION CRITERIA .......................................................................... 49 
10.2. 
DEFINITION ....................................................................................................................... 49 
10.2.1. 
Adverse event .............................................................................................................. 49 
10.2.2. 
Serious adverse event ................................................................................................... 49 
10.2.3. 
Non serious adverse event ............................................................................................ 50 
10.2.4. 
Adverse effect .............................................................................................................. 50 
10.2.5. 
Expected/Unexpected character .................................................................................... 50 
10.2.6. 
Intensity criterion ......................................................................................................... 50 
10.2.7. 
New information ........................................................................................................... 51 
10.2.8. 
Special considerations ................................................................................................... 51 
10.3. 
SERIOUS ADVERSE EVENT AND NEW INFORMATION NOTIFICATION (RESPONSIBILITY OF THE INVESTIGATOR) 52 
10.4. 
REPORTING PREGNANCY CASES OCCURRED WITHIN THE CLINICAL TRIAL ............................................. 53 
10.5. 
REPORT OF OVERDOSE .......................................................................................................... 54 

 
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10.6. 
REPORT OF HEPATIC FUNCTION ABNORMALITY ............................................................................ 54 
10.7. 
REPORTING EVENTS OF CLINICAL INTEREST AND IMMUNE-MEDIATED ADVERSE EVENTS ........................... 54 
10.8. 
REPORT OF NON SERIOUS ADVERSE EVENT .................................................................................. 55 
10.9. 
RESPONSIBILITY OF VIGILANCE UNIT ........................................................................................ 55 
10.10. 
NOTIFICATION AND REGISTRATION OF UNEXPECTED SERIOUS ADVERSE EVENTS AND NEW INFORMATION 
(RESPONSIBILITY OF THE SPONSOR) ....................................................................................................... 56 
11. 
QUALITY ASSURANCE AND TRIAL MONITORING ......................................................... 57 
11.1. 
MONITORING OF THE TRIAL .................................................................................................... 57 
11.1.1. 
Steering Committee ...................................................................................................... 57 
11.1.2. 
Independent Data Monitoring Committee ....................................................................... 57 
11.2. 
QUALITY ASSURANCE ............................................................................................................ 58 
11.2.1. 
Data collection.............................................................................................................. 58 
11.2.2. 
Monitoring .................................................................................................................... 58 
11.2.3. 
Handling of missing data ............................................................................................... 59 
11.2.4. 
Audits/Inspections ........................................................................................................ 59 
11.2.5. 
Data management ........................................................................................................ 59 
12. 
REGULATORY ASPECTS AND ETHICAL CONSIDERATIONS ........................................... 60 
12.1. 
CLINICAL TRIAL AUTHORIZATION ............................................................................................. 60 
12.2. 
INSURANCE POLICY .............................................................................................................. 61 
12.3. 
INFORMING AND OBTAINING CONSENT FROM PATIENTS .................................................................. 61 
12.4. 
SPONSOR’S RESPONSIBILITIES ................................................................................................. 61 
12.5. 
INVESTIGATORS’ RESPONSIBILITIES .......................................................................................... 61 
12.6. 
AUTHORITY TO EXECUTE THE TRIAL .......................................................................................... 62 
12.7. 
REGULATIONS GOVERNING THE COLLECTION OF HUMAN BIOLOGICAL SAMPLES ...................................... 62 
12.8. 
FEDERATION DES COMITES DE PATIENTS POUR LA RECHERCHE CLINIQUE EN CANCEROLOGIE (FCPRCC) 
(FEDERATION OF PATIENT COMMITTEES FOR CLINICAL RESEARCH IN ONCOLOGY) ............................................. 63 
12.9. 
DATA PROCESSING ............................................................................................................... 63 
13. 
CONFIDENTIALITY AND OWNERSHIP OF DATA ........................................................... 64 
14. 
PUBLICATION AND VALORISATION .............................................................................. 64 
14.1. 
SCIENTIFIC COMMUNICATION .................................................................................................. 64 
14.2. 
INFORMATION TO PATIENTS .................................................................................................... 64 
15. 
REFERENCES .................................................................................................................. 65 
16. 
BIOMARKER STUDIES ................................................................................................... 69 
16.1. 
BLOOD SAMPLE FOR IMMUNOLOGICAL BIOMARKERS ....................................................................... 69 
16.1.1. 
Collection of available specimen .................................................................................... 69 
16.1.2. 
BM analysis .................................................................................................................. 69 
16.1.3. 
Site performing BM study .............................................................................................. 69 
16.2. 
BLOOD SAMPLE FOR CIRCULATING DNA ..................................................................................... 69 
16.2.1. 
Collection of available specimen .................................................................................... 69 
16.2.2. 
Collection – storage and shipping procedure .................................................................. 69 
16.3. 
TUMOR SAMPLE ................................................................................................................... 70 
16.3.1. 
Collection of specimen .................................................................................................. 70 
16.3.2. 
Handling and shipping of specimen ................................................................................ 70 
16.3.3. 
Site performing analysis ................................................................................................ 70 
APPENDIX 1: ECOG PERFORMANCE STATUS ASSESSMENT SCALE ........................................ 71 
APPENDIX 2: COCKROFT FORMULA ........................................................................................ 72 
APPENDIX 3: EVALUATION OF RESPONSE. THE RECIST ........................................................ 73 

 
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APPENDIX 4: DOSING MODIFICATION AND TOXICITY MANAGEMENT GUIDELINES FOR 
IMMUNE-MEDIATED, INFUSION RELATED, AND NON IMMUNE-MEDIATED REACTIONS FOR 
DURVALUMAB ......................................................................................................................... 76 
APPENDIX 5: SERIOUS ADVERSE EVENT NOTIFICATION FORM ............................................ 99 
APPENDIX 8 : DECLARATION OF HELSINKI ......................................................................... 105 

Institut Bergonié 
Protocol TRAMUNE 
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APPROVAL AND SIGNATURES OF PROTOCOL  
Title of protocole : Trabectedin combined with durvalumab (MEDI4736) in patients with advanced 
pretreated soft-tissue sarcomas and ovarian carcinomas. A phase Ib study 
 
Competent 
authority 
Name : ANSM 
Date of initial authorization 
05/05/2017 
Date of MSA 1 authorization 
18/10/2017 
Date of MSA 2 authorization 
09/02/2018 
Date of MSA 3 authorization 
28/09/2018 
Date of MSA 4 authorization 
08/02/2019 
Date of MSA 5 authorization 
16/03/2020 
Date of MSA 6 authorization 
NA 
Date of MSA 7 authorization 
NA 
Date of MSA 8 authorization 
07/06/2021 
Date of MSA 9 authorization 
02/02/2022 
Référence :  
160939A-12 
Ethic  
Committee 
Name : CPP du Sud-
Ouest et d'Outre-Mer III 
Date of initial approval 
21/12/2016 
Date of MSA 1 approval 
27/09/2017 
Date of MSA 2 approval 
31/01/2018 
Date of MSA 3 approval 
29/08/2018 
Date of MSA 4 approval 
27/02/2019 
Date of MSA 5 approval 
20/04/2020 
Date of MSA 6 approval 
NA 
Date of MSA 7 approval 
NA 
Date of MSA 8 approval 
26/05/2021 
Date of MSA 9 approval 
23/02/2022 
Référence :  
2016/98 
 
Name and 
responsability 
Address 
Date 
Signature 
Managing 
Director 
Pr François-Xavier MAHON 
Institut Bergonié – Bordeaux  
Phone:+335.56.33.33.33/Fax:+335.56.33.33.30 
Mail : f.mahon@bordeaux.unicancer.fr  
16/11/2021 
Coordinating 
Investigator 
Dr Maud TOULMONDE  
Institut Bergonié – Bordeaux  
Phone :+335.56.33.78.05/Fax :+335.56.33.04.85 
Mail : m.toulmonde@bordeaux.unicancer.fr  
16/11/2021 
 
Scientific 
responsive  
Dr Anne FLOQUET  
Institut Bergonié – Bordeaux  
Phone :+335.56.33.32.46/Fax :+335.56.33.04.85 
Mail : a.floquet@bordeaux.unicancer.fr  
16/11/2021 
Responsible of 
Unit Clinical 
Research  
Pr Simone MATHOULIN-PÉLISSIER 
Institut Bergonié – Bordeaux  
Phone:+335.56.33.33.98 / Fax:+335.56.33.04.66 
Mail : s.mathoulin@bordeaux.unicancer.fr  
16/11/2021 
Biostatistician  
Marina PULIDO 
Institut Bergonié – Bordeaux  
Phone: +335.24.07.19.29/Fax:+335.56.33.04.85 
Mail : m.pulido@bordeaux.unicancer.fr     
16/11/2021 
Data-Manager 
Sandrine BARBOTIN 
Institut Bergonié – Bordeaux  
Phone: +335.56.33.33.33/Fax:+335.56.33.04.85 
Mail : s.barbotin@bordeaux.unicancer.fr 
16/11/2021 

 
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Clinical 
research 
Manager  
Sabrina SELLAN-ALBERT 
Institut Bergonié – Bordeaux  
Phone:+335.56.33.78.05  Fax:+335.56.33.04.85 
Mail : s.albert@bordeaux.unicancer.fr         
16/11/2021 
 
Pharmacist 
Ludivine POIGNIE 
Institut Bergonié – Bordeaux  
Phone:+335.56.33.33.94/Fax:+335. 56.33.04.85 
Mail : l.poignie@bordeaux.unicancer.fr  
16/11/2021 
 
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 : 
 

Institut Bergonié 
Protocol TRAMUNE 
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SYNOPSIS 
 
Title of the study  
Trabectedin combined with durvalumab (MEDI4736) in patients with 
advanced pretreated soft-tissue sarcomas and ovarian carcinomas. 
A Phase Ib study 
Abbreviation  
of the trial 
TRAMUNE 
Sponsor 
Identification 
Institut Bergonié, Regional Comprehensive Cancer Center 
Coordinating 
Investigator 
Doctor Maud TOULMONDE  
Department of Medical Oncology 
 Scientific 
responsive 
Doctor Anne FLOQUET 
Department of Medical Oncology 
Number of 
investigational 
sites planned 
Phase I (dose escalation):  
2 centers 
- Institut Bergonié, Bordeaux, France (PI : Pr Antoine Italiano) 
- Centre Léon Bérard, Lyon, France (PI : Dr Mehdi Brahmi) 
Phase I (expansion cohorts):  
3 centers 
- Institut Bergonié (PI : Pr Antoine Italiano) 
- Centre Léon Bérard (PI : Dr Mehdi Brahmi) 
- Institut Gustave Roussy, Villejuif, France (PI : Dr Olivier MIR) 
Number of patients 
Phase I (Dose escalation): 20 patients 
Phase I (Expansion cohorts):  30 patients (15 patients STS/15 patients ovarian 
carcinomas) 
Duration of the 
study 
Planned enrollment period: 30 months 
Treatment duration: until progression 
Follow-up: 1 year 
Study period: 3 years 
Medical conditions 
Adult patients with: 
- 
locally advanced or metastatic soft-tissue sarcoma (STS) who have failed 
anthracycline-containing chemotherapy (CT), 
- 
or ovarian carcinoma, without known g/s BRCA mutation, and must have 
received at least one line of platinum-containing regimen.  
 
Objectives 
Primary objective 
To determine the recommended phase II dose (RP2D), the maximum tolerated 
dose (MTD) evaluated on the first 21 days (D1 to D21), the safety profile and the 
dose limiting toxicities (DLT) of trabectedin given in combination with durvalumab 
in patients with advanced pretreated soft-tissue sarcoma and ovarian carcinomas. 
 
Secondary objectives  
 To evaluate the toxicity profile of trabectedin in association with durvalumab 
(NCI-CTCAE v4.03) 
 To determine preliminary signs of anti-tumor activity of trabectedin given in 
combination with durvalumab in two expansion cohorts (STS and ovarian 
carcinomas) in terms of: 
o Best overall response  as per RECIST v1.1,  
o Objective response under treatment as per RECIST v1.1,  
o 6-month objective response as per RECIST v1.1,  
o 6-month progression-free status defined as per RECIST v1.1,  
o 1-year progression-free survival (PFS), 
o 1-year overall survival (OS). 
 To explore the pharmacodynamics (PD) of trabectedin in association with 

 
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durvalumab as well as potential predictive biomarkers of activity and efficacy 
(blood and tumor tissue samples). 
Study design  
STUDY DESIGN 
This is a multicenter, prospective open-labeled phase Ib trial based on a dose 
escalation study design (3+3 traditional design) assessing three dose levels of 
trabectedin when prescribed in combination with durvalumab followed by two 
expansion cohorts (STS and ovarian carcinomas) once the MTD is established. 
 
DEFINITIONS 
 
Dose-limiting toxicity (DLT): A DLT is defined as an adverse event (AE) or 
laboratory abnormality that fulfills all the criteria below:  
o Begins on the first 21 days of treatment. 
o Is considered to be at least possibly related to the study treatment.  
o Meets one of the criteria below, graded as outlined or according to NCI 
CTCAE v4.03 : 
 
Any grade 4 toxicity (except for vomiting without maximal 
symptomatic/prophylactic treatment and if toxicity is transaminitis, 
but which have to be resolved at Day 21, i.e. return to Baseline or 
grade 1). 
 
Grade 3 non-haematological toxicity lasting > 7 days (except for 1st 
episode of nausea and if toxicity is transaminitis, which have to be 
resolved at Day 21, i.e. return to Baseline or grade 1). 
 
Grade 3 hematologic toxicity lasting for > 7days. 
 
Grade 4 neutropenia with fever. 
 
Grade > 2 thrombocytopenia with bleeding. 
 
Maximum tolerated dose (MTD): the MTD is defined as the highest dose at 
which no more than 1 in 6 of the patients in the cohort experienced a DLT in 
the first 21 days. Conclusions of the steering committee for the definition of 
the MTD will be sumbmitted for approval to an independent data monitoring 
committee (IDMC) before opening the expansion cohorts. 
 
Recommended phase II dose (RP2D): The RP2D dose corresponds to the 
dose level to be recommended for further investigations in phase II trials. 
Following the expansion cohorts, the RP2D for Trabectedin will be identified by 
the steering committee based on safety data from patients included in the dose 
escalation part and the expansion cohorts, as well as PD data. Data from all 
patients (escalation + expansion cohorts) will be used to define the RP2D.  
 
DOSE ESCALATION PART 
 
3 doses of trabectedin given in combination with durvalumab (fixed dose) will 
be investigated: 
 
 
 
 
 
 
The starting dose of trabectedin is 1 mg/m2. 
 
The maximum dose of trabectedin administered (1.5 mg/m2) will not be 
exceeded. 
 
No skipping of the dose will be allowed. 
 
For a given patient, dose will never be escalated.  
 
Patients will be allocated to the 3 dose levels following a 3 + 3 design. 
 
A minimum of 3 patients and a maximum of 6 patients will be entered on each 
dose level. 
 
All 3 patients within a dose level will be observed during 21 days (the period of 
Level 
-1 
1 
2 
3 
Trabectedin  
(3h) 
0.8 
mg/m² 
1 
mg/m² 
1.2 
mg/m² 
1.5 
mg/m² 

 
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observation of DLTs) before accrual to the next higher dose level may begin.  
 
Dose escalation will proceed according to the following scheme: 
Number of 
patients with 
DLT at one 
dose level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
≥2 
Dose escalation will be stopped. This dose level will 
be declared as the maximum administered dose 
(MAD). Three additional patients will be entered at 
the next lowest dose level if only 3 patients were 
treated previously at that dose. 
1 out of 3 
Enter at least 3 more patients at this dose level. 
 If 0 of these 3 patients experience DLT, 
proceed to the next dose level. 
 If 1 or more of this group suffer DLT, dose 
escalation will be stopped, and this dose is 
declared as the MAD. Three additional patients 
will be entered at the next lowest dose if only 3 
patients were treated previously at that dose.
≤1 out of 6  
This will be the maximum tolerated dose (MTD).  
 
As described above, the maximum administered dose (MAD) for Trabectedin is 
the dose in which ≥ 2/3 or ≥ 2/6 patients experience DLT.  
 
If the MAD for Trabectedin is seen at the starting dose level, then dose level “-
1” will be the recommended dose. 
 
The MTD for Trabectedin is defined as the highest dose at which no more than 
1 in 6 of the patients in the cohort experienced a DLT during the period of 
observation of DLTs. 
 
The steering committee will meet before proceeding or not to each dose 
escalation. In addition, , the steering committee will be consulted to resolve 
any specific  issue regarding the DLT status.  
 
Conclusions of the steering committee for the definition of MTD will be 
submitted for approval to an independent data monitoring committee (IDMC) 
before opening the expansion cohorts. 
 
EXPANSION COHORT 
Once the MTD has been defined, the expansion cohorts will be opened. All patients 
will be treated at the MTD of Trabectedin (as defined in the dose escalation trial) 
given in association with Durvalumab with the same schedule as in the dose 
escalation trial. Following the expansion cohorts, the RP2D for Trabectedin will be 
identified by the steering committee based on safety data from patients included in 
the dose escalation part and the expansion cohorts, as well as PD data. Data from 
all patients (escalation + expansion cohorts) will be used to define the RP2D. 
Inclusion criteria 
1. Histology :  
-  Soft-tissue sarcoma histologically confirmed. In care outside a center of the 
RRePS Network, a central review is necessary (Pr. Coindre team),  
- histologically confirmed ovarian carcinoma (carcinosarcoma included), 
without known g/s BRCA mutation 
2. ovarian carcinoma must have received at least one line of platinum-containing 
regimen.  
3. Metastatic or unresectable locally advanced disease, not ammenable to curative 
therapy, 
4. Age ≥ 18 years, 
5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1, 

 
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6. Life expectancy > 3 months, 
7. Patients must have measurable disease (lesion in previously irradiated field can 
be considered as measurable if progressive at inclusion according to RECIST v1.1) 
defined as per RECIST v1.1 with at least one lesion that can be measured in at 
least one dimension (longest diameter to be recorded) as ≥10 mm with spiral CT 
scan. 
8. Documented disease progression according to RECIST v1.1 before study entry, 
9. Patient must comply with the collection of tumor biopsies, 
10. At least 1 line of chemotherapy in the palliative setting with use of 
Anthracyclines (for STS), 
11. At least three weeks since last chemotherapy, immunotherapy or any other 
pharmacological treatment for neoplastic disease and/or radiotherapy, 
12. 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), aspartate aminotransferase (AST)  2.5 x 
upper limit of normality (ULN) and alkaline phosphatase (AP)  2.5 x ULN.  
c. Total bilirubin  ULN. 
d. Albumin ≥ 25 g/l. 
e. Calculated creatinine clearance (CrCl) > 60 ml/min (according to Cockroft 
Gault formula). 
f. Thyroid function within normal laboratory ranges (TSH, free T3, free T4) 
g. Creatine PhosphoKinase (CPK) ≤ 2.5 x ULN 
13. Women of childbearing potential must have a negative serum pregnancy test 
within 72 hours prior to receiving the first dose of trial medication. Both women 
and men must agree to use a highly effective method of contraception throughout 
the treatment period and for six months after discontinuation of treatment. 
Acceptable methods of contraception are described in protocol section 7.6.1.1, 
14. No prior or concurrent malignant disease diagnosed or treated in the last 2 
years except for adequately treated in situ carcinoma of the cervix, concomitant 
endometrial carcinoma stage IA grade 1, basal or squamous skin cell carcinoma, or 
in situ transitional bladder cell carcinoma, 
15. 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 Events (NCI-CTCAE, version 4.03), 
16. Voluntarily signed and dated written informed consent prior to any study 
specific procedure, 
17. Patients with a social security in compliance with the French law. 
Exclusion  criteria 
1. Previous treatment with Trabectedin or an anti-PD-1, anti-PD-L1, anti-PD-L2, 
including durvalumab 
2. Current or prior use of immunosuppressive medication including any use of oral 
glucocorticoids, within 21 days before the first dose of durvalumab, with the 
exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at 
physiological doses 
3. Active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, 
ulcerative colitis), 
4. Has an active autoimmune disease requiring systemic treatment within the past 
2 years (ie, with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) 
is not considered a form of systemic treatment, 
5. Has evidence of active non-infectious pneumonitis,  
6. Has an active infection requiring systemic therapy, 
7. Currently active bacterial or fungus infection (> grade 2 NCI-CTCAE] HIV1, 
HIV2, hepatitis A or hepatitis B or hepatitis C infections), 
8. Known central nervous system malignancy (CNS),  

 
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9. 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, 
10. Previous enrolment in the present study, 
112. Patient unable to follow and comply with the study procedures because of any 
geographical, social or psychological reasons, 
12. Has received a live vaccine within 30 days prior to the first dose of trial 
treatment, 
Note: the killed virus vaccines used for seasonal influenza vaccines for 
injection are allowed; however intranasal influenza vaccines (e.g., FluMist®) 
are live attenuated vaccines and are not allowed. 
13. Known hypersensitivity to any involved study drug or any of its formulation 
components, 
14. Tumors not accessible for biopsy, 
15. Known history of active tuberculosis. 
16. Person under judicial protection or deprived of liberty 
17. Cardiac dysfunction :  
- LVEF (Left Ventricular Ejection Fraction)< 40% at baseline;  
- or clinically symptomatic cardiac dysfunction (any % of LVEF at baseline) 
18. Concomitant use of strong inhibitors or inductors of cytochrome CYP3A4 taken 
within 21 days prior to the first dose of study drug 
Route of 
administration 
Durvalumab will be administered by intravenous infusion every 3 weeks.  
Trabectedin will be administered by intravenous infusion every 3 weeks. 
Treatment 
schedule 
Phase I: Dose escalation part 
Agent 
Dose 
Route 
Schedule 
Cycle 
Length 
Trabectedin 
Doses as appropriate for 
assigned dose level 
IV 
Day 1 
3 weeks 
Durvalumab 
Fixed doses of 1120 mg   
IV 
Day 2  
A treatment cycle consists of 3 weeks (21 days). Treatment may continue until 
disease progression or study discontinuation (withdrawal of consent, intercurrent 
illness, unacceptable adverse event or any other changes unacceptable for further 
treatment, etc.). 
Patients will be allocated to 3 dose levels of Trabectedin following a 3 + 3 design: 
 
 
 
 
 
Expansion cohorts: All patients will receive the same treatment administration 
modalities at the MTD defined in the dose escalation part of the study. 
Level 
-1 
1 
2 
3 
Trabectedin  
(3h) 
0.8 
mg/m² 
1 
mg/m² 
1.2 
mg/m² 
1.5 
mg/m² 
Safety and efficacy 
evaluations 
Safety: Dose-limiting toxicities will be assessed for 3 weeks. 
Toxicities will be assessed on Day 8, 15, 22 and every 3 weeks afterwards. 
Efficacy will be assessed every 2 cycles (6 weeks). 
Endpoints 
Primary endpoint  
Phase I /Dose escalation part 
 
Toxicity graded using the common toxicity criteria from the NC-CTCAE v4.03  
 
Incidence rate of DLT at each dose level during the first 21 days.  
Phase I /Expansion cohorts 
Preliminary signs of the antitumor activity of trabectedin given in combination with 
durvalumab will be assessed in terms of objective response rate (ORR) under 
treatment defined as the proportion of patients with complete or partial response 
(CR, PR) as per RECIST v1.1 criteria. Disease status under treatment, whatever the 

 
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response observed, will be centrally reviewed for all patients, by an independent 
expert radiologist. Reviewed data will be used for the efficacy analysis. 
Secondary endpoints 
Phase I / Dose escalation part  
 
Preliminary signs of antitumor activity in terms of: 
o Best overall response 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.  
o Objective response rate (ORR) defined as the proportion of patients with 
complete response or partial response, as per RECIST 1.. ORR  under 
treatment and 6-month ORR will be reported . 
o Progression-free rate (PFR) at 6 months defined as the proportion of 
patients with complete response, partial response or stable disease more 
than 24 weeks as per RECIST v1.1 criteria.  
o Progression-free survival (PFS) 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 PFS rate will be reported.  
o Overall Survival (OS) defined as the time from study treatment initiation to 
death (of any cause). 1-year OS rate will be reported. 
 
Pharmacodynamic study:  
o Blood samples:  
 Serum level of cytokines, kynurenine and immunophenotyping of 
circulating immune cells.  
 Analyses of circulating DNA for identification and monitoring of 
mutations observed at the level of the circulating tumor cells (liquid 
biopsies concept).  
o Tumor samples: Fresh pre-treatment and on-treatment tumor biopsies will 
be performed. Samples will be formalin fixed and paraffin-embedded or 
fresh frozen, and will be analyzed for: 
 Hematoxylin and eosin staining (H&E). 
 Immunohistochemistry (IHC) assessments including, but not limited 
to, the following markers: SP263, SP28-8  (PDL1), CSF-1R, 
CD68/CD163, CD8, MHC class I/II, CD31 (microvessel density), 
Ki67 and other exploratory markers. The analysis will be prioritized 
based on the amount of material available.  
 Genomics and transcriptomics exploratory analysis for predictive 
signatures in responders and mechanisms of resistance in non-
responders. 
 
Phase I / Expansion cohorts 
 
Preliminary signs of antitumor activity will be assessed in terms of 6-month 
ORR, best overall response, 6-month PFR, 1-year OS and PFS rates defined as 
for the escalation part of the phase I trial. 
 
Toxicity defined above as for the escalation part. 
 Phamacodynamics study defined above as for the escalation part. 
 
Statistical 
considerations 
SAMPLE SIZE CONSIDERATIONS 
Phase I (Dose escalation part):  
 
3 dose levels 
 
A minimum of 3 patients and a maximum of 6 patients per dose level  
 
Therefore, the maximum number of patients is estimated to be 18 patients 
assessable for safety. To account for patients not assessable, we anticipate 
accruing a maximum of 20 patients for the dose escalation part of the 
phase I trial. 

 
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Phase I (Expansion cohorts): 
 
The primary objective is to determine preliminary signs of anti-tumor activity of 
trabectedin given in combination with Durvalumab among two selected cohorts 
of patients (STS and ovarian carcinomas) in terms of objective response rate 
(ORR) under treatment as per RECIST v1.1 criteria. 
 
Once the MTD is established for trabectedin, 2 distinct cohorts will be treated 
at the MTD: 
o 
Cohort A: patients with advanced STS. 
o 
Cohort B: patients with advanced ovarian carcinomas 
 
For each cohort: 
o 
Sample size is calculated based on the first stage of a 2-stage Gehan 
design assuming a 20% efficacy rate, 5% false positive rate and 10% 
precision (Gehan 1961). 
o 
14 eligible and assessable subjects are required. 
o 
If at least one objective response (CR or PR as per RECIST v1.1) is 
observed under treatment, the study drug association will be considered 
worthy of further testing in this indication.  
o 
Assuming, 10% are not eligible or cannot be assessed for the primary 
endpoint, 15 patients will be recruited for each of the 2 cohorts, i.e. 
a total of 30 patients will be included in the expansion cohorts. 
 
STATISTICAL ANALYSIS 
 
All analyses for the dose escalation part trial and the expansion cohorts will be 
descriptive; no p-values will be calculated.  
 
For the dose escalation part:  
- 
Data analyses will be provided by dose groups and for all study patients, 
combined wherever appropriate.  
- 
Toxicity observed at each dose level, graded according to the common 
toxicity criteria from the NCI-CTCAE v4.03, will be recorded in terms of 
event type, severity, dates of beginning and end, reversibility and 
evolution. Data will be gathered in tables summarizing toxicities and side 
effects for each dose level and cycle.  
- 
DLT will be described in terms of number and incidence rates at each 
dose level. The number and percentage of patients who will have 
developed a DLT in each dose level will also be reported. 
- 
Categorical endpoints (e.g. response) will be reported in terms of counts 
by dose level.  
 
For the expansion cohorts:  
- 
Categorical endpoints will be reported in terms of counts and 
proportions. Objective response rate under treatment, best response 
rate, 6-month PFR  and 6-month ORR rates will be estimated using 
binomial estimates and reported with their 95% confidence interval (CI). 
 
Continuous endpoints will be reported in terms of summary statistics that will 
include number of patients, median, minimum, and maximum, and additional 
percentiles if appropriate.  
 
Survival endpoints (PFS and OS) will be analyzed 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. We will describe also the observed median follow-up. 
 

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Schedule of assessments and procedures for treatment by the combination of trabectedin with durvalumab 
 
SCREENING 
CYCLE 1 
CYCLE 2 
CYCLE 3 
CYCLE N 
END OF 
TREATMENT 
W1 
W2 
W3 
W1 
W2 
W3 
W1 
W2 
W3 
W1 
W2 
W3 
Trabectedin (IV) 
 
D1 
 
 
D1 
 
 
D1 
 
 
D1 
 
 
 
Durvalumab (IV) 
 
D2 
 
 
D2 
 
 
D2 
 
 
D2 
 
 
 
Consultation 
X 
 
D8 
 
 
 
 
 
 
 
 
 
 
X 
24h-hospitalization 
 
D1-2 
 
 
D1-2 
 
 
D1-2 
 
 
D1-2 
 
 
 
Written Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
history/baseline 
condition 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant treatments 
X 
Throughout the treatment period 
 
Physical examination 
Xd 
X 
X 
 
X 
 
 
X 
 
 
D1 
 
 
Xj 
Assessment 
of 
signs 
and 
symptoms 
Xd 
X 
X 
 
X 
 
 
X 
 
 
D1 
 
 
X 
Performance status (ECOG) 
Xd 
X 
X 
 
X 
 
 
X 
 
 
D1 
 
 
X 
Vital signs (heart rate, blood 
pressure, temperature) 
Xd 
X 
X 
 
X 
 
 
X 
 
 
D1 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
Xd 
X 
X 
 
X 
 
 
X 
 
 
D1 
 
 
X 
Hematologya 
Xd 
Xe 
X 
X 
X 
X 
X 
X 
X 
 
D1 
 
 
X 
Biochemistryb 
Xd 
Xe 
X 
X 
X 
X 
X 
X 
X 
 
D1 
 
 
X 
Urinalysisi 
Xd 
Xe 
 
 
X 
 
 
X 
 
 
D1 
 
 
X 
Thyroid test: T3, T4 and TSH 
Xd 
Xe 
 
 
X 
 
 
X 
 
 
D1f 
 
 
X 
CA 125 (ovarian only) 
Xd 
Xe 
 
 
 
 
 
X 
 
 
D1f 
 
 
X 
aPTT, INR 
Xd 
To be repeated if clinically indicated 
 
Serologyh 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum 
pregnancy 
test 
(if 
indicated) 
Xd 
If indicated, to be repeated within 72 hours before C1D1 (serum) and to be repeated on Day 1 of each cycle (urine) 
 
Adverse Events 
X 
Throughout the treatment period 
X 
Tumor measurement 
Xc 
Repeated every 6 weeks. Documentation (radiologic) must be provided  for patients removed from study for progressive disease, and response 
must be confirmed  > 4 weeks 
Xj 
Echocardiography 
Xk 
To be repeated every 2-3 months 
 
Immunological biomarkers 
 
D1 
 
 
D1 
 
 
 
 
 
 
 
 
 
Circulating DNA 
 
D1 
 
 
D1 
 
 
D1 
 
 
D1g 
 
 
 
Biopsy 
Baseline 
 
 
 
D8 
 
 
 
 
 
 
 
 
a: NFS, platelets 
b: Serum electrolytes (Na+, K+, Cl-,Mg++and Ca++), liver function tests (AST, ALT, total bilirubin, GGT and AP), LDH, creatinine, creatinine clearance , glucose, CPK, total proteins, urea, albumin, bicarbonates, uric acid. Amylase 
and lipase at screening and Day 1 of each cycle. 
c: baseline tumor assessment should be performed within 28 days (+/- 1 week) before treatment initiation 
d: to be done in the 7 days prior inclusion  
e : to be done within 24 hours before Day 1 of Cycle 1 
f : every 3 cycles (ie. C3, C6, etc…) 
g : until progression 
h : Hepatitis A antibody, Hepatitis B surface antigen, Hepatitis C antibody and HIV antibody 
i: bilirubin, blood, glucose, ketones, pH, protein, specific gravity. 
j : Clinical and radiological tumor assessment (CT-scan/MRI), except for patients with confirmed PD at discontinuation or who had started a new treatment since. 
k: Within 14 days prior to Day 1 of cycle 1 (+1 day tolerance) 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ADCC 
Antibody-Dependent Cell-mediated Cytotoxicity 
AE(s) 
Adverse Event(s) 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
ANSM 
Agence Nationale de sécurité du Médicament 
AP 
Alkalin Phosphatase 
aPTT 
Activated Partial Thromboplastin Time 
ASCO 
American Society of Clinical Oncology 
AST  
Aspartate Aminotransferase 
BER 
Base Excision Repair 
βhCGs 
Beta Human Chorionic Gonadotrophins 
BP 
Blood Pressure 
CAEPR 
Comprehensive Adverse Events and Potential Risks 
CD 
Cluster of Differentiation 
CDC 
Complement-Dependent Cytotoxicity 
CI 
Confidence Interval 
CNS 
Central Nervous System 
CPK 
Creatine PhosphoKinase 
CPP 
Ethic Committee 
CR 
Complete Response 
CRA 
Clinical Research Associate 
CrCl 
Creatinine clearance 
CRF  
Case Report Form 
CT 
Computerized Tomography 
CT 
Chemotherapy 
DBP 
Diastolic Blood Pressure 
DCF 
Data Clarification Form 
DLT 
Dose-limiting Toxicity 
DNA 
Deoxyribonucleic Acid 
DSB 
Double-Strand Break 
EC 
Ethic Committee 
ECG  
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EOC 
Epithelial Ovarian Cancer 
ESMO 
European Society for Medical Oncology 
FFPE 
Formalin-Fixed Paraffin-Embedded 
FUP 
Follow-up 
GCP 
Good Clinical Practice 
G-SCF 
Granulocyte Colony Stimulating Factor 
GIST 
Gastro-Intestinal Stromal Tumor 
HCC 
HepatoCellular Carcinoma 
HCG 
Chorionic Gonadotropin 
HGSOC 
High-Grade Serous Ovarian Cancer 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IDMC 
Independant Data Monitoring Committee 
IEC 
Investigational Ethics Committee 
IHC 
ILD 
Immunohistochemistry 
Interstitial lung disease 
IMP 
Investigational Medicinal Product 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IUD 
Intrauterine Device 
IV 
Intravenous 

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LDH 
Lactate Dehydrogenase 
LLN 
Lower Limit of Normality - 
LVEF 
MAD 
Left Ventricular Ejection Fraction 
Maximum Administered Dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NER 
Nucleotide Excision Repair 
NSCLCC 
Non-Small Cell Lung Cancer 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PD 
Pharmacodynamy 
PD 
Progressive Disease 
PFR 
PFS 
Progression-free rate 
Progression-free Survival 
PK 
Pharmacokinetics 
PLD 
Pegylated Liposomal Doxorubicine 
PPC 
Primary Peritoneal Cancer 
PR 
Partial Response 
PRE TT 
Pre-treatment 
PS 
Performance Status 
PT 
Prothrombin Time 
PTT 
Partial Thromboplastin Time 
RBC 
Red Blood Cell 
RECIST 
RDI 
Response Evaluation Criteria in Solid Tumors 
Relative Dose Intensity 
RP2D 
Recommended Phase II Dose 
SAE(s) 
Serious Adverse Event(s) 
SAP 
Statistical Analyses Plan 
SBP 
Systolic Blood Pressure 
SCLC 
Small Cell Lung Cancer 
SCCHN 
Squamous Cell Carcinoma of the Head and Neck 
SD 
Stable Disease 
SoC 
SPC 
Standard of Care 
Summary of Product Characteristics 
SSB 
Single Strand Break 
STS 
Soft Tissue Sarcoma 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TAM 
Tumor-Associated Macrophages 
TCGA 
The Cancer Genome Atlas 
TT 
Treatment 
ULN 
Upper Limit of Normality 
WBC 
White Blood Cells 
 

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1. RATIONALE OF THE TRIAL 
1.1. 
MANAGEMENT OF SOFT-TISSUE SARCOMA IN ADVANCED SETTING 
Soft tissue sarcomas (STS) are uncommon tumors (1% of all adult malignancies) arising from 
mesodermal precursors [1;2]. Their diversity in site, histological subtypes (>50 recognized) [3] and 
frequency make difficult to draw universal conclusions and to find commons guidelines. 
Surgery remains the principal therapeutic modality: the usual first-line treatment is wide margin 
surgery plus radiotherapy [4,5]; nevertheless, despite improved local control rates, more than half of 
the patients still develop and die from unresectable, locally advanced and/or metastatic disease [1]. 
Chemotherapy is currently used for the treatment of advanced and/or metastatic sarcomas, but very 
few cytotoxic drugs have shown activity in this clinical setting. Doxorubicin is considered the most 
active first-line agent and the most frequently used in advanced sarcoma, followed by ifosfamide and 
dacarbazine [1,6,7]. No survival benefit has been demonstrated for patients receiving doxorubicin-
based combination therapy for advanced or metastatic disease [8,9], and conventional-dose, single-
agent chemotherapy is considered the standard treatment for metastatic disease [10]. Combination 
therapy may be considered in some specific cases in order to maximize chance for tumor response, 
such as in locally advanced STS, in potentially resectable lung oligometastases, especially in young 
patients with high grade sarcomas), or when patients are symptomatic of their advanced unresectable 
disease.  
In the palliative setting, when confronted with primary resistance or subsequent progression to 
standard anthracycline- and ifosfamide-based chemotherapy, the number of active cytotoxic agents 
for the treatment of relapsed/recurrent disease is very limited [11].  
The last decade has seen major advances in the development of therapeutic agents in the field of STS 
with approval of trabectedine [12-16] and pazopanib [17;18] for the treatment of patients with STS 
after failure of anthracycline- and ifosfamide-based chemotherapy. However, with low response rates 
and ultimate disease progression, this situation represents an unmet medical need. 
 
1.2. 
MANAGEMENT OF PLATINUM-SENSITIVE RELAPSED OVARIAN CARCINOMA 
Ovarian cancer is the second most common gynecologic malignancy worldwide and the leading cause 
of death attributed to gynecological cancer [19,20]. The median age at presentation of epithelial 
ovarian cancer (EOC) is 60 years. Due to the non-specific nature of symptoms, many women present 
with advanced disease and therefore have a poor prognosis.  
After initial therapy, most women will have a progression-free interval of approximately 1.5 to 2 years, 
depending on the extent of post-operative residual disease and response to chemotherapy [21]. 
However, relapse occurs in the majority of cases, and only 10−30% of women experience long-term 
survival [21]. Advanced stage disease is associated with a 5-year survival rate of only 30−40% [19].  
Approximately 90% of ovarian tumors are surface epithelial in origin, and the papillary serous 
histology subtype accounts for approximately 75%, of which the large majority (70%) is high-grade 
[21]. The site of origin of epithelial ovarian cancer remains unclear. Some studies suggest that serous 
epithelial ovarian cancer (EOC) and primary peritoneal cancer (PPC) arise from the fallopian tube 
epithelium [21-25]. EOC, PPC and fallopian tube cancer behave very similarly and are therefore 
treated in the same way. 
The standard approach to treatment of advanced high-grade serous ovarian cancer (HGSOC) is 
cytoreductive surgery, either at time of diagnosis or interval debulking, with the goal of minimizing 
residual tumor to no visible residual disease, a major prognostic indicator for improved survival. Six to 
eight cycles of platinum- and taxane-based chemotherapy [26;27] is the global standard of care. 
Platinum analogues, such as carboplatin and cisplatin, are the most active agents, mediating their 
effects through the formation of inter- and intra-strand cross-links with deoxyribonucleic acid (DNA) 
[21, 28]. 
The choice of treatment for relapsed disease is based on the treatment-free interval relative to last 
therapy administered and chemotherapy agents used. Platinum-based regimens dominate ovarian 
cancer therapy and define treatment groups [29]. In general, patients whose disease progresses 
during treatment with a platinum-based regimen are considered to have platinum-refractory disease; 
patients whose disease relapses within 6 months after the last platinum agent was administered are 
considered to have platinum-resistant disease; and patients whose disease relapses more than 6 

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months after the last platinum-based therapy was administered are considered to have platinum-
sensitive disease. 
However, these classifications are somewhat arbitrary and do not take into account the molecular 
characteristics of a patient’s tumor such as BRCA mutations. 
In later lines of therapy, treatment choice is often restricted according to individual patient situation 
(e.g. performance status, organ function, residual toxicities from prior treatment, other comorbidities, 
and patient choice).  
 
The two major types of DNA damage are the formation of DNA single-strand breaks (SSBs) and 
double-strand breaks (DSBs). SSBs are normally quickly repaired by a process known as base excision 
repair (BER). An additional DNA repair process known as homologous recombination repair (HRR) can 
repair double-strand breaks (DSBs). HR is a complex, multistep process that involves notably 2 
proteins encoded by the breast cancer susceptibility 1 and 2 genes (BRCA1 and BRCA2).  
Germline mutations in BRCA1 and BRCA2 genes are the strongest known hereditary factors for breast 
and EOC, accounting for up to 5% of all breast cancers and 15% of all EOCs [30,31]. Moreover, 
approximately 6 – 8% of patients with HGSOC have somatic mutations in BRCA1 or BRCA2 [30,32].  
However, defects in the HRR pathway are not limited solely to mutations of BRCA1/2. The Cancer 
Genome Atlas (TCGA), which completed an analysis of molecular changes in HGSOC, estimated that 
approximately 50% of patients with HGSOC have alterations in genes involved in the HRR DNA repair 
[33]. 
 
 
1.3. 
TRABECTEDIN 
1.3.1. Chemical structure 
Trabectedin [Ecteinascidin 743, Yondelis®, ET 743] is a potent cytotoxic alkaloid isolated from the 
Caribbean sea squirt Ecteinascidia turbinata. It is formed by a monobridged pentacyclic skeleton 
composed of two fused tetrahydroisoquinoline rings (A and B), linked to a 10-member lactone bridge 
through a benzylic sulfide linkage, and attached through a spiro ring to an additional ring system 
made up of a tetrahydroisoquinoline (subunit C). The molecular formula is C39H43N3O11S [ 
(1'R,6R,6aR,7R,13S,14S,16R)-6',8,14-trihydroxy-7',9-dimethoxy-4,10,23-trimethyl-19-oxo-
3',4',6,7,12,13,14,16-octahydrospiro[6,16-(epithiopropano-oxymethano)-7,13-imino-6aH-1,3-
dioxolo[7,8]isoquino[3,2-b][3]benzazocine-20,1'(2'H)-isoquinolin]-5-yl acetate] ] and the molecular 
mass 761.84 g/mol. 
Unlike conventional alkylating agents which bind to the major groove of DNA and predominantly form 
crosslinks to the Guanine N7 or O6 position, trabectedin predominantly binds to the minor groove of 
DNA and binds to the Guanine N2 position, (18) through an iminium intermediate generated in situ by 
dehydration of the carbinolamine moiety present in the ring A. The carbinolamine moiety is imperative 
for the pharmacological activity of trabectedin; van der Waals interactions stabilize the adduct, 
through hydrogen bonds between rings A and B, with neighboring nucleotides in the same or opposite 
strand of the DNA double helix, thus creating the equivalent to a functional interstrand crosslink. 
1.3.2. Preclinical and mechanism of action 
Cytotoxic concentrations of trabectedin delay cell cycle as progression through the S phase and 
produce arrest at G2/M, ultimately resulting in p53-independent apoptosis [34-37]. 
Trabectedin-induced DNA damage is recognized by the nucleotide excision repair (NER) pathway, 
resulting in stalled DNA-protein repair complexes [38,39] and cell death. Therefore, in contrast to that 
expected for a DNA-damaging agent, sensitivity to trabectedin is correlated to a functional NER [39-
41]. On the other hand, trabectedin also induces DNA DSBs, mainly during early S phase, and this 
damage is repaired by the HRR pathway [44]. Moreover, there is evidence suggesting that trabectedin 
is particularly effective in cells lacking functional HR repair mechanisms, such as those with BRCA 
gene mutation or BRCAness phenotype [36,42,43]. Overall, preclinical data indicate that a functional 
transcription-coupled nucleotide excision repair (TC-NER) machinery and a deficient homologous 
recombination repair (HRR) machinery are required for in vitro sensitivity to trabectedin [43]. 
Besides its role as an alkylating agent, trabectedin has also an impact on tumor microenvironment. 
Trabectedin affects not only the neoplastic compartment but also monocytes and macrophages [45]. 
These findings opened an important area of research for the implications of macrophage pro-tumoral 
functions in disease progression. The exquisite selectivity of trabectedin against mononuclear 
phagocytes (monocytes and macrophages) was recently related to the activation of caspase 8 by 
membrane signalling TRAIL receptors that are selectively expressed by monocytes/macrophages and 

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not neutrophils and lymphocytes [46]. Exposure to trabectedin also causes a strong decrease in the 
production of several cytokines and chemokines secreted by monocytes/macrophages and tumour 
cells such as IL-6, CCL2, CXCL8, Angiopoietin 2 or VEGF, but not of other biological stimulating 
mediators such as TNFα [47,48]. The importance of this anti-cancer activity was also demonstrated in 
vivo. The anti-inflammatory effects of trabectedin were indeed confirmed in different tumour 
xenografts and in human soft-tissue sarcoma samples from patients receiving trabectedin as neo-
adjuvant therapy [46]. Interestingly, trabectedin still showed anti-tumour activity in xenograft with 
tumor cells resistant to trabectedin injected into mice indicating that the macrophage-targeted effect 
can be sufficient to significantly reduce neoplastic growth, under conditions where tumour cells are 
unresponsive to the drug [46]. Thus, trabectedin effects on the TME and on macrophages are—at 
least in part—important contributors of its anti-tumour and anti-metastatic activity. A summary of 
these effects are depicted in the figure below: 
 
 
 

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1.3.3. Clinical data 
Trabectedin is approved in Europe for the treatment of patients with advanced soft-tissue sarcoma 
(STS) after failure of anthracyclines and ifosfamide, or when they are not eligible to receive these 
agents. In this setting, the 6-month progression-free rate is about 35-40% [12-16]. 
Recently, Le Cesne et al [49] published a retrospective pooled analysis of trabectedin safety in 1132 
patients with solid tumors enrolled in 19 worldwide phase II trials from 1998 to 2008, in order to 
summarize the safety experience of single agent trabectedin. Three schedules of administration were 
considered: 24-hour infusion every 3 weeks, 3-hour infusion every 3 weeks and 3-hour infusion for 
three consecutive weeks every 4 weeks. Tolerance was good in phase II development, with a rate of 
toxic death of 1.7%. Neutropenia (69.2%) and thrombocytopenia (36.3%) were the most frequent 
drug-related toxic events. The incidence and severity of neutropenia were higher with the q3wk 24-h 
schedule, grade 3 in 26.6% and grade 4 in 23.9% of patients. Of note, prophylactic use of 
granulocyte colony stimulating factor (G-CSF) was generally not permitted in the trabectedin trials 
and, therefore, only administered to 9.8% of the patients. Other common trabectedin-related adverse 
events reported in at least 20% of patients were nausea (64.7%), fatigue (58.3%), and vomiting 
(40.1%). 
Transaminase increase was common with trabectedin, with a peak elevation at days 5–7 and a return 
to grade ≤1 at approximately day15 of each cycle. Dexamethasone was routinely administered to 
improve tolerance, including hepatic toxicity, and was given prior to infusion at the recommended 
dose of 20 mg 30 min before trabectedin in the majority of clinical studies. Rhabdomyolysis was 
uncommon (0.8%). 
Extravasation-related AEs following injection were rare (6 out of 1132 patients, 0.5%), and only 3 of 
these events were serious or treatment limiting (grade 4). The use of a central-line was mandatory in 
the clinical trials. 
No cumulative toxicities were apparent and trabectedin was able to be administered for prolonged 
periods (up to 59 cycles) to patients who exhibited sustained clinical benefit from stable disease or 
objective responses. 
 
Trabectedin is also approved in recurrent platinum sensitive advanced ovarian cancer. In the study 
published by Monck et al. [50], trabectedin in combination with pegylated liposomal doxorubicine 
(PLD) provided a significant 21% risk reduction for progression or death compared with PLD 
monotherapy. Median PFS was 7.3 months for trabectedin/PLD and 5.8 months for PLD alone. 
Trabectedin/PLD also improved PFS compared with PLD alone by independent radiology analysis in 
platinum-sensitive patients (9.2 v 7.5 months, p = 0.0170). No significant difference in median PFS 
was observed in platinum-resistant patients (median, 4.0 and 3.7 months with combination and 
monotherapy, respectively). 
Grade 3 or 4 neutropenia (28.8% and 33.9%) and grade 3 to 4 ALT elevations (28.5% and 8%) were 
more frequent with trabectedin/PLD. However, Grade 3 to 4 febrile neutropenia was uncommon 
(6,9%) and liver toxicity was never severe and rapidly resolved in all cases. 
 
1.4. 
Durvalumab (MEDI4736) 
1.4.1. Chemical structure 
Durvalumab is a human monoclonal antibody (mAb) of the immunoglobulin G1 kappa (IgG1κ) 
subclass that inhibits binding of programmed cell death ligand 1 (PD-L1) (B7 homolog 1 [B7-H1], 
cluster of differentiation [CD]274) to programmed cell death 1 (PD-1; CD279) and CD80 (B7-1) 
Durvalumab is composed of 2 identical heavy chains and 2 identical light chains, with an overall 
molecular weight of approximately 149 kDa. Durvalumab contains a triple mutation in the constant 
domain of the immunoglobulin (Ig) G1 heavy chain that reduces binding to complement protein C1q 
and the fragment crystallizable gamma (Fcγ) receptors involved in triggering effector function. 
1.4.2. Preclinical data and mechanism of action 
Durvalumab binds with high affinity and specificity to human PD-L1 and blocks its interaction with PD-
1 and CD80. In vitro studies demonstrate that durvalumab antagonizes the inhibitory effect of PD-L1 
on primary human T cells, resulting in their restored proliferation and release of interferon gamma 
(IFN-γ). Additionally, Durvalumab demonstrated a lack of antibody-dependent cell-mediated 
cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) in cell-based functional assays.  
In vivo studies show that durvalumab inhibits tumor growth in a xenograft model via a T-lymphocyte 
(T-cell) dependent mechanism. Moreover, an anti-mouse (m)PD-L1 antibody demonstrated improved 

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survival in a syngeneic tumor model when given as monotherapy and resulted in complete tumor 
regression in > 50% of treated mice when given in combination with chemotherapy.  
 
In general, treatment of cynomolgus monkeys with durvalumab was not associated with any 
durvalumab-related adverse effects that were considered to be of relevance to humans (Investigator 
Brochure). Data from the pivotal 3-month GLP toxicity study with durvalumab in cynomolgus monkeys 
showed that subchronic dosing of durvalumab was not associated with any adverse effects. Therefore, 
the NOAEL of durvalumab in all the general toxicity studies was considered to be 100 mg/kg, the 
highest dose tested in these studies. In addition to the in vivo toxicology data, no unexpected 
membrane binding of durvalumab to human or cynomolgus monkey tissues was observed in GLP 
tissue cross-reactivity studies using normal human and cynomolgus monkey tissues. 
1.4.3. Clinical data 
As of the DCO dates (15Apr2015 to 18Sep2015), a total of 1,910 subjects have been enrolled and 
treated in 30 ongoing durvalumab clinical studies, including 20 sponsored and 10 collaborative studies 
(Investigator Brochure).  
Durvalumab exhibits nonlinear PK likely due to saturable target-mediated CL at doses < 3 mg/kg and 
approaches linearity at doses ≥ 3 mg/kg. Near complete target saturation (soluble programmed cell 
death ligand 1 [sPD-L1] and membrane bound) is expected with durvalumab ≥ 3 mg/kg Q2W. 
Exposures after multiple doses showed accumulation consistent with PK parameters estimated from 
the first dose. In addition, PK simulations indicate that following durvalumab 10 mg/kg Q2W dosing, > 
90% of subjects are expected to maintain PK exposure ≥ 40 μg/mL throughout the dosing interval. 
Of the 1,910 subjects, 1,279 received durvalumab monotherapy and 631 received durvalumab in 
combination with other anticancer agents. To date, no PK interaction has been observed between 
Durvalumab and these agents.  
 
Of the 1,279 subjects who have received durvalumab monotherapy across the clinical development 
program, the majority of treatment related AEs were manageable with dose delays, symptomatic 
treatment, and in the case of events suspected to have an immune basis, the use of established 
treatment guidelines for immune-mediated toxicity. No studies have been completed or terminated 
prematurely due to toxicity. As of 07May2015, among the 694 subjects treated with durvalumab 10 
mg/kg Q2W in Study CD-ON-MEDI4736-1108, a total of 378 subjects (54.5%) experienced a 
treatment-related AE, with the most frequent being fatigue (17.7%), nausea (8.6%), diarrhea (7.3%), 
decreased appetite (6.8%), pruritus (6.3%), rash (6.1%), and vomiting (5.0%). A majority of the 
treatment-related AEs were Grade 1 or Grade 2 in severity with ≥ Grade 3 events occurring in 65 
subjects (9.4%).  
Treatment-related ≥ Grade 3 events reported in 3 or more subjects (≥ 0.4%) were fatigue (12 
subjects, 1.7%); increased aspartate aminotransferase (AST; 7 subjects, 1.0%); increased gamma-
glutamyltransferase (GGT; 6 subjects, 0.9%); increased alanine aminotransferase (ALT; 5 subjects, 
0.7%); and colitis, vomiting, decreased appetite, and hyponatremia (3 subjects, 0.4% each). Six 
subjects had treatment-related Grade 4 AEs (upper gastrointestinal hemorrhage, increased AST, 
dyspnea, neutropenia, colitis, diarrhea, and pneumonitis) and 1 subject had a treatment-related Grade 
5 event (pneumonia). Treatment related serious adverse events (SAEs) that occurred in ≥ 2 subjects 
were colitis and pneumonitis (3 subjects each) and resolved with or without sequelae. AEs that 
resulted in permanent discontinuation of durvalumab were considered as treatment related in 18 
subjects (2.6%), with colitis being the most frequent treatment-related AE resulting in discontinuation 
(3 subjects). 
 
Partial efficacy data are available for 2 monotherapy studies (CD-ON-MEDI4736-1108 and 
D4190C00007) and 2 combination therapy studies (CD-ON-MEDI4736-1161 and D4190C00006). 
Clinical activity has been observed across the 4 studies. 
Study CD-ON-MEDI4736-1108: Overall, 456 of 694 subjects treated with durvalumab 10 mg/kg Q2W 
were evaluable for response. In PD-L1 unselected patients, the objective response rate (ORR), based 
on investigator assessment per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, ranged 
from 0% in uveal melanoma (n = 23) to 20.0% in bladder cancer (n = 15), and disease control rate 
at 24 weeks (DCR-24w) ranged from 4.2% in triple-negative breast cancer (TNBC; n = 24) to 39.1% 
in advanced cutaneous melanoma (n = 23). PD-L1 status was known for 383 of the 456 response 
evaluable subjects. Across the PD-L1-positive tumors, ORR was highest for bladder cancer, advanced 
cutaneous melanoma, hepatocellular carcinoma (HCC; n = 3 each, 33.3% each), NSCLC (n = 86, 
26.7%), and squamous cell carcinoma of the head and neck (SCCHN; n = 22, 18.2%). In the PD-L1- 

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positive subset, DCR-24w was highest in advanced cutaneous melanoma (n = 3, 66.7%), NSCLC (n = 
86, 36.0%), HCC and bladder cancer (n = 3 each, 33.3% each), and SCCHN (n = 22, 18.2%). 
1.4.4. Fixed dosing rationale 
A population PK model was developed for MEDI4736 using monotherapy data from Study 1108 (Phase 
I study; N=292; doses=0.1 to 10 mg/kg q2w or 15 mg/kg q3w; solid tumors [66]). Population PK 
analysis indicated only a minor impact of body weight (WT) on the PK of MEDI4736 (coefficient of 
≤0.5). The impact of body WT-based (10 mg/kg q2w) and fixed dosing (750 mg q2w) of MEDI4736 
was evaluated by comparing predicted steady state PK concentrations (5th, median, and 95th 
percentiles) using the population PK model. A fixed dose of 750 mg was selected to approximate 10 
mg/kg (based on a median body WT of approximately 75 kg). A total of 1000 patients were simulated 
using a body WT distribution of 40 to 120 kg.  Simulation results demonstrated that body WT-based 
and fixed dosing regimens yield similar median steady state PK concentrations with slightly less overall 
between-patient variability with the fixed dosing regimen. 
Similar findings have been reported by others [62-65]. Wang and colleagues investigated 12 mAbs 
and found that fixed and body size-based dosing perform similarly, with fixed dosing being better for 
7 of 12 antibodies [64]. In addition, they investigated 18 therapeutic proteins and peptides and 
showed that fixed dosing performed better for 12 of 18 in terms of reducing the between-patient 
variability in PK/pharmacodynamics parameters [65]. 
A fixed dosing approach is preferred by the prescribing community due to ease of use and reduced 
dosing errors. Given the expectation of similar PK exposure and variability, AstraZeneca considered it 
feasible to switch to fixed dosing regimens.  Based on an average body WT of 75 kg, fixed doses of 
1.12 g q3w (equivalent to 15 mg/kg q3w) of MEDI 4736 is included in the current study. 
 
1.5. 
STUDY RATIONALE 
Trabectedin is an agent approved for the treatment of STS and ovarian cancer. Recent data suggest 
that the antitumor activity of trabectedin is not only mediated by its interaction with DNA but also 
mediated by targeting tumor-associated macrophages (TAM) [51]. TAMs play a pivotal role in tumor 
growth and progression. They produce several molecules that sustain malignant cell survival, modify 
neoplastic extra-cellular matrix proteins, promote the development of a newly formed vessel, and 
assist tumor cells in their progression. Moreover, TAMs affect adaptive immune responses significantly 
by recruiting and stimulating Tregs and recruiting Th2 lymphocytes, which in turn inhibit Th1 cells, 
and by inducing anergy of naïve T cells.  
 
Recent studies have shown that PDL1 is expressed in up to 58% of cases of STS, osteosarcomas and 
GIST [52-54]. This overexpression has been associated with prognosis. Besides, preliminary 
unpublished data from our lab corroborates the finding that a substantial proportion of STS express 
PDL1 on immune cells, notably type M2 macrophages (M.Toulmonde et al. JAMA ONCOL.2017 29), 
leading to speculate that drugs targeting this immune checkpoint would be of great interest in these 
tumors and particularly in sarcomas with complex genomics (including leiomyosarcomas and 
undifferentiated sarcomas).  
PD-L1 is expressed in ovarian cancer and is a factor of poor prognosis [55]. Moreover a rapidly 
growing set of preclinical and clinical data promotes use of immunotherapy in ovarian cancer and 
numerous studies are ongoing [56,57]. 
 
TAM targeting has been associated with anti-tumor activity in sarcoma and ovarian cancer models 
[58-59]. Moreover, TAM targeting in combination with PD-1 checkpoint inhibitor has been shown to be 
effective in several tumor models, including a murine model of ovarian cancer [60-61]. 
We hypothesized that the combination of Durvalumab and Trabectedin could have a synergic 
immunomodulatory and antitumoral effect, in patients with relapsed unresectable or metastatic STS 
and ovarian carcinoma. Despite the existence of potential overlapping toxicities (transaminitis), the 
tolerance profile is also expected to be good. 
 
 
 

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2. OBJECTIVES 
2.1. 
Primary objective 
To determine the recommended phase II dose (RP2D), the maximum tolerated dose (MTD) evaluated 
on the first 21 days (D1 to D21), the safety profile and the dose limiting toxicities (DLT) of trabectedin 
given in combination with durvalumab in patients with advanced pretreated soft-tissue sarcoma and 
ovarian carcinoma. 
 
2.2. 
Secondary objectives 
 To evaluate the toxicity profile of trabectedin in association with durvalumab (NCI-CTCAE v4.03) 
 To determine preliminary signs of anti-tumor activity of trabectedin given in combination with 
durvalumab in two expansion cohorts (STS and ovarian carcinomas) in terms of : 
o Best overall response as per RECIST v1.1,  
o objective response under treatment as per RECIST v1.1,  
o 6-month objective response as per RECIST v1.1,  
o 6-month progression-free status defined as per RECIST v1.1,  
o 1-year progression-free survival (PFS),  
o 1-year overall survival (OS). 
 To explore the pharmacodynamics (PD) of Trabectedin in association with Durvalumab as well as 
potential predictive biomarkers of activity and efficacy (blood and tumor tissue samples). 
 
3. STUDY DESIGN 
3.1. 
OVERALL STUDY DESIGN 
This is a multicenter, prospective open-labeled phase Ib trial based on a dose escalation study design 
(3+3 traditional design) assessing three dose levels of trabectedin given in combination with 
durvalumab, followed by two expansion cohorts (STS and ovarian carcinomas) once the MTD has 
been established. 
 
3.2. 
DEFINITIONS 
Dose-limiting toxicity (DLT):  
A DLT is defined as an AE or laboratory abnormality that fulfills all the criteria below:  
 Begins on the first 21 days of treatment. 
 Is considered to be at least possibly related to the study treatment.  
 Meets one of the criteria below, graded as outlined or according to NCI-CTCAEv4.03 : 
o 
Any grade-4 toxicity (except for vomiting without maximal symptomatic/prophylactic 
treatment and if toxicity is transaminitis, but which have to be resolved at Day 21, i.e. return 
to Baseline or grade 1). 
o 
 Grade-3 non-haematological toxicity lasting > 7days (except for 1rst episode of nausea and if 
toxicity is transaminitis, which have to be resolved at Day 21, i.e. return to Baseline or grade 
1). 
o 
 Grade-3 hematologic toxicity lasting for > 7days. 
o 
 Grade 4 neutropenia with fever. 
o 
 Grade > 2 thrombocytopenia with bleeding. 
DLT status: 
In addition, the steering committee will resolve any specific issue regarding the DLT status (see 
section 12.1.1). 
Maximum tolerated dose (MTD): 
The MTD is defined as the highest dose at which no more than 1 in 6 patients in the cohort 
experience a DLT in the first 21 days. The conclusions of the steering committee for the definition of 

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of the MTD will be submitted for approval to an independent data monitoring committee (IDMC) 
before opening the expansion cohorts. 
Recommended phase II dose (RP2D): 
The RP2D dose corresponds to the dose level to be recommended for further investigations in phase 
II trials. The RP2D dose for trabectedin when given in combination with Durvalumab, will be identified 
by the steering committee based on safety data from patients included in the dose escalation part and 
the expansion cohorts, as well as PD data. Data from all patients (dose escalation trial and expansion 
cohorts) will be used to define the RP2D. 
 
3.3. 
Dose escalation part 
3.3.1. Treatment scheme 
Trabectedin will be administered intraveinously, on day 1 of each cycle, every three weeks, as 
appropriate for assigned dose level. 
Durvalumab will be administered intraveinously, at fixed doses of 1120 mg (equivalent to 15 mg/kg), 
on day 2 of each cycle, every three weeks. 
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 unacceptable for further treatment, etc.). 
3.3.2. Dose levels 
Dose escalation study assessing 3 doses level of Trabectedin given in combination with durvalumab 
(fixed dose). 
 
 
 
 
- 
The starting dose of Trabectedin is 1 mg/m². 
- 
The maximum dose of Trabectedin administered (1.5 mg/m²) will not be exceeded. 
- 
Patients will be allocated to 3 doses levels following a 3 + 3 design. 
- 
A minimum of 3 patients and a maximum of 6 patients will be entered on each dose level. 
- 
All 3 patients within a dose level will be observed during 21 days (the period of observation 
of DLTs) before accrual to the next higher dose level may begin.  
- 
Dose escalation will proceed according to the following scheme: 
Number of 
patients with 
DLT at one 
dose level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
≥2 
Dose escalation will be stopped. This dose level will 
be declared as the maximum administered dose 
(MAD). Three additional patients will be entered at 
the next lowest dose level if only 3 patients were 
treated previously at that dose. 
1 out of 3 
Enter at least 3 more patients at this dose level. 
 If 0 of these 3 patients experience DLT, 
proceed to the next dose level. 
 If 1 or more of this group suffer DLT, dose 
escalation will be stopped, and this dose is 
declared as the MAD. Three additional patients 
will be entered at the next lowest dose if only 3 
patients were treated previously at that dose.
≤1 out of 6  
This will be the maximum tolerated dose (MTD).  
- 
As described above, the maximum administered dose (MAD) for Trabectedin is the dose in 
which ≥2/3 or ≥2/6 patients experience DLT.  
Level 
-1 
1 
2 
3 
Trabectedin  
(3h) 
0.8 
mg/m² 
1 
mg/m² 
1.2 
mg/m² 
1.5 
mg/m² 

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- 
If the MAD for Trabectedin is seen at the starting dose level, then dose level “-1” will be the 
recommended dose. 
- 
The MTD for Trabectedin is defined as the highest dose at which no more than 1 in 6 of the 
patients in the cohort experienced a DLT during the period of observation of DLTs. 
- 
The steering committee will meet before proceeding or not to each dose escalation. In 
addition, , the steering committee will be consulted to resolve any specific question 
regarding the DLT status (see section 12.1.1).  
- 
Conclusions of the steering committee for the definition of MTD will be submitted for 
approval to an independent data monitoring committee (IDMC) before opening the 
expansion cohorts. 
 
3.4. 
EXPANSION cohorts 
- 
Once the MTD has been defined based on the dose escalation study, the expansion cohorts 
will be opened. All patients will be treated at the MTD of Trabectedin (as defined in the 
escalation trial) given in association with durvalumab with the same schedule as in the 
phase I trial.  
- 
Following the expansion cohorts, the RP2D for Trabectedin will be identified by the steering 
committee based on safety data from patients included in the dose escalation part and the 
expansion cohorts, as well as PD data. Data from all patients (escalation + expansion 
cohorts) will be used to define the RP2D. 
 
3.5. 
Patient’s replacement 
See section 10.2. 
 
4.  SELECTION OF PATIENTS 
4.1. 
Inclusion Criteria 
1. Histology :  
- Soft-tissue sarcoma histologically confirmed.  In care outside a center of the RRePS Network, a 
central review is necessary (Pr. Coindre team),  
- histologically confirmed ovarian carcinoma (carcinosarcoma included) without known g/s BRCA 
mutation, 
2. Ovarian carcinoma  must have received at least one line of platinum-containing regimen.   
3. Metastatic or unresectable locally advanced disease, not ammenable to curative therapy, 
4. Age ≥ 18 years, 
5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1, 
6. Life expectancy > 3 months, 
7. Patients must have measurable disease (lesion in previously irradiated field can be considered as 
measurable if progressive at inclusion according to RECIST v1.1) defined as per RECIST v1.1 with at 
least one lesion that can be measured in at least one dimension (longest diameter to be recorded) as 
≥ 10 mm with spiral CT scan, 
8. Documented disease progression according to RECIST v1.1 before study entry, 
9. Patient must comply with the collection of tumor biopsies,  
10. At least 1 line of chemotherapy in the palliatve setting, with use of anthracyclines (for STS), 
11. At least three weeks since last chemotherapy, immunotherapy or any other pharmacological 
treatment for neoplastic disease and/or radiotherapy, 
12. 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), aspartate aminotransferase (AST)  2.5 x upper limit of 
normality (ULN) and alkaline phosphatase (AP)  2.5 x ULN  
c. Total bilirubin  ULN 
d. Albumin ≥ 25 g/l 
e. Calculated creatinine clearance (CrCl) > 60 ml/min (according to Cockroft Gault formula). 

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f. Thyroid function within normal laboratory ranges (TSH, free T3, free T4) 
g. Creatine PhosphoKinase (CPK) ≤ 2.5 x ULN. 
13. Women of childbearing potential must have a negative serum pregnancy test within 72 hours prior 
to receiving the first dose of trial medication. Both women and men must agree to use a highly 
effective method of contraception throughout the treatment period and for six months after 
discontinuation of treatment. Acceptable methods of contraception are described in protocol section 
7.5, 
14. No prior or concurrent malignant disease diagnosed or treated in the last 2 years except for 
adequately treated in situ carcinoma of the cervix, concomitant endometrial carcinoma stage IA grade 
1, basal or squamous skin cell carcinoma, or in situ transitional bladder cell carcinoma, 
15. 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 Events (NCI-CTCAE, version 4.03), 
16. Voluntarily signed and dated written informed consent prior to any study specific procedure, 
17. Patients with a social security in compliance with the French law. 
 
4.2. 
Exclusion  Criteria 
1. Previous treatment with Trabectedin or an anti-PD-1, anti-PD-L1, anti-PD-L2, including Durvalumab, 
2. Current or prior use of immunosuppressive medication including any use of oral glucocorticoids, 
within 21 days before the first dose of Durvalumab, with the exceptions of intranasal and inhaled 
corticosteroids or systemic corticosteroids at physiological doses, 
3. Active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis), 
4. Has an active autoimmune disease requiring systemic treatment within the past 2 years (ie, with 
use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy 
(e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency) is not considered a form of systemic treatment, 
5. Has evidence of active non-infectious pneumonitis, 
6. Has an active infection requiring systemic therapy, 
7. Currently active bacterial or fungus infection (> grade 2 NCI-CTCAE HIV1, HIV2, hepatitis A or 
hepatitis B or hepatitis C infections), 
8. Known central nervous system malignancy (CNS),  
9. 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, 
10. Previous enrolment in the present study, 
11. Patient unable to follow and comply with the study procedures because of any geographical, social 
or psychological reasons, 
12. Has received a live vaccine within 30 days prior to the first dose of trial treatment, 
Note: the killed virus vaccines used for seasonal influenza vaccines for injection are allowed; 
however intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not 
allowed. 
13. Known hypersensitivity to any involved study drug or any of its formulation components, 
14. Tumors not accessible for biopsy, 
15. Known history of active tuberculosis, 
16. Person under judicial protection or deprived of liberty, 
17. Cardiac dysfunction:  
- LVEF (Left Ventricular Ejection Fraction) < 40% at baseline;  
- or clinically symptomatic cardiac dysfunction (any % of LVEF at baseline). 
18. Concomitant use of strong inhibitors or inductors of cytochrome CYP3A4 taken within 21 days 
prior to the first dose of study drug 
 
 
 
 
 

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STUDY PLAN 
4.3. 
Duration of Study (Whole Population) 
The total duration of the study will be approximately 36 months, including about 18 months of active 
enrolment.  
Planned start date (first patient on study): February 2017. 
Follow-up: 12 months 
4.3.1. Dose escalation part 
Follow-up: 6 months 
End of study occurs when all of the following criteria have been satisfied: 
 The trial is closed to recruitment 
AND  
 All patients have disease progression or are no longer on study medication 
AND 
 The last included patient has been followed for 6 months or is deceased 
4.3.2. Expansion cohort 
Follow-up: 12 months 
End of study occurs when all of the following criteria have been satisfied: 
 The trial is closed to recruitment 
AND  
 All patients have disease progression or are no longer on study medication 
AND 
 The last included patient has been followed for 12 months or is deceased 
 
4.4. 
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. 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 later 
for toxicities, and beyond if grade 3 or 4 toxicity, until resolution.  
Patients who discontinue treatment without progression will be followed every 12 weeks until: 
1. Disease progression, 
2. Initiation of other antitumor therapy,  
3. Death, or  
4. The date of study termination, 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 date of study termination, 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) after the last treatment administration, except if the patient starts a new antitumor therapy 
before this period. 

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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 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 treatments should be permanently 
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 Withdrawal of consent or lost to follow-up, 
o Disease progression, 
o Adverse event that, in the opinion of the investigator or the sponsor, contraindicates further 
dosing, 
o Subject is determined to have met one or more of the exclusion criteria for study participation at 
study entry and continuing investigational therapy might constitute a safety risk, 
o Pregnancy or intent to become pregnant, 
o Grade ≥ 3 infusion reaction, 
o Initiation of alternative anticancer therapy including another investigational agent, 
o Intercurrent illness of sufficient magnitude to preclude safe 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 
Patients still experiencing a non-progression after 6 cycles will then be able to continue treatment off-
study at the discretion of the investigator. 
 
Study discontinuation occurs when an enrolled patient ceases to participate in the study, 
regardless of the reason (as detailed under “Follow-up” in Section 3.2.8). 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. 
 
4.5. 
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 (SAEs), etc. 

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The investigators may suggest to the Sponsor the authorization of certain protocol deviations, 
especially if they are related to the inclusion/exclusion criteria or if they may have an effect on the 
evaluability of the patients. 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. 
 
4.6. 
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 Day 1 of cycle 1 
(+1 week tolerance)  
 D-14 to D-1 
 Vital signs: heart rate, blood pressure, body 
temperature, weight and height 
Within 7 days prior to Day 1 of cycle 1 (+3 
day tolerance)  
D-7 to D-1 
 Demographic data 
 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 
Within four weeks prior to Day 1 of cycle 1 
D-28 to D-1 
2. Pathology 
 Central review to confirm soft-tissue sarcoma 
diagnosis, except in case of diagnosis confirmed 
by the RRePS Network 
 Histologically confirmed ovarian carcinomas 
Material sent within 7 days after signed 
informed consent 
3. Laboratory 
tests 
 Hematology: 
neutrophils, 
lymphocytes, 
basophils, eosinophils, monocytes, haemoglobin, 
haematocrit, platelet count, red blood cell count, 
total white cell count, VGM, CCMH, TCMH. 
 Biochemistry: Serum electrolytes (Na+, K+, Cl-
,Mg++and Ca++), liver function tests (AST, ALT, 
total bilirubin, GGT and AP), LDH, creatinine, 
glucose, CPK, total proteins, urea, creatinine 
clearance albumin, lipase, amylase, bicarbonates, 
uric acide. 
 Thyroid function: TSH, T3 and T4 
 CA 125 for ovarian carcinoma only 
 Coagulation: aPTT, INR 
 Serology: Hepatitis A antibody, Hepatitis B 
surface antigen, Hepatitis C antibody, and HIV 
antibody  
 Urinalysis: bilirubin, blood, glucose, ketones, 
pH, 
protein, 
specific 
gravity, 
colour 
and 
appearance 
Within 7 days prior to inclusion (+3 days 
tolerance).  
D-7 to D-1 

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ASSESSMENT 
TIME 
4. Creatinine 
clearance 
 Calculated using the Cockroft formula (see 
Appendix 2) 
Within 7 days prior to inclusion (+3 days 
tolerance)  
D-7 to D-1 
5. Pregnancy 
test, if 
applicable 
Measurement of serum human chorionic 
gonadotropin (HCG) 
Within 7 days prior to Day 1 of cycle 1 (+1 
day tolerance)  
D-7 to D-1 
6. Tumor 
assessment 
 CT-scan or MRI of all measurable sites, as per 
RECIST 1.1 (Appendix 3) 
Within four weeks prior to Day 1 of cycle 1 
(+1 week tolerance)  
D-28 to D-1 
7. Other tests 
 Intercurrent events, concomitant diseases and 
treatments. 
Within two weeks prior to Day 1 of cycle 1. 
D-14 to D-1 
8. LVEF 
 Echocardiography 
Within 14 days prior to Day 1 of cycle 1 (+1 
day tolerance)  
D-14 to D-1 
ALT, alanine aminotransferase; AP, alkaline phosphatase; aPTT, activated partial thromboplastin time; AST, aspartate 
aminotransferase; CCMH: Mean corpuscular hemoglobin concentration ; CPK, creatine phosphokinase; ECOG PS, Eastern Cooperative 
Oncology Group Performance Status; GGT: gamma-glutamyltransferase ; INR: international normalized ratio; LDH, lactate 
dehydrogenase; MRI, magnetic resonance imaging; RECIST v1.1, Response Evaluation Criteria In Solid Tumors; TCMH: mean 
corpuscular haemoglobin; TSH, thyroid stimulating hormone; VGM, Mean corpuscular volume. 
():If Total bilirubin is ≥2xULN (and no evidence of Gilbert’s syndrome) then fractionate into direct and indirect  bilirubin 
 
4.7. 
EVALUATIONS DURING TREATMENT 
The following assessments will be done while the patient is on treatment. 
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 
Day 1 of cycle 1 
Repeat on Day 8 of Cycle 1 
Repeat on Day 1 of each subsequent cycle 
 Assessment of signs and symptoms 
Throughout the treatment period 
 Concomitant diseases and treatments 
Throughout the treatment period 
2. Laboratory 
tests* 
 Hematology: 
neutrophils, 
lymphocytes, 
basophils, eosinophils, monocytes, haemoglobin, 
haematocrit, platelet count, red blood cell count, 
total white cell count, VGM, CCMH, TCMH. 
 Biochemistry: Serum electrolytes (Na+, K+, Cl-
,Mg++and Ca++), liver function tests (AST, ALT, 
total bilirubin, GGT and AP), LDH, creatinine, 
glucose, CPK, total proteins, urea, albumin, 
bicarbonates, uric acide. Lipase and amylase (*). 
 Coagulation: aPTT and INR if clinically indicated 
 Urinalysis(*): bilirubin, blood, glucose, ketones, 
pH, 
protein, 
specific 
gravity, 
colour 
and 
appearance 
Within 24 hours before Day 1 of cycle 1 
(except coagulation) 
Repeat on Days 8 and 15 of Cycle 1* 
Repeat on Days 1, 8 and 15 of Cycle 2* 
Repeat on Days 1 and 8 of Cycle 3* 
Repeat on Day 1 of each subsequent 
cycle* 
 
(*): at day 1 of each cycle only 
 Thyroid function: TSH. If TSH is abnormal, free 
T3 and free T4 
Within 24 hours before Day 1 of cycle 1 
Repeat on day 1 of cycle 2* 
Repeat on day 1 of subsequent cycles (ie. 
C3, C6, C9, etc.)* 

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ASSESSMENT 
TIME 
 CA 125 for ovarian carcinoma only 
Repeat on day 1 Cycle 3 and every 3 
subsequent cycle* 
3. Creatinine 
clearance 
 Calculated using the Cockroft formula (see 
Appendix 2) 
Within 24 hours before Day 1 of cycle 1 
Repeat on Days 8 and 15 of Cycle 1* 
Repeat on Days 8 and 15 of Cycle 2* 
Repeat on Days 8 of Cycle 3* 
Repeat on Day 1 of each subsequent 
cycle* 
4. Pregnancy 
test, if 
applicable 
 Measurement of human chorionic gonadotropin 
(HCG) 
Within 72 hours prior to Day 1 of cycle 1 
(serum) 
Will be repeated on day 1 of each cycle, in 
women with childbearing potential (urine) 
5. Tumor 
assessment 
 CT-scan or MRI of all measurable sites, as per 
RECIST (see Appendix 3) 
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 – 
immunological 
biomarkers 
 Blood samples :  
 
1 EDTA x 4ml ; 1 EDTA x6 ml and 1 heparin x 6 ml 
 
At cycle 1 day 1 and at cycle 2 day 1 
For more details; see section 15.1.1 
7. Circulating 
DNA 
 Blood samples :  
2 EDTA x 10 ml 
At D1 of each cycle, until progression 
8. Biopsy 
 Tumor biopsy 
At baseline and at cycle 2 day 8  
(+/- 2 days) 
For more details; see section 15.1.1 
9. Adverse 
events 
As per NCI-CTCAE, v4.03. 
Throughout the treatment period 
10. LVEF 
Echocardiography 
Every 2-3 months throughout the 
treatment period 
*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; CCMH: Mean corpuscular hemoglobin concentration; ECOG PS, Eastern Cooperative Oncology Group 
Performance Status; GGT: gamma-glutamyltransferase; INR, international normalized ratio; LDH, lactate dehydrogenase; MRI, 
magnetic resonance imaging; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; PD: 
pharmacodynamics assessment; RECIST, Response Evaluation Criteria In Solid Tumors TCMH: mean corpuscular haemoglobin; VGM, 
Mean corpuscular volume. 
():If Total bilirubin is ≥2xULN (and no evidence of Gilbert’s syndrome) then fractionate into direct and indirect  bilirubin 
4.8. 
EVALUATION AT the END OF TREATMENT 
The end-of-treatment visit will be scheduled 30 days (4 weeks) 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, weight and temperature]. 
 
Hematology. 
 
Biochemistry. 
 
Urinalysis 
 
Calculated CrCl. 
 
Thyroid function 

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 
CA 125 measurement 
 
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 30 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). 
 
 
4.9. 
FOLLOW-UP AFTER the END-OF-TREATMENT VISIT 
 
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 for 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 date of study termination, 
whichever occurs first. 
 
 After disease progression, patients will be followed every 6 months until death or until the 
date of study termination, whichever occurs first. 
 
Patients who withdraw consent will not be followed with any study procedures.  
All AEs (including SAEs) suspected to be treatment-related (trabectedin and/or durvalumab) or 
research-related will be followed-up until the events or their sequelae resolve or stabilize at a level 
acceptable to the Investigator and the Sponsor. 
 
5. REGISTRATION PROCEDURES 
5.1. 
Screening 
Upon signature of consent, screened patient will be entered on study centrally at the Institut Bergonié 
Coordinating Center by the Study Coordinator.  
See procedure of study 
 
5.2. 
Inclusion 
Upon signature of consent, eligible patient will be entered in the study centrally at the Institut 
Bergonié Coordinating Center by the Study Coordinator. 
See procedure of study 
 
6. STUDY TREATMENT 
Sponsor will provide Trabectedin and Durvalumab, with identifying labels that will include all the 
information required by local regulations. 
Investigational medicinal products (IMPs) will have to be requested to Institut Bergonié using 
appropriate forms provided by the Sponsor.  
The study sites will have to ensure drug traceability at all times. 
 
6.1. 
Description of treatment 

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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. 
6.2. 
Pharmaceutical Informations 
Product 
description 
Galenic 
Dosage 
Route 
of 
administration 
Storage 
Supply 
Trabectedin 
Infusion 
0.05 mg/ml 
Intravenous 
2°C < temp < 8°C 
Yes 
Durvalumab 
Infusion 
50 mg/ml 
Intravenous 
2°C < temp < 8°C 
Yes 
 
6.3. 
Administration of treatment 
Treatment will be administered on an inpatient/outpatient basis. 
In a first time, on Day 1, Trabectedin should be administered as a 3-hour intravenous (IV) infusion. All 
patients must receive corticosteroids e.g. 20 mg of dexamethasone intravenously 30 minutes prior to 
Trabectedin administration; not only as anti-emetic prophylaxis but also because it appears to provide 
hepatoprotective effects. Additional anti-emetics may be administered as needed. 
Durvalumab should be administered on Day 2 as a 1-hour intravenous (IV) infusion. 
Regimen description 
Agent 
Dose 
Route 
Schedule 
Cycle 
Length 
Trabectedin 
Doses as appropriate for 
assigned dose level 
IV 
Day 1 
3 weeks 
Durvalumab 
Fixed doses of 1120 mg  
IV 
Day 2  
6.4. 
Durvalumab 
6.4.1. Formulation/packaging/storage 
Durvalumab will be supplied as a 500-mg vial solution for infusion after dilution. The solution contains 
50 mg/mL durvalumab, 26 mM histidine/histidine-hydrochloride, 275 mM trehalose dihydrate, and 
0.02% (weight/volume) polysorbate 80; it has a pH of 6.0. The nominal fill volume is 10 mL.  
Investigational product vials are stored at 2°C to 8°C and must not be frozen. Durvalumab must be 
used within the individually assigned expiry date on the label. 
 
6.4.2. Study drug preparation 
For patients, a fixed doses of 1120 mg should be prepared.  
Preparation of durvalumab doses for administration with an IV bag. 
The dose of durvalumab for administration must be prepared by the Investigator’s or site’s designated 
IP manager using aseptic technique.  Total time from needle puncture of the durvalumab vial to the 
start of administration should not exceed:  
24 hours at 2°C to 8°C  
4 hours at room temperature 
If the final product is stored at both refrigerated and ambient temperatures, the total time must not 
exceed 24 hours (that is, the individual storage time limits are not additive). If in-use storage time 
exceeds these limits, a new dose must be prepared from new vials. Infusion solutions must be allowed 
to equilibrate to room temperature prior to commencement of administration.  
No incompatibilities between durvalumab and polyvinylchloride or polyolefin IV bags have been 
observed. Fixed doses of 1120 mg of Durvalumab for patients will be administered using an IV bag 
containing 0.9% (w/v) saline with a final durvalumab concentration ranging from 1 to 20 mg/mL, and 
delivered through an IV administration set with a 0.2- or 0.22-μm in-line filter.  

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Remove a volume of IV solution from the IV bag equal to the calculated volume of durvalumab to be 
added to the IV bag prior to addition of durvalumab.  Next, the volume of durvalumab is added to the 
IV bag volume 250 mL (possibility of use IV bag volumes 100 to 1000 mL such that final concentration 
is within 1 to 20 mg/mL). Mix the bag by gently inverting to ensure homogeneity of the dose in the 
bag. 
Durvalumab will be administered at room temperature (approximately 25°C) by controlled infusion via 
an infusion pump into a peripheral or central vein. Following preparation of durvalumab, the entire 
contents of the IV bag should be administered as an IV infusion over approximately 60 minutes (±5 
minutes), using a 0.2, or 0.22-μm in-line filter. Less than 55 minutes is considered a deviation. 
The IV line will be flushed with a volume of IV solution (0.9% [w/v] saline) equal to the priming 
volume of the infusion set used after the contents of the IV bag are fully administered, or complete 
the infusion according to institutional policy to ensure the full dose is administered and document if 
the line was not flushed. 
Standard infusion time is 1 hour.  However, if there are interruptions during infusion, the total allowed 
time should not exceed 8 hours at room temperature.  The table below summarizes time allowances 
and temperatures. 
Durvalumab hold and infusion times 
Maximum time from needle puncture to start of 
administration 
4 hours at room temperature, 24 hours at 2°C to 
8°C 
Maximum time for IV bag infusion, including 
interruptions 
8 hours at room temperature 
In the event that either preparation time or infusion time exceeds the time limits outlined above, a 
new dose must be prepared from new vials. Durvalumab does not contain preservatives, and any 
unused portion must be discarded. 
 
6.4.3. Monitoring of dose administration 
Subjects will be monitored before, during and after the infusion with assessment of vital signs at the 
times specified in the Schedule of Assessment. Subjects are monitored (pulse rate, blood pressure) 
every 30 minutes during the infusion period (including times where infusion rate is slowed or 
temporarily stopped). 
 
6.5. 
Trabectedin 
For instructions regarding drug inventory, handling, reconstitution, dilution, storage, accountability 
and disposal, please refer to the more updated Summary of Product Characteristics (SPC), provided as 
separate documents. 
 
No lock of the BSA is required. 
 
6.6. 
General Concomitant Medication and supportive care guidelines 
6.6.1. 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). If changes occur during the 
trial period, documentation of drug dosage, frequency, route, and date may also be included on the 
CRF. 

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All concomitant medications received within 28 days before the first dose of trial treatment and 30 
days after the last dose of trial treatment should be recorded. Concomitant medications administered 
30 days after the last dose of trial treatment should be recorded for SAEs only. 
6.6.2. 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 Trabectedin and Durvalumab 
• 
Radiation therapy 
o Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may be allowed after 
consultation with Sponsor.  
 
Live vaccines within 30 days prior to the first dose of trial treatment and while participating in 
the trial. Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, varicella zoster, yellow fever, intranasal influenza, rabies, BCG and typhoid 
vaccine. 
 
Systemic glucocorticoids for any purpose other than to modulate symptoms from an event of 
clinical interest of suspected immunologic etiology 
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. 
Other medications that are prohibited in this trial are described in the exclusion criteria section. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
 
6.6.3. Restrictions during study 
6.6.3.1. 
CONTRACEPTION 
The following restrictions apply while the patient is receiving study treatment and for the specified 
times before and after: 
 
Female patient of child-bearing potential:  
Females of childbearing potential who are sexually active with a non-sterilized male partner 
must use at least 1 highly effective method of contraception (table below) from the time of 
screening and must agree to continue using such precautions for 180 days after the last dose 
of study treatment. Non-sterilised male partners of a female patient must use male condom 
plus spermicide throughout this period. Cessation of birth control after this point should be 
discussed with a responsible physician.  Not engaging in sexual activity for the total duration 
of the drug treatment and the drug washout period is an acceptable practice; however, 
periodic abstinence, the rhythm method, and the withdrawal method are not acceptable 
methods of birth control.  Female patients should also refrain from breastfeeding throughout 
this period. 
 
Male patients with a female partner of childbearing potential: 
 Non-sterilized males who are sexually active with a female partner of childbearing potential 
must use a male condom plus spermicide from screening through 180 days after receipt of 
the final dose of study treatment. Not engaging in sexual activity is an acceptable practice; 
however, occasional abstinence, the rhythm method, and the withdrawal method are not 
acceptable methods of contraception. Male patients should refrain from sperm donation 
throughout this period. 
 Female partners (of childbearing potential) of male patients must also use a highly 
effective method of contraception throughout this period (Table below).   
 

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N.B Females of childbearing potential are defined as those who are not surgically sterile (ie, bilateral 
tubal ligation, bilateral oophorectomy, or complete hysterectomy) or post-menopausal.   
 
Women will be considered post-menopausal if they have been amenorrheic for 12 months without an 
alternative medical cause.  The following age-specific requirements apply:  
 Women <50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal treatments 
and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-
menopausal range for the institution or underwent surgical sterilization (bilateral 
oophorectomy or hysterectomy).  
 Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatments, had radiation-induced menopause with last menses >1 year ago, had 
chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical 
sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy). 
Highly effective methods of contraception, defined as one that results in a low failure rate (ie, less 
than 1% per year) when used consistently and correctly are described in table below.  Note that some 
contraception methods are not considered highly effective (e.g. male or female condom with or 
without spermicide; female cap, diaphragm, or sponge with or without spermicide; non-copper 
containing intrauterine device; progestogen-only oral hormonal contraceptive pills where inhibition of 
ovulation is not the primary mode of action [excluding Cerazette/desogestrel which is considered 
highly effective]; and triphasic combined oral contraceptive pills). 
Table 1. Highly Effective Methods of Contraception (<1% Failure Rate) 
 
Barrier/Intrauterine methods 
 
Hormonal Methods 
 
Copper T intrauterine device 
 
Levonorgestrel-releasing intrauterine 
system (e.g., Mirena®)a 
 
 
Implants: Etonogestrel-releasing implants: e.g. 
Implanon® or Norplant®  
 
 
Intravaginal: Ethinylestradiol/etonogestrel-
releasing intravaginal devices: e.g. NuvaRing®  
 
 
Injection: Medroxyprogesterone injection: e.g. 
Depo-Provera®  
 
 
Combined Pill: Normal and low dose combined 
oral contraceptive pill 
 
 
Patch: Norelgestromin/ethinylestradiol-releasing 
transdermal system: e.g. Ortho Evra®  
 
 
Minipillc: Progesterone based oral contraceptive 
pill using desogestrel: Cerazette® is currently the 
only highly effective progesterone-based  
a 
This is also considered a hormonal method 
6.6.3.2. 
BLOOD DONATION 
Subjects should not donate blood while participating in this study and for 90 days after receipt of the 
final dose of investigational products. 
6.6.4. Potential drug interaction 
6.6.4.1. 
DURVALUMAB 
No formal drug-drug interaction studies have been conducted with durvalumab.  
There are no known clinically significant interactions of durvalumab with other medicinal products. 
6.6.4.2. 
TRABECTEDIN 
Since Trabectedin is metabolised mainly by CYP3A4: 

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 
Co-administration of trabectedin with potent inhibitors of the isoenzyme CYP3A4 (e.g. oral 
ketoconazole, fluconazole, ritonavir, clarithromycin or aprepitant) is prohibited. 
 
Co-administration of trabectedin with potent inductors of the isoenzyme CYP3A4 (e.g. 
rifampicin, phenobarbital, Saint John’s Wort) is prohibited as it would decrease the exposure 
to trabectedin.  
The following website may be referenced for a more extensive list of P450 inhibitors and inducers: 
http://medicine.iupui.edu/clinpharm/ddis/main. 
Alcohol consumption must be avoided during treatment with trabectedin due to the hepatotoxicity 
of the medicinal product. Caution should be taken if medicinal products associated with 
hepatotoxicity are administred concomitantly with trabectedin, since the risk of hepatotoxicity may 
be increased. 
 
Caution should be taken if medicinal products associated with rhabdomyolysis (e.g. statins) are 
administred concomitantly with trabectedin, since the risk of rhabdomylolysis may be increased. 
Concomitant use of trabectedin with phenytoin may reduce phenytoin absorption leading to an 
exacerbation of convulsions. Combination of trabectedin with phenytoin or live attenuated vaccines is 
not recommended and with yellow fever vaccine is specifically contraindicated. 
 
Concomitant administration of inhibitors of P-gp, e.g. cyclosporine and verapamil, may alter 
trabectedin distribution and/or elimination. The relevance of this interaction e.g. central nervous 
system (CNS) toxicity has not been established. Caution should be taken in such situations. 
 
6.7. 
Dosing delays/dose modifications and adverse event management 
No changes in durvalumab dose are allowed. If immune related adverse events occur, the durvalumab 
administration will be adjusted (delayed doses) as per the toxicity management guidelines (Appendix 
4). 
Dose escalation: Toxicities that would lead to dose modification should be discussed with the 
sponsor. 
Expansion cohorts: 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 4.03 (NI-CTCAE). 
 
6.7.1. General rules for dose modification 
6.7.1.1. 
DURVALUMAB 
Management of toxicity is described in appendix 4. 
Reactions may occur during or after the infusion of study medication.  The reaction may cause fever 
or chills and a change in blood pressure or difficulty in breathing. 
 
In the event of a ≤Grade 2 infusion-related reaction, the infusion rate of study drug may be 
decreased by 50% or interrupted until resolution of the event (up to 4 hours) and re-initiated at 50% 
of the initial rate until completion of the infusion.  For subjects with a ≤Grade 2 infusion-related 
reaction, subsequent infusions may be administered at 50% of the initial rate.  Acetaminophen and/or 
an antihistamine (e.g., diphenhydramine) or equivalent medications per institutional standard may be 
administered at the discretion of the investigator.   
If the infusion-related reaction is Grade 3 or higher in severity, study drug will be discontinued.  
The standard infusion time is one hour, however if there are interruptions during infusion, the total 
allowed time from infusion start to completion of infusion should not exceed 4 hours at room 
temperature, with maximum total time at room temperature not exceeding 4 hours (otherwise 
requires new infusion preparation). 
As with any antibody, allergic reactions to dose administration are possible.  Appropriate drugs and 
medical equipment to treat acute anaphylactic reactions must be immediately available, and study 
personnel must be trained to recognize and treat anaphylaxis.  The study site must have immediate 
access to emergency resuscitation teams and equipment in addition to the ability to admit subjects to 
an intensive care unit if necessary. 
 

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6.7.1.2. 
TRABECTEDIN 
Prior to re-treatment, patients must fulfil the baseline criteria defined previously (see Inclusion criteria 
section). If any of the following events occur at any time between cycles, the dose must be reduced 
to the lower level according to table below, for subsequent cycles:  
- Neutropenia < 500/mm3 lasting for more than 5 days or associated with fever or infection  
- Thrombocytopenia < 25,000/mm3  
- Increase of bilirubin >ULN and/or AP >2.5 xULN 
- Increase of AST or ALT > 5xULN which has not recovered by day 21 
- Any other grade 3 or 4 adverse reactions (such as nausea, vomiting, fatigue)  
For more information, please see trabectedin’s SPC. 
 
Once a dose has been reduced because of toxicity, dose escalation in the subsequent cycles is not 
allowed. 
 
Dose level 
Trabectedin dose 
(mg/m²) 
-1 
0.8 
1 
1 
2 
1.2 
3 
1.5 
 
 
Capillary Leak Syndrome cases (CLS) have been reported with trabectedin (frequency uncommon). If 
symptoms of possible CLS develop, such as unexplained edema with or without hypotension, reassess 
albumin level. A rapid decline in albumin level may be indicative of CLS. If a diagnosis of CLS is 
confirmed after exclusion of other causes, discontinue trabectedin and promptly initiate CLS treatment 
according to institutional guidelines. 
 
Recommendation for management of LVEF results from baseline cardiac echography: 
- 
Patients with a LVEF >50% and asymptomatic will be regularly clinically monitored for cardiac 
symptoms, and cardiac echography will be performed if clinically indicated. 
- 
Patients with LVEF between 40% and <50% but asymptomatic will be regularly clinically 
monitored for cardiac symptoms, and cardiac echography will be performed at 6 weeks and 
12 weeks and every 12 weeks thereafter.  
- 
Patients with LVEF <40% or with clinically symptomatic cardiac dysfunction (any % of LVEF at 
baseline) will be excluded from the trial and specialised cardiac management will be 
advised. 
 
 
Recommandation for dose adaptation in case of LVEF drop during treatment with trabectedin : 
- 
For patients with Grade 3 or 4 cardiac adverse events indicative of cardiomyopathy or for 
patients with a LVEF that decreases below the LLN (assessed as either an absolute decrease 
of LVEF of ≥15% or <LLN with an absolute decrease of ≥5%), trabectedin should be 
discontinued. 
- 
In case of cardiac symptoms, no matter the LVEF, trabectedin will be stopped and specialised 
cardiac management will be advised. 
 
6.7.2. Events of clinical interest and immune mediated adverse event (imeics) 
Events of clinical interest of a potential immunologic etiology (imECIs) may be defined as an adverse 
event of unknown etiology, associated with drug exposure and is consistent with an immune 
phenomenon.  imAEs may be predicted based on the nature of the durvalumab compound, its 
mechanism of action, and reported experience with immunotherapies that have a similar mechanism 
of action.  Special attention should be paid to AEs that may be suggestive of potential imAEs.  An 
imAE can occur shortly after the first dose or several months after the last dose of treatment.   
If an imAE 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 imAE.   
 
All imAE should be reported to sponsor (see section 11.7).  

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imAE will be managed according to the toxicity management guidelines (appendix 4).Durvalumab will 
be delayed until if the adverse reaction remains at Grade 1 or less.   
If another episode of a severe adverse reaction occurs, only Durvalumab will be permanently 
discontinued. 
Patient requiring 2 delays of Durvalumab injection should go off protocol therapy. 
 
Ir-AE are described in this section, but not limited to the items outlined below. For management, refer 
to the appendix 4 and to most updated Investigator Brochure. 
 
6.7.2.1. 
PNEUMONITIS 
Pneumonitis has been reported in patients receiving Durvalumab.  
Presentations of pneumonitis can range from asymptomatic lung infiltrates to those that mimic severe 
bacterial pneumonia. Early consideration of pneumonitis should be realised when patients present 
with new onset or worsening of respiratory symptoms such as dyspnoea or cough. Prompt treatment 
with steroids is important as per current established toxicity management guidelines. 
 
If new or worsening pulmonary symptoms (e.g. dyspnea) or radiological abnormality suggestive of 
pneumonitis/interstitial lung disease is observed, the Dosing Modification and Toxicity Management 
Guidelines will be applied (appendix 4). The results of the full diagnostic workup (including high-
resolution computed tomography (HRCT), blood and sputum culture, hematological parameters etc) 
will be captured in the eCRF. It is strongly recommended to perform a full diagnostic workup, to 
exclude alternative causes such as lymphangitic carcinomatosis, infection, allergy, cardiogenic edema, 
or pulmonary hemorrhage. In the presence of confirmatory HRCT scans where other causes of 
respiratory symptoms have been excluded, a diagnosis of pneumonitis (ILD) should be considered and 
the Dosing Modification and Toxicity Management Guidelines should be followed.  
 
Pneumonitis (ILD) investigation 
The following assessments, and additional assessments if required, will be performed to enhance the 
investigation and diagnosis of potential cases of pneumonitis. The results of the assessment will be 
collected. 
- 
Physical examination: Signs and symptoms (cough, shortness of breath and pyrexia, etc.) 
including auscultation for lung field will be assessed. 
- 
SpO2: Saturation of peripheral oxygen (SpO2) 
When pneumonitis (ILD) is suspected during study treatment, the following markers should be 
measured where possible: ILD Markers (KL-6, SP-D) and β-D-glucan; Tumour markers: Particular 
tumour markers which are related to disease progression; Additional Clinical chemistry: CRP, LDHFor 
recurrente moderate (Grade 2) pneumonitis: permanently discontinue Durvalumab.  
6.7.2.2. 
COLITIS 
Colitis has been reported in subjects receiving Durvalumab.  
Patients should be monitored for signs and symptoms of colitis or diarrhoea. Investigators are 
instructed to begin diarrhoea management early to minimise the risk of colitis.  
 
6.7.2.3. 
HEPATITIS 
Hepatitis has been reported in subjects receiving Durvalumab.  
Immune-mediated hepatitis/hepatic toxicity is the inflammation of the liver. Hepatic AEs induced by 
PD-1/PD-L1 inhibitors commonly present as asymptomatic increase of AST and ALT, rarely total 
bilirubin. A proportion of patients may be presenting with fatigue, fever and radiologic appearances 
including hepatomegaly, periportal lymphadenopathy and periportal oedema.  
 
6.7.2.4. 
NEPHRITIS 
Nephritis has been reported in subjects receiving Durvalumab.  
The major clinical syndromes produced by immune-mediated renal injury include nephrotic syndrome, 
rapidly progressive glomerulonephritis, and acute renal failure. 
Signs and symptoms include increase in serum creatinine, decrease in urine output, peripheral 
oedema, haematuria, loss of appetite 
 

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6.7.2.5. 
ENDOCRINOPATHIES 
The 
clinical 
presentation 
of 
immune-mediated 
endocrinopathies 
include 
hypothyroidism, 
hyperthyroidism, type 1 diabetes mellitus and nonspecific symptoms of headache and fatigue, but 
may also include myalgias, visual field defects, behavioural changes, electrolyte disturbances, loss of 
appetite and hypotension. Patients will generally have abnormal endocrine laboratory test results that 
include thyroid-stimulating hormone, free T4, total and free T3, cortisol, adrenocorticotrophic 
hormone, luteinising hormone,  folliclestimulating hormone, and testosterone. 
 
6.7.2.6. 
SEVERE SKIN REACTIONS (RASH, DERMATITIS) 
Immune-mediated severe skin reactions has been reported in patients treated with Durvalumab.  
 
Immune-mediated dermatitis is generally mild and presents as mild local or diffuse maculopapular, 
erythematous rash on the trunk or extremities, which may be accompanied by pruritus, alopecia, and 
vitiligo, suggestive of inflammatory response to melanocytes.  
 
For rash and dermatitis: prompt treatment with steroids (topical or systemic based on severity) is 
important. 
 
In rare cases, severe dermatitis has been reported to manifest as Stevens-Johnson syndrome, toxic 
epidermal necrolysis, or rashes complicated by dermal ulceration or necrotic, bullous, or haemorrhagic 
manifestations. In such cases, withhold Durvalumab and refer the patient for specialized care for 
assessment and treatment. 
If diagnosis is confirmed, permanently discontinue Durvalumab. 
 
6.7.2.7. 
 IMMUNE-MEDIATED MYOCARDITIS 
Investigators should exercise clinical judgment in managing actual patients alongside the guidelines 
presented in the protocol(s).  An event that exhibits rapid progression and/or the likelihood for high 
morbidity/mortality requires that clinical judgment be exercised above and beyond toxicity 
management guidelines to ensure that treatment is optimally tailored to any given patient’s specific 
case.  
For example, the general principles outlined in the toxicity management guidelines describe prompt 
initiation of corticosteroids for both Grade 2 events (that have persisted for 4-5 days) and Grade 3-4 
events; clinical judgment applied to this baseline guidance for an event that exhibits rapid progression 
and/or the likelihood for high morbidity/mortality – such as myocarditis – would warrant prompt 
initiation of high-dose corticosteroids without delay even for grade 2 cases. Similarly, clinical judgment 
for patients with suspected myocarditis should lead investigators to obtain a cardiology consult and 
institute a thorough diagnostic work-up (that includes exclusion of other alternate causes such as 
infection), and the appropriate management that includes discontinuing drug (permanently if biopsy-
proven immune-mediated myocarditis) and, as already noted, the prompt use of steroids or other 
immunosuppressives. 
 
6.8. 
Packaging and Labeling 
The following information will appear on the labels: 
 
Name of the Sponsor. 
 
Study number/Patient number. 
 
Dosage and route of administration. 
 
Quantity or contents of container. 
 
Batch number/packaging number. 
 
Expiration date and storage conditions. 
 
Local legal information, as appropriate. 
 

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6.9. 
Supplies and Drug Accountability 
Trabectedin and Durvalumab will be supplied to investigators. 
For ordering study drugs, please confer process of this study and pharmaceutical procedure. 
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. 
All unused drug supplied by the Sponsor will be properly destroyed at the study site, at the end of the 
study. The documentation of this procedure must be provided to the clinical trial monitor. 
 
6.10. Treatment Compliance 
The Investigator is responsible for supervising compliance with the instructions described in this study 
protocol. 
 
 
 
 
 
 

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7. STUDY EVALUATIONS 
Study evaluations aim to assess:  
 
Diagnosis  
 
Efficacy 
 
Safety 
 
7.1. 
Central review for diagnosis of soft-tissue sarcoma 
7.1.1. Diagnosis of soft-tissue sarcoma 
If diagnosis of sarcoma was not confirmed by the RRePS Network, pathological central review will be 
performed to confirm histological diagnosis of soft-tissue sarcoma by Pr Coindre and collaborators, 
Department of Pathology, Institut Bergonié, Bordeaux, France. The reviewer will assess the 
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 soft-tissue sarcoma 
will be considered ineligible and will not be included in the study. 
7.1.2. 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) are mandatory for central review. 
7.1.3. Pathological process schedule and implementation (not applicable if diagnosis 
reviewed in the RRePS Network) 
Each site will send to Institut Bergonié within 7 days after the signature of informed consent: 
 
A completed pathology request form  
 
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 to: 
Institut Bergonie - Service Pathologie 
Technicienne Anapath Recherche Clinique 
Protocole TRAMUNE 
229 cours de l'Argonne - 33076 Bordeaux Cedex, France 
Tél: +33 5.56.33.78.53  
 
7.2. 
Efficacy – Expansion cohort only  
The antitumor activity of trabectedin given in combination with durvalumab will be evaluated as per 
RECIST v1.1, in terms of objective response under treatment, best overall response, 6-month 
objective response, 6-month progression-free status, , 1-year PFS and OS. 
7.2.1.   Assessing Objective Tumor Response (RECIST v1.1) 
 
A comprehensive workup will be performed at baseline and every six weeks. 
 
Whenever the 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 (Einsenhauer, 2009). 

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7.2.2. Centralized Radiological Review (Institut Bergonié)  
7.2.2.1. 
GENERAL PROCEDURE 
Centralized radiological review will be performed to confirm disease status in comparison with 
baseline, Week#6, Week#12, Week#18, etc…. For patients included in the reference center, CT scan 
will be initially read by a radiologist who differs from the expert. 
Review process will be centralized at Institut Bergonié and will be performed by a radiologist expert in 
soft tissue sarcomas.The judgment provided by the expert reviewer will be retained and used in 
statistical analyses. 
7.2.2.2. 
REVIEW PROCESS SCHEDULE  
All tumor evaluations will be sent as soon as they become available. 
Patient’s information must be recorded on a provided imaging CD. 
 
7.2.2.3. 
PRACTICAL IMPLEMENTATION 
For each shipment, each media should be accompanied by the Radiological Forms provided by the 
Sponsor. 
All CDs must be sent to the sponsor CRA as described in guidelines provided as a separate document. 
 
7.3. 
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 30 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, v4.03. 
 
8. STUDY ENDPOINTS 
8.1. 
Primary endpoint 
Phase I / Dose escalation part  
Primary objective of the phase I trial is to establish the recommended phase II dose (RP2D), the 
maximum tolerated dose (MTD) evaluated on the first cycle (D1 to D21), the safety profile, and the 
Dose Limiting Toxicities (DLT) of trabectedin given in combination with durvalumab. 
 
Definition: 
Dose-limiting toxicity (DLT):  
A DLT is defined as an AE or laboratory abnormality that fulfills all the criteria below:  
 Begins on the first 21 days of treatment. 
 Is considered to be at least possibly related to the study treatment.  
 Meets one of the criteria below, graded as outlined or according to NCI-CTCAEv4.03 : 
o 
Any grade-4 toxicity (except for vomiting without maximal symptomatic/prophylactic 
treatment and if toxicity is transaminitis, but which have to be resolved at Day 21, i.e. return 
to Baseline or grade 1). 
o 
 Grade-3 non-haematological toxicity lasting > 7days (except for 1rst episode of nausea 
without maximal symptomatic/ prophylactic treatment and if toxicity is transaminitis, which 
have to be resolved at Day 21, i.e. return to Baseline or grade 1). 
o 
 Grade-3 hematologic toxicity lasting for > 7days. 
o 
 Grade 4 neutropenia with fever. 
o 
 Grade > 2 thrombocytopenia with bleeding. 
Endpoints: 
 
Toxicity graded using the common toxicity criteria from the NCI-CTCAE v4.03.  
 
Incidence rate of DLT at each dose level during the first 21 days.  

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Phase I /Expansion cohorts 
Primary objective of the expansion cohorts is to evaluate preliminary signs of the antitumor activity of 
trabectedin given in combination with durvalumab in terms of objective response under treatment.  
Following RECIST v1.1 recommendations (appendix 3): 
 Objective response rate (ORR) is defined as the proportion of patients with complete or partial 
response (CR, PR) as per RECIST v1.1 criteria. 
 Objective response under treatment is recorded from study treatment initiation until the end 
of treatment and determined once all the data for the patient is known. 
 Claimed responses will have to be confirmed at least 4 weeks later to ensure responses 
identified are not the result of measurement errors. 
 Disease status under treatment, whatever the response observed, will be centrally 
reviewed for all patients, by an independent expert radiologist. Reviewed data will 
be used for the efficacy analysis. 
 
 
8.2. 
Secondary endpoints 
Phase I / Dose escalation part  
 
Preliminary signs of antitumor activity 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 3):  
Following RECIST v1.1 recommendations:  
 The best overall response is determined once all the data for the patient is known. 
 Claimed responses will have to be confirmed at least 4 weeks later to ensure responses 
identified are not the result of measurement errors. 
o Objective response rate (ORR) is defined as the proportion of patients with complete response 
or partial response according to RECIST v1.1 criteria (appendix 3). ORR under treatment and 
6-month ORR will be reported ORR  under treatment is recorded from study treatment 
initiation until the end of treatment. Following RECIST v1.1 recommendations:  
 ORR under treatment is determined once all the data for the patient is known. 
 Claimed responses will have to be confirmed at least 4 weeks later to ensure responses 
identified are not the result of measurement errors. 
o Progression-free rate (PFR) is defined as the proportion of patients with complete response, 
partial response or stable disease more than 24 weeks as defined as per RECIST v1.1 criteria 
(appendix 3). 6-month PFR will be reported. . Following RECIST v1.1 recommendations, 
claimed responses will have to be confirmed at least 4 weeks later to ensure responses 
identified are not the result of measurement errors. 
o Progression-free survival (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 
PFS rate will be reported. 
o Overall Survival (OS) is defined as the time from study treatment initiation to death (of any 
cause). 1-year OS rate will be reported. 
 
Pharmacodynamic study:  
o Blood samples:  
 Serum level of cytokines, kynurenine and immunophenotyping of circulating immune cells  
 Analyses of circulating DNA for identification and monitoring of mutations observed at the 
level of the circulating tumor cells (liquid biopsies concept).  
o Tumor samples: Fresh pre-treatment and on-treatment tumor biopsies will be performed. 
Samples will be formalin fixed and paraffin-embedded or fresh frozen, and will be analyzed 
for: 
 Hematoxylin and eosin staining (H&E). 
 Immunohistochemistry (IHC) assessmentsincluding, but not limited to, the following 
markers: SP263 SP28-8 (PDL1), CSF-1R, CD68/CD163, CD8, MHC class I/II, CD31 
(microvessel density), Ki67 and other exploratory markers. The analysis will be prioritized 
based on the amount of material available.  

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 Genomics and transcriptomics exploratory analysis for predictive signatures in responders 
and mechanisms of resistance in non-responders. 
Phase I / Expansion cohorts 
 
Preliminary signs of antitumor activity in terms of 6-month ORR, best overall response, 6-month 
PFR , 1-year OS and PFS rates defined as for the escalation part of the phase I trial. 
 
Toxicity defined above as for the escalation part. 
 
Phamacodynamics study defined above as for the escalation part. 
 
9. STATISTICAL CONSIDERATIONS 
9.1. 
Hypotheses and number of subjects needed  
9.1.1. Phase I (Dose escalation part) 
- 
3 dose levels 
- 
A minimum of 3 patients will be entered in each dose level 
- 
A maximum of 6 patients will be entered in each dose level  
Therefore, the maximum number of patients is estimated to be 18 patients assessable for safety.  To 
account for patients not assessable, we anticipate accruing a maximum of 20 patients for the dose 
escalation part of the phase I trial. 
 
9.1.1. Phase I (Expansion cohorts) 
 
The primary objective is to determine preliminary signs of anti-tumor activity of trabectedin given 
in combination with DURVALUMAB among two selected cohorts of patients (STS and ovarian 
carcinomas) in terms of objective response under treatment as per RECIST v1.1 criteria. 
 
Once the Maximum Tolerated Dose (MTD) is established for trabectedin, 2 distinct cohorts will be 
treated at the MTD: 
o 
Cohort A: patients with advanced STS. 
o 
Cohort B: patients with advanced ovarian carcinomas 
 
For each cohort: 
o 
Sample size is calculated based on the first stage of a 2-stage Gehan design assuming a 20% 
efficacy rate, 5% false positive rate and 10% precision (Gehan 1961). 
o 
14 eligible and assessable subjects are required. 
o 
If at least one objective response (CR or PR as per RECIST v1.1) is observed under treatment, 
the study drug association will be considered worthy of further testing in this indication.  
Assuming 10% patients not eligible or that cannot be assessed for the primary endpoint, 15 patients 
will be recruited for each of the 2 cohorts, i.e. a total of 30 patients will be included in the 
expansion cohorts. 
 
9.2. 
Definition of study populations 
9.2.1. Phase I (Dose escalation part) 
 
The following patients will not be included in the population assessable for safety (primary analysis) 
and thus will be replaced: 
• Patients who received ≤ 75% RDI (Relative Dose Intensity) for trabectedin OR ≤ 75% RDI for 
durvalumab over cycle 1, due to drug-related AE not considered as DLT. 
• Patients who goes off treatment over cycle 1 for reasons unrelated to toxicity (DLT or any other 
AE), e.g. progression, lost to follow-up, will be replaced 
9.2.2. Phase I (Expansion cohorts) 
 
 
Eligible population: All patients included without major violation of eligibility criteria. 

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 
Population assessable for efficacy: All patients eligible and for whom the following conditions are 
statisfied: 
o Received at least one complete or two incomplete treatment cycles,  
o At least one disease measurement recorded not less than six weeks after treatment onset. 
 
The following patients will also be included in the population assessable for efficacy; they will be 
considered as “inevaluable for response”  for the primary endpoint as per RECIST v1.1 criteria (i.e. 
objective response under treatment) and not be replaced in the primary efficacy analysis:  
o Any eligible patients who received at least one treatment cycle or two incomplete 
treatment cycles and experience disease progression or die due to disease progression 
prior to response evaluation (will be considered as “inevaluable for response” due to early 
progression). 
o Patients withdrawn due to drug-related toxicity without any tumor assessments after the 
start of study treatment (will be considered as “inevaluable for response” due to toxicity). 
o Patients who received at least one administration of the treatment AND withdrawn due to 
significant clinical deterioration of unknown reason AND without any tumor assessments 
after the start of study treatment (will be considered as “inevaluable for response" due to 
significant clinical deterioration).  
 
Safety population: all patients having received at least one (any) treatment administration. 
 
Patient’s replacement:  
 
Any patient not eligible or not assessable for efficacy will be replaced.  
 
However, any patient who received at least one administration of the study drug will be included 
in the safety analysis. 
 
9.3. 
Statistical analysis 
A statistical analyse plan (SAP) will be produced by the statistician and validated by the steering 
committee before the first statistical analysis. At the end of the dose escalation part of the phase I 
trial and before opening the expansion cohorts, an IDMC (see section 12.1.2) will be requested to 
assess safety data and validate MTD based on the statistical report produced by the statistician of the 
study.  
9.3.1. Patient characteristics at baseline  
The patients entered into the study will be described according to the following characteristics:  
 
Compliance with eligibility criteria,  
 
Epidemiological characteristics,  
 
Clinical and laboratory characteristics,  
 
Treatment characteristics.  
9.3.2. Endpoint analyses 
9.3.2.1. 
PHASE I TRIAL (DOSE ESCALATION PART) 
 
All analyses will be descriptive; no p-values will be calculated.  
 
Primary endpoint will be analyzed on the population assessable for safety of the phase I trial 
(escalation part).  
 
Toxicity observed at each dose level, graded according to the Common Terminology Criteria for 
Adverse Events v4.0 from the NCI, will be recorded in terms of event type, severity, dates of 
beginning and end, reversibility and evolution. Data will be gathered in tables summarizing 
toxicities and side effects for each dose level and cycle. 
 
DLT will be described in terms of number and incidence rates at each dose level. The number and 
percentage of patients who will have developed a DLT in each dose level will also be reported. 
 
Data analyses will be provided by dose groups and for all study patients, combined wherever 
appropriate.  
 
Categorical endpoints: best overall response, ORR under treatment and at 6 months, 6-month 
ORR and 6-month PFR, will be reported in terms of counts by dose level.  

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 
Continuous endpoints will be reported in terms of summary statistics that will include number of 
patients, median, minimum, and maximum, and additional percentiles if appropriate.  
 
Survival endpoints (PFS and OS) will be analyzed 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. 
 
Missing data will not be imputed. 
9.3.2.2. 
EXPANSION COHORTS 
 
All analyses will be descriptive; no p-values will be calculated.  
 
Analyses will be conducted separately for sarcoma and ovarian cancer patients.  
 
Primary efficacy endpoint will be analysed based on the eligible and assessable population (see 
chapter 10.2 for definition):  
 
Each patient will be assigned one of the following categories:  
o 
Complete response 
o 
Partial response 
o 
Stable disease 
o 
Progression 
o 
Inevaluable for response 
 
The rate of objective response (complete or partial response) under treatment will be 
reported: 
o 
All eligible and assessable patients (section 10.2) will be included in the 
denominator for the calculation of the objective response rate (ORR). 
o 
The 95% two-sided confidence limits will be provided for the ORR (binomial law). 
o 
First endpoint conclusions will be based on the objective response rate ORR for all 
eligible and assessable patients (section 10.2) after centralized radiological review 
of the data. 
 
As regards to the other efficacy endpoints, the analyses will be carried out in the eligible and 
assessable population: 
 
Each patient will be assigned one of the following categories: 
o 
Complete response 
o 
Partial response 
o 
Stable disease 
o 
Progression 
o 
Inevaluable for response 
 
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).   
 
The 6-month progression-free rate 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 6-month objective response rate 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 (binomial 
law) 
 
The safety analysis will be performed on the safety population.  
 
Quantitative variables will be described using mean and standard deviations if the normality 
assumption is satisfied, else other descriptive statistics (median, range, quartiles) will be reported.  
 
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.  

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10. ADVERSE EVENTS 
10.1. Description of safety evaluation criteria 
The safety evaluation will comprise an evaluation of the patient’s general condition (ECOG Appendix 
1), a physical examination, regular blood tests and the recording of adverse events occurring 
throughout the study. Toxicity will be evaluated using the NCI-CTCAE v4.03 scale available on the 
world wide web at http://ctep.info.nih.gov. All appropriate treatment areas should have access to a 
copy of the NCI-CTCAE v4.03.   
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. 
 
10.2. Definition 
10.2.1. 
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. 
10.2.2. 
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. 
Medical and scientific judgment is exercized 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 
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. 

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Any abnormal laboratory’s result resulting as a grade 4 in the CTCAE v4.03 will be considered a 
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 a 
serious by any IMP, any healthcare professional or any investigator should be handled as a serious 
adverse event. 
10.2.2.1. 
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. 
10.2.2.2. 
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. 
10.2.2.3. 
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. However, these circumstances will be collected in the CRF. 
 Pre-planned hospitalizations: Any pre-planned surgery or procedure must be documented in the 
source documentation and collected in the CRF. 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.  
10.2.3. 
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. 
10.2.4. 
Adverse effect 
An adverse effect is any untoward and unintended responses to an experimental drug regardless of 
the dose. 
10.2.5. 
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. 
In practice, the term “new effect” is sometimes used as a synonymous of “unexpected adverse 
effect”. 
10.2.6. 
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). 
 
 

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10.2.7. 
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 conduct of the research or the research documents or to suspend or interrupt or modify 
the protocol of research or similar research. 
For trials of first administration or use of a health product in persons without any conditions: any 
serious adverse reactions. The study TRAMUNE is not concerned by this situation. 
10.2.8. 
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. 
 
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. 
 

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10.3. Serious adverse event and new information notification (responsibility of the 
investigator) 
Serious adverse events, regardless of relationship to the study drugs, will be reported by the 
investigator in the patient’s CRF. 
The investigator will notify to 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 until the start of a new antitumor 
therapy, whichever occurs first, 
- Beyond this period of time, only those SAEs suspected to be related to the IMP or the research 
(other treatments used, diagnostic procedures, examinations carried out during the research) will be 
collected without any limitation in terms of deadline. 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. 
- Whenever possible the investigator will record the main diagnosis instead of the signs and 
symptoms. 
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 5) 
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) – R&D UNICANCER 
Fax: +33 1 44 23 55 70 
Or contact : R&D Unicancer – Mail : pv-R&D@unicancer.fr 
 
For each event, the investigator will record: 
 - A description of the event that is as clearly as possible, using medical terminology, 
 - Date AE met criteria for serious AE, the date the event ended 
- Date of the serious adverse event notification form report - The steps taken and whether or not 
corrective treatment was required, whether or not the investigational treatment was discontinued, etc. 
- Date of hospitalization 
- Date of discharge 
- Probable cause of death 
- Date of death 
- Autopsy performed 
- The patient’s relevant medical history 
- 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.) : 
 Causality assessment in relation to all study medications 
 Causality assessment in relation to Study procedure(s) 
 Causality assessment in relation to Additional Study Drug 

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 In addition, when applicable, the investigator must also indicate if this event is related 
to disease progression. 
-  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. 
The investigator is responsible for providing appropriate medical follow-up for patients until resolution 
or stabilization of the adverse event or until the patient’s death. 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. 
 
New cancers : the development of a new cancer should be regarded as an SAE. New primary cancers 
are those that are not the primary reason for the administration of the IP and have been identified 
after the patient’s inclusion in this study. 
 
10.4. 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 within 90 days from the patient’s discontinuation visit, 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 7). 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. 
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 90 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. 

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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. 
 
10.5. Report of Overdose 
An overdose is defined as a subject receiving a dose of durvalumab in excess of that specified in the 
Investigator’s Brochure, unless otherwise specified in this protocol. 
Any overdose of a study subject with durvalumab and/or trabectedin, with or without associated 
AEs/SAEs, is required to be reported within 24 hours of knowledge of the event to the sponsor. If the 
overdose results in an AE, the AE must also be recorded as an AE. Overdose does not automatically 
make an AE serious, but if the consequences of the overdose are serious, for example death or 
hospitalization, the event is serious and must be recorded and reported as an SAE. There is currently 
no specific treatment in the event of an overdose of durvalumab.  
The investigator will use clinical judgment to treat any overdose. 
 
10.6. Report of Hepatic function abnormality 
Hepatic function abnormality (as defined by cases where a subject shows an AST or ALT ≥3xULN and 
total bilirubin ≥ 2xULN in a study subject, with or without associated clinical manifestations, is 
required to be reported as “hepatic function abnormal” within 24 hours of knowledge of the event to 
the sponsor using the SAE form unless a definitive underlying diagnosis for the abnormality (e.g., 
cholelithiasis or bile duct obstruction) that is unrelated to investigational product has been confirmed. 
Hy’s Law: Cases where a patient shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN may need to be 
reported as SAEs. Please refer to Appendix 4, the Toxicity Management Guidelines, for further 
instruction on cases of increases in liver biochemistry and evaluation of Hy’s law. 
 
 
If the definitive underlying diagnosis for the abnormality has been established and is unrelated 
to investigational product, the decision to continue dosing of the study subject will be based 
on the clinical judgment of the investigator. 
 
If no definitive underlying diagnosis for the abnormality is established, dosing of the study 
subject must be interrupted immediately. Follow-up investigations and inquiries must be 
initiated by the investigational site without delay. 
10.7. Reporting events of clinical interest and immune-mediated adverse events 
Information on how to identify and evaluate imAE/imAEs has been developed and is included in 
appendix 4.  . All imAE imAEs should be reported to sponsor. 
 
ImAE observed with durvalumab include: 
o Colitis, Intestinal perforation 
o Pneumonitis 
o ALT/AST increases / hepatitis / hepatotoxicity 
Increase of AST and ALT should be reported as event of clinical interest if it meets the criteria of 
seriousness such as hospitalization and especially if treatment was given because of the event. 
o Neuropathy / neuromuscular toxicity (i.e. events of encephalitis, peripheral motor and sensory 
neuropathies, Guillain-Barré, and myasthenia gravis) 

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o Endocrinopathy (i.e. events of hypophysitis, adrenal insufficiency, and hyper- and hypothyroidism, 
type I diabetes mellitus) 
o Dermatitis 
o Nephritis 
o Pancreatitis (or labs suggestive of pancreatitis - increased serum lipase , increased serum amylase) 
o Rash / dermatitis (including Stevens-Johnson syndrome, toxic epidermal necrolysis, rashes 
complicated by dermal ulceration or necrotic, bullous or haemorragic manifestations) 
o Myositis/Polymyositis 
o Vasculitis 
o Non-infectious meningitis 
o Non-infectious encephalitis 
o Other inflammatory responses that are rare with a potential immune-mediated aetiology include, 
but are not limited to, myocarditis, pericarditis,  uveitis, haematological events, sarcoidosis and 
rheumatological events. 
 
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a different 
underlying pharmacological etiology are also considered AESIs. 
 
The investigator will notify the Vigilance Unit without delay about any events of clinical interest. 
The investigator must complete the specific form (Appendix 6) 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) – R&D UNICANCER 
Fax: +33 1 44 23 55 70 
Or contact : R&D Unicancer – Mail : pv-R&D@unicancer.fr 
 
Adverse events that are both an SAE and an imAEimAEs should be reported one time as an SAE only, 
however the event should be appropriately identified as an imAEimAEs too in the database. 
 
10.8. report of 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 wishes to decrease the trial treatment dose or temporarily stop the study 
management without respecting protocol procedures, he/she should previously discuss it 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. 
 
10.9. Responsibility of Vigilance Unit   
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) for the Durvalumab (MEDI4736) 
- and Summary Product Characteristic (SmPC) for the Trabectedine (Yondelis®).  

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10.10. Notification and registration of unexpected serious adverse events and new 
information (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. 
 
 

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11. QUALITY ASSURANCE AND TRIAL MONITORING 
11.1. Monitoring of the trial 
11.1.1. 
Steering Committee 
The study will be supervised and monitored by a steering committee comprising members 
participating in the study: 
 
Dr. M. Toulmonde, Coordinating Investigator and Chairman of the committee.  
 
Dr. A. Floquet, Scientific responsive, medical oncologist. 
 
A representative of the sponsor (Pr S. Mathoulin-Pélissier or a substitute). 
 
The biostatistician of the trial (Ms. M. Pulido, or a substitute).  
 
The pharmacist of the trial (Ms. L. Poignie, or a substitute). 
 This committee must ensure the following:  
 
Implementation and regular follow-up of the study 
 
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.  
 
For the dose escalation part, the steering committee will be consulted before proceeding or not to the 
next dose level.  
In addition, the steering committee will resolve any specific issue regarding the DLT status. Note 
however, that medical oncologists of the steering committee cannot comment on the DLT status of 
patients they have been in charge of. In such case, the opinion of another medical oncologist who has 
not treated the patient will be sought.    
 
The  steering committee 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. 
11.1.2. 
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. 
 
Conclusions of the steering committee for the MTD definition based on the dose escalation trial 
will be submitted for approval to the IDMC before opening the expansion cohorts. If necessary, a 
second IDMC may be set up at the end of the expansion cohorts. 
 
Implementation of the IDMC committee will be performed according to the internal procedures at 
Institut bergonié. 
Composition of the IDMC 
 
This Committee must comprise at least one qualified oncologist, one pharmacologist and one 
statistican:  
o 
Qualified oncologist (Pr Jean Emmanuel KURTZ) 
o 
Pharmacologist (Dr Berdaï) 
o 
Statistician (Thomas Filleron) 
 
 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. 

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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 
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)]. 
 
11.2. Quality assurance 
11.2.1. 
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. 
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. 
11.2.2. 
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. 

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 
The possible audit and inspection 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. 
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. 
11.2.3. 
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. 
 
11.2.4. 
Audits/Inspections 
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. 
 
11.2.5. 
Data management 
The data are entered using an electronic case report form (e-CRF) created with Macro 4.2 (Infermed 
limited 2010). Data entry is performed by the CRA-I using login and password provided by the 
database administrator. It is carried out at the research unit of Bergonie Institute. 
Each step of the data management is described in the data management plan (DMP) drafted by the 
data manager. This document is validated by the coordinating investigator, the statistician, the CRA-C 
and the database administrator and is performed according to the internal procedures of the research 
unit. 
The process of data lock/unlock is performed according to our procedure and after validating a check 
list. 
All data will be backed-up daily and kept for 30 days. 

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12. REGULATORY ASPECTS AND ETHICAL CONSIDERATIONS  
 
Clinical Research Management Unit – Institut Bergonié 
Contacts:  
Lucie Bard – Tel.: +33 5 47 30 61 96, e-mail: l.bard@bordeaux.unicancer.fr  
or 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 (law “Jardé”) 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).(Appendix 4) 
 
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). 
 
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 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. 
 
12.1. Clinical Trial authorization 
This trial is registered under Eudract N° 2016-004720-33. 
The protocol has been approved by the South West and Overseas Territories III Ethics Committee, 
Bordeaux.  Approval was given on |_2_|_1_|/|_1_|_2_|/|_2_|_0_|_1_|_6_|. 
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 
|_0_|_5_|/|_0_|_5_|/|_2_|_0_|_1_|_7_|. 
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. 

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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. 
12.2. Insurance policy  
The Institut Bergonié has taken out an insurance policy (policy No 0100871914011 160002 10998) 
with société HDI-Gerling, Tour opus 12, 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 Cedex, Tel. 02 97 69 19 19) in case compensation is payable to investigators or 
patients taking part in the study. 
 
12.3. 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. 
 
12.4. 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. 
 
 
12.5.  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. 

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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, 
 
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. 
 
12.6. 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. 
 
12.7. 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 “Ancillary 
Study”. 
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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12.8. Fédération des Comités de Patients pour la Recherche Clinique en Cancérologie 
(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. 
 
12.9. 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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13. 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. 
 
14. PUBLICATION AND VALORISATION 
14.1. Scientific communication 
All of the information arising from this study shall be considered confidential (cf. section 12). 
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. 
For the principal publication, either in French or English, the authors are: 
 
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 ot two last positions). 
 
14.2. 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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34. Carter NJ, Keam SJ (2010). Trabectedin, a review of its use in soft tissue sarcoma and ovarian 
cancer. Drugs;70(3):355–76 
35. Martinez, N., Sanchez-Beato, M., Carnero, A., et al (2005). Transcriptional signature of 
Ecteinascidin 743 (Yondelis, Trabectedin) in human sarcoma cells explanted from chemo-naive 
patients. Mol Cancer Ther;4:814-23 
36. Erba, E., Bergamaschi, D., Bassano, et al (2001). Ecteinascidin-743 (ET-743), a natural marine 
compound, with a unique mechanism of action. Eur J Cancer;37:97-105 
37. Martinez, E. J., Corey, E. J. and Owa, T (2001). Antitumor activity- and gene expression-based 
profiling of ecteinascidin Et 743 and phthalascidin Pt 650. Chem Biol;8:1151-1160 
38. Damia, G., Silvestri, S., Carrassa, L., et al (2001). Unique pattern of ET-743 activity in 
different cellular systems with defined deficiencies in DNA-repair pathways. Int J 
Cancer;92:583-8 
39. Takebayashi, Y., Pourquier, P., Zimonjic, D. B., et al (2001). Antiproliferative activity of 
ecteinascidin 743 is dependent upon transcription-coupled nucleotide-excision repair. Nat 
Med;7:961-6 
40. Furuta, T., Ueda, T., Aune, G., et al (2002). Transcription-coupled nucleotide excision repair 
as a determinant of cisplatin sensitivity of human cells. Cancer Res;62:4899-902 
41. Soares DG, Machado MS, Rocca CJ et al. Trabectedin and its C subunit modified analogue 
PM01183 attenuate nucleotide excision repair and show activity toward platinum-resistant 
cells. Mol Cancer Ther 2011; 10(8): 1481–1489. 
42. Tavecchio M, Simone M, Erba E et al. Role of homologous recombination in trabectedin-
induced DNA damage. Eur J Cancer 2008; 44(4): 609–618. 
43. Delaloge S, Wolp-Diniz R, Byrski T et al. Activity of trabectedin in germline BRCA1/2-mutated 
metastatic breast cancer: results of an international first-in-class phase II study. Ann Oncol 
2014; 25(6): 1152–1158. 
44. Casado, J. A., Rio, P., Marco, E., et al (2008). Relevance of the Fanconi anemia pathway in 
the response of human cells to trabectedin. Mol Cancer Ther;7:1309-18 
45. Galmarini CM, D’Incalci M, Allavena P (2014) Trabectedin and plitidepsin: drugs from the sea 
that strike the tumor microenvironment. Mar Drugs 12: 719–733. 
46. Germano G, Frapolli R, Belgiovine (2013). C Role of macrophage targeting in the antitumor 
activity of trabectedin. Cancer Cell.23:249-62 
47. Allavena P, Signorelli M, Chieppa M, Erba E, Bianchi G, Marchesi F, Olimpio CO, Bonardi C, 
Garbi A, Lissoni A, de Braud F, Jimeno J, D’Incalci M (2005) Anti-inflammatory properties of 
the novel antitumor agent yondelis (trabectedin): inhibition of macrophage differentiation and 
cytokine production. Cancer Res 65: 2964–2971 
48. Germano G, Frapolli R, Simone M, Tavecchio M, Erba E, Pesce S, Pasqualini F, Grosso F, 
Sanfilippo R, Casali PG, Gronchi A, Virdis E, Tarantino E, Pilotti S, Greco A, Nebuloni M, 
Galmarini CM, Tercero JC, Mantovani A, D’Incalci M, Allavena P (2010) Antitumor and anti-
inflammatory effects of trabectedin on human myxoid liposarcoma cells. Cancer Res 70: 
2235–2244. 
49. Le Cesne A, Ray-Coquard I, Duffaud F, Chevreau C, Penel N, Bui Nguyen B, Piperno-Neumann 
S, Delcambre C, Rios M, Chaigneau L, Le Maignan C, Guillemet C, Bertucci F, Bompas E, 
Linassier C, Olivier T, Kurtz JE, Even C, Cousin P, Yves Blay J; French Sarcoma Group. 
Trabectedin in patients with advanced soft tissue sarcoma: a retrospective national analysis of 
the French Sarcoma Group. Eur J Cancer. 2015 
50. Monck et al. JCO 2010 
51. Germano G, Frapolli R, Belgiovine C Role of macrophage targeting in the antitumor activity of 
trabectedin. Cancer Cell. 2013;23:249-62.  
52. D'Angelo SP et al. (2014). “PD-L1 expression and immune infiltrates in sarcoma”. J Clin Oncol 
32:5s, (suppl; abstr 10522)  

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53. 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): 
e82870. 
54. Shen JK et al. (2014). “Programmed cell death ligand 1 expression in osteosarcoma”. Cancer 
Immunol Res.;2:690-8.  
55. Clin Immunol. 2011 Dec;141(3):338-47. doi: 10.1016/j.clim.2011.08.013. Epub 2011 Sep 2. 
The comprehensive assessment of local immune status of ovarian cancer by the clustering of 
multiple immune factors. Hamanishi J1 
56. Hamanishi J, Mandai M, Ikeda T, Minami M, Kawaguchi A, Murayama T, Kanai M, Mori Y, 
Matsumoto S, Chikuma S, Matsumura N, Abiko K, Baba T, Yamaguchi K, Ueda A, Hosoe Y, 
Morita S, Yokode M, Shimizu A, Honjo T, Konishi I. Safety and Antitumor Activity of Anti-PD-1 
Antibody, Nivolumab, in Patients With Platinum-Resistant Ovarian Cancer. J Clin Oncol. 2015 
57. Zsiros E, Tanyi J, Balint K, Kandalaft LE. Immunotherapy for ovarian cancer: recent advances 
and perspectives. Curr Opin Oncol 2014; 26: 492-500.  
58. Edris B, Weiskopf K, Weissman IL, van de Rijn M. Flipping the script on macrophages in 
leiomyosarcoma.Oncoimmunology. 20121;1:1202-1204.  
59. Colvin EK; Tumor-associated macrophages contribute to tumor progression in ovarian cancer. 
Front Oncol. 2014 6;4:137. 
60. Zhu Y, Knolhoff BL, Meyer MA, Nywening TM, West BL, Luo J, Wang-Gillam A, Goedegebuure 
SP, Linehan DC, DeNardo DG. CSF1/CSF1R blockade reprograms tumor-infiltrating 
macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer 
models.Cancer Res. 2014;74:5057-69.   
61. Guo Z, Wang H, Meng F, Li J, Zhang S. Combined Trabectedin and anti-PD1 antibody 
produces a synergistic antitumor effect in a murine model of ovarian cancer. J Transl Med. 
2015 Jul 29;13:247. 
62. Narwal R, Roskos LK, Robbie GJ. Population pharmacokinetics of sifalimumab, an 
investigational anti-interferonalpha monoclonal antibody, in systemic lupus erythematosus. 
Clin Pharmacokinet 2013;52:1017–27. 
63. Ng CM, Lum BL, Gimenez V, Kelsey S, Allison D. Rationale for fixed dosing of pertuzumab in 
cancer patients based on population pharmacokinetic analysis. Pharm Res 2006;23(6):1275–
84. 
64. Wang DD, Zhang S, Zhao H, Men AY, Parivar K. Fixed dosing versus body size based dosing of 
monoclonal antibodies in adult clinical trials. J Clin Pharmacol 2009;49(9):1012–24. 
65. Zhang S, Shi R, Li C, Parivar K, Wang DD. Fixed dosing versus body size-based dosing of 
therapeutic peptides and proteins in adults. J Clin Pharmacol 2012;52(1):18–28. 
66. Antonia S, Goldberg S, Balmanoukian A, Narwal R, Robbins P, D’Angelo G, et al. A Phase 1 
open-label study to evaluate the safety and tolerability of MEDI4736, an anti-programmed cell 
death-ligand 1 (PD-L1) antibody, in combination with tremelimumab in patients with advanced 
non-small cell lung cancer (NSCLC). Poster presented at European Society of Medical 
Oncology (ESMO) Meeting, 2014 Sep 26-30; Madrid, Spain. 
67. M Toulmonde et al.   JAMA Oncol. 2017 Jun 29. Use of PD-1 Targeting, Macrophage 
Infiltration, and IDO Pathway Activation in Sarcomas: A Phase 2 Clinical Trial   
 
 

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16.  BIOMARKER STUDIES 
16.1. Blood sample for immunological biomarkers 
16.1.1. 
Collection of available specimen 
The main objective of this biomarker study is to explore pharmacodynamics and mechanisms of action 
of trabectedin + durvalumab as well as potential predictive biomarkers. 
Blood biomarkers method guidelines will be provided by the sponsor as a separate 
document. 
16.1.2. 
BM analysis 
For each patient, blood samples will be collected at C1D1 and at C2D1.  
- 
Immunophenotyping : 1x 4 ml sample of peripheral blood on EDTA (Purple cap tube). 
- 
Kynurenine : 1x 6  ml sample of peripheral blood on EDTA (Purple cap tube).  
- 
Cytokines : 1x6 ml sample of peripheral  blood on Heparin  (Green  cap tube).   
For more details, please refer to laboratory Guidelines. 
 
16.1.3. 
Site performing BM study 
- 
Immunophenotyping will be performed in each investigating site according to method 
guidelines provided by the sponsor as a separate document. 
 
- 
Cytokines dosage and kynurenine dosage will be performed centrally  
The samples will be stored in dedicated labeled boxes and containers labeled with coded numbers to 
ensure full compliance with privacy policy. Samples will be grouped in each institution and sent once 
and frozen for centralized processing as described in a specific SOP provided by the Sponsor. 
 
 
16.2. Blood sample for circulating DNA 
16.2.1. 
Collection of available specimen 
The main objective of this study is to analyse circulating DNA and to identify mutations observed in 
tumor tissue in the blood (liquid biopsies concept). 
Circulating DNA method guidelines regarding sample processing, storage conditions and 
shipment procedures will be provided by the sponsor as a separate document. 
 
16.2.2. 
Collection – storage and shipping procedure 
For ctDNA study, three   6 mL EDTA (Purple cap tube) samples of peripheral blood will be taken at D1 
of each cycle, until progression. Samples will be grouped in each institution and sent once and frozen 
for centralized processing to:  
Institut Bergonie – Laboratory bio pathology 
Protocol TRAMUNE 
229 cours de l’Argonne - 33076 Bordeaux Cedex, France 
 

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16.3. Tumor sample 
16.3.1. 
Collection of specimen 
For all patients, fresh pre-treatment and on-treatment (D8 cycle 2 with +/- 2 days) tumor biopsies will 
be performed (two core needle biopsy). One core needle biopsy will be formalin fixed and paraffin 
embedded [FFPE (Formalin-Fixed Paraffin-Embedded)] and one core needle biopsy will be fresh frozen 
at -80°C. 
Note: if tissue of tumor lesion from < 3 months old archival tissue sample (both frozen and paraffin-
embedded) obtained on locally advanced disease or metastasis with no subsequent treatment since; 
such tissue must be used as baseline tumor sample.  
 
16.3.2. 
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). 
16.3.3. 
Site performing analysis 
All pathological specimens sampling with documents must be sent to:  
Institut Bergonie – Pathology Unit 
Protocol TRAMUNE 
229 cours de l’Argonne 
33076 Bordeaux Cedex, France 
 
Tumor samples will be collected to explore the pharmacodynamics (PD) of trabectedin in association 
with durvalumab as well as potential predictive biomarkers of activity and efficacy. Tumor sample wille 
be analysed for : 
 Hematoxylin and eosin staining (H&E). 
 Immunohistochemistry (IHC) assessments including, but not limited to, the following markers: 
SP263 SP28-8 (PDL1), CSF-1R, CD68/CD163, CD8, MHC class I/II, CD31 (microvessel 
density), Ki67 and other exploratory markers. The analysis will be prioritized based on the 
amount of material available.  
 Genomics and transcriptomics exploratory analysis for predictive signatures in responders and 
mechanisms of resistance in non-responders. 

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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: COCKROFT FORMULA 
 
 
Creatinine clearance (ml/min) =  
   [(140-age (years)) x weight (Kg)] 
x G1  
      72 x serum creatinine (mg/dl) 
 
1G (Gender) = 0.85 if Female; 1 if Male  
 
Reference: Cockcroft, DW, Gault, H. Prediction of creatinine clearance from serum creatinine. Nephron 
1976; 16(1):31-41 [84]. 

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APPENDIX 3: 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 4: DOSING MODIFICATION AND TOXICITY MANAGEMENT GUIDELINES FOR IMMUNE-
MEDIATED, INFUSION RELATED, AND NON IMMUNE-MEDIATED REACTIONS FOR DURVALUMAB 
 
General Considerations Regarding Immune-Mediated Reactions 
These guidelines are provided as a recommendation to support investigators in the management of potential immune-
mediated adverse events (imAEs).  
 
Immune-mediated events can occur in nearly any organ or tissue, therefore, these guidelines may not include all the possible immune-
mediated reactions. Investigators are advised to take into consideration the appropriate practice guidelines and other society guidelines 
(e.g., National Comprehensive Cancer Network (NCCN), European Society of Medical Oncology (ESMO)) in the management of these events.  
Refer to the section of the table titled “Other -Immune-Mediated Reactions” for general guidance on imAEs not noted in the “Specific 
Immune-Mediated Reactions” section. 
Early identification and management of immune-mediated adverse events (imAEs) is essential to ensure safe use of the study drug.  Monitor 
patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse events. Patients with 
suspected imAEs  should be thoroughly evaluated to rule out any alternative etiologies (e.g., disease progression, concomitant medications, 
infections). In the absence of a clear alternative etiology, all such events should be managed as if they were immune-mediated.  Institute 
medical management promptly, including specialty consultation as appropriate. In general, withhold study drug/study regimen  for severe 
(Grade 3) imAEs. Permanently discontinue study drug/study regimen for life-threatening (Grade 4) imAEs, recurrent severe (Grade 3) imAEs 
that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks of initiating corticosteroids.  
 
Based on the severity of the imAE, durvalumab should be withheld and corticosteroids administered. Upon improvement to Grade ≤ 1, 
corticosteroid should be tapered over ≥ 28 days.  More potent immunosuppressive  agents such as TNF inhibitors (e.g., infliximab) should be 
considered for events not responding to systemic steroids. Alternative immunosuppressive agents not listed in this guideline may be 
considered at the discretion of the investigator based on clinical practice and relevant guidelines. With long-term steroid and other 
immunosuppressive use, consider need for Pneumocystis jirovecii pneumonia (PJP, formerly known as Pneumocystis carinii pneumonia) 
prophylaxis, gastrointestinal protection, and glucose monitoring. 
 
Dose modifications of study drug/study regimen should be based on severity of treatment-emergent toxicities graded per NCI CTCAE version 
in the applicable study protocol. 
AE Adverse event; CTC Common Toxicity Criteria; CTCAE Common Terminology Criteria for Adverse Events; imAE immune-mediated adverse event; NCI National 
Cancer Institute; NCCN  National Comprehensive Cancer Network; ESMO European Society for Medical Oncology 
 

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Adverse 
Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
 
Pneumonitis/
Interstitial 
lung 
disease 
(ILD) 
Any Grade 
(Refer to NCI CTCAE 
applicable 
version 
in 
study 
protocol 
for 
defining 
the 
CTCAE 
grade/severity) 
General Guidance  
For Any Grade: 
- 
Monitor patients for signs and symptoms of pneumonitis or ILD (new onset or worsening shortness of 
breath or cough).  Patients should be evaluated with imaging and pulmonary function tests including 
other diagnostic procedures as described below 
- 
Suspected pneumonitis should be confirmed with radiographic imaging and other infectious and 
disease-related aetiologies excluded, and managed as described below. 
- 
Initial work-up may include clinical evaluation, monitoring of oxygenation via pulse oximetry (resting 
and exertion), laboratory work-up and high-resolution computed tomography (CT) scan 
- 
Consider Pulmonary and Infectious Diseases consults. 
Grade 1  
 
No dose modification required. However, 
consider 
holding 
study 
drug/study 
regimen dose as clinically appropriate 
and during diagnostic work-up for other 
etiologies 
For Grade 1  
- 
Monitor and closely follow up in 2-4 days for clinical symptoms, pulse oximetry (resting and exertion) 
and laboratory work-up and then as clinically indicated 
Grade 2  
 
Hold study drug/study regimen dose 
until Grade 2 resolution to ≤ Grade 1 
• 
If  toxicity worsens then treat as 
Grade 3 or Grade 4  
• 
If toxicity improves to Grade ≤ 1 
then the decision to reinitiate study 
drug/regimen will be based upon 
treating physician’s clinical judgment 
and after completion of steroid 
taper.  
Study drug/study treatment can be 
resumed at the next scheduled dose 
once event stabilizes to grade ≤1 and 5-
7 days have passed after completion of 
steroid taper   
For Grade 2  
- 
Monitor symptoms daily and consider hospitalization 
- 
Obtain Pulmonary and Infectious Diseases Consults; consider discussing with Clinical Study Lead, as 
needed 
- 
Promptly start systemic steroids (e.g., prednisone 1 to 2mg/kg/day PO or IV equivalent) 
- 
Reimaging as clinically indicated, consider Chest CT with contrast and repeat in 3-4 weeks 
- 
If no improvement within 2 to 3 days, additional workup should be considered and prompt treatment 
with IV methylprednisolone 2 to 4mg/kg/day started  
- 
If no improvement within 2 to 3 days despite IV methylprednisolone at 2 to 4 mg/kg/day, promptly 
start immunosuppressive therapy such as tumor necrosis factor (TNF) inhibitors (e.g. infliximab at 5 
mg/kg IV once, may be repeated at 2 and 6 weeks after initial dose at the discretion of the treating 
provider or relevant practice guidelines). Caution: It is important to rule out sepsis and refer to 
infliximab label for general guidance before using infliximab  
- 
Consider as necessary discussing with Clinical Study Lead 
Grade 3 or 4  
  
Permanently discontinue study 
drug/study regimen 
For Grade 3 or 4  
- 
Promptly initiate empiric IV methylprednisolone 1 to 4 mg/kg/day or equivalent  
- 
Obtain pulmonary and infectious disease consults; consider, as necessary, discussing with Clinical Study 
Lead. 
- 
Hospitalize the patient 
- 
Supportive Care (e.g. oxygen) 
- 
If no improvement within 2 to 3 days, additional workup should be considered and prompt treatment 
with additional immunosuppressive therapy such as TNF inhibitors (e.g. infliximab at 5 mg/kgIV, may 
be repeated at 2 and 6 weeks after initial dose at the discretion of the treating provider or relevant 
practice guidelines) started. Caution: rule out sepsis and refer to infliximab label for general guidance 

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Adverse 
Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
before using infliximab  
 
Adverse 
Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Diarrhea/ 
Colitis 
Large 
intestine 
perforation / 
Intestine 
perforation 
Any Grade 
(Refer to NCI CTCAE 
applicable version in 
study protocol for 
defining the CTCAE 
grade/severity) 
General Guidance  
For Any Grade: 
- 
Monitor for symptoms that may be related to diarrhea/enterocolitis (abdominal pain, cramping, or 
changes in bowel habits such as increased frequency over baseline or blood in stool) or related to 
bowel perforation (such as sepsis, peritoneal signs and ileus) 
- 
When symptoms or evaluation indicate an intestinal perforation is suspected, consult a surgeon 
experienced in abdominal surgery immediately without any delay 
- 
Permanently discontinue study drug for any grade of intestinal perforation 
- 
Patients should be thoroughly evaluated to rule out any alternative etiology (e.g., disease progression, 
other medications, or infections) including testing for clostridium difficile toxin, etc.) 
- 
Steroids should be considered in the absence of clear alternative etiology, even for low grade events, 
in order to prevent potential progression to higher grade event, including intestinal perforation 
- 
Use analgesics carefully; they can mask symptoms of perforation and peritonitis 
Grade 1   
 
No dose modification 
For Grade 1 :  
- 
Monitor closely  for worsening symptoms 
- 
Consider symptomatic treatment, including hydration, electrolyte replacement, dietary changes (e.g., 
American Dietetic Association colitis diet), loperamide and other supportive care measures.  
- 
If symptoms persist, consider checking lactoferrin; if positive, treat as Grade 2 below. If negative and 
no infection, continue Grade 1 management. 
Grade 2  
 
Hold study drug/study regimen until 
resolution to Grade ≤ 1 
• If  toxicity worsens then treat as 
Grade 3 or Grade 4 
• If toxicity improves to Grade ≤ 1, 
then  study drug/study regimen can 
be 
resumedafter 
completion 
of 
steroid taper    
For Grade 2:  
- 
Consider symptomatic treatment, including hydration, electrolyte replacement, dietary changes (e.g., 
American Dietetic Association colitis diet), and loperamide and/or budesonide  
- 
Promptly start  prednisone 1 to 2 mg/kg/day PO or IV equivalent  
- 
If event is not responsive within 2 to 3 days or worsens despite prednisone at 1 to 2 mg/kg/day PO or 
IV equivalent, consult a gastrointestinal (GI) specialist for consideration of further workup such as 
imaging and/or colonoscopy to confirm colitis and rule out perforation,  
- 
If still no improvement within 2 to 3 days despite 1 to 2mg/kg IV methylprednisolone, promptly start 
immunosuppressant agent  such as infliximab at 5mg/kg IV, may be repeated at 2 and 6 weeks after 
initial dose at the discretion of the treating provider or relevant practice guidelines.   
Caution: Important to rule out bowel perforation and refer to infliximab label for general guidance 
before using infliximab   
- 
If perforation is suspected, consult a surgeon experienced in abdominal surgery immediately without 
any delay 
- 
Consider, as necessary, discussing with Clinical Study Lead if no resolution to Grade ≤ 1 in 3 to 4 days 
 

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Grade 3 or 4  
 
Grade 3:  
 
Hold study drug/study regimen until 
resolution 
to 
grade≤1; 
study 
drug/study regimen can be resumed 
after completion of steroid taper. 
 
Permanently discontinue study 
drug/study regimen if toxicity does not 
improve to Grade ≤1 within 14 days;  
 
 
Grade 4: 
Permanently 
discontinue 
study 
drug/study regimen  
For Grade 3 or 4: 
- 
Promptly initiate empiric IV methylprednisolone 1 to 2 mg/kg/day or equivalent  
- 
Monitor stool frequency and volume and maintain hydration   
- 
Urgent GI consult and imaging and/or colonoscopy as appropriate 
- 
If still no improvement within 2 days, continue steroids and , promptly add further 
immunosuppressives (e.g. infliximab at 5mg/kg IV, may be repeated at 2 and 6 weeks after initial 
dose at the discretion of the treating provider or relevant practice guidelines).    Caution: Ensure GI 
consult to rule out bowel perforation and refer to infliximab label for general guidance before using 
infliximab.  
- 
If perforation is suspected, consult a surgeon experienced in abdominal surgery immediately without 
any delay 
 
 

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Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Hepatitis (Elevated 
Liver function 
tests (LFTs)) 
Infliximab should 
not be used for 
management of 
Immune Related 
Hepatitis 
 
 
Any Grade 
(Refer to NCI CTCAE 
applicable version in study 
protocol for defining the 
CTCAE grade/severity) 
 
General guidance  
For Any Grade 
- 
Monitor and evaluate LFTs: aspartate aminotransferase (AST), alanine Aminotransferase (ALT), 
alkaline phosphatase (ALP) and total bilirubin  
- Evaluate for alternative etiologies (e.g., viral hepatitis, disease progression, concomitant 
medications)  
Grade 1  
 
No dose modification 
If it worsens, consider holding therapy 
- Continue LFT monitoring per protocol   
Grade 2  
 
Hold Study drug/study regimen 
dose until resolution to Grade ≤ 1 
 
If toxicity worsens, then treat as 
Grade 3 or grade 4. 
 
If toxicity improves to Grade ≤1 or 
baselin and there were no 
elevations in bilirubine, resume 
study drug / study regimen after 
completion of steroid taper (<10 
mg prednisone or equivalent). 
Permanently 
discontinue 
study 
drug/study 
regimen 
for 
any 
case 
meeting Hy’s law criteria (AST and/or 
ALT >3 × ULN + bilirubin >2 × ULN 
without initial findings of cholestasis 
(i.e., elevated ALP) and in the absence 
of any alternative cause 
- 
Regular and frequent checking of LFTs (e.g., every 1 to 2 days) until LFT elevations improve or 
resolve. 
- 
If no resolution to ≤Grade 1 in 1 to 2 days, consider, as necessary, discussing with Clinical 
Study Lead. 
- 
If event is persistent (>2 to 3 days) or worsens, promptly start prednisone 1 to 2 mg/kg/day PO 
or IV equivalent. 
- 
Restart once resolved to Grade ≤1 WITH DOSE REDUCTION FOR TRABECTEDIN 
- 
Keep checking transaminitis twice weekly for the next cycle 
Grade 3:  
 
 
 
Hold study drug/study regimen For 
elevations in transaminases ≤8 × 
ULN (and no elevations in 
bilirubin), or elevations in bilirubin 
≤5 × ULN until resolution to Grade 
<1 or baseline  
 
Permanently discontinue study 
drug/study regimen for elevations 
in transaminases >8 × ULN or any 
elevations in bilirubin >5 × ULN 
For Grade 3 or 4 
 
- 
Promptly initiate empiric IV methylprednisolone at 1 to 2 mg/kg/day or equivalent. 
- 
If still no improvement within 2 to 3 days despite 1 to 2 mg/kg/day methylprednisolone IV or 
equivalent, promptly start treatment with an immunosuppressant therapy (i.e., mycophenolate 
mofetil 0.5-1 g every 12 hours then taper in consultation with hepatology consult or relevant 
practice guidelines). Discuss with Clinical Study Lead if mycophenolate is not available. 
Infliximab should NOT be used. 
- 
Perform Hepatology consult, abdominal workup and imaging as appropriate. 

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Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
- Dose modification for Trabectedin is 
mandatory if grade 3 
If No decreasing of Transaminitis  
kinetic within the 4th week after 
previous infusion, permanently 
discontinue entire study regimen 
 
 
Grade 4 
 
Permanently 
discontinue 
study 
drug/study 
 
 
 
 
 
 
Hepatitis  
(elevated LFTs) 
Any Elevations of AST, 
ALT, or TB as 
Described Below 
General Guidance 
For Any Elevations Described 
 
Infliximab should not 
be 
used 
for 
management 
of 
immune-related 
hepatitis.  
See instructions at  
bottom of shaded area  
if transaminase rise is  
not isolated but (at any 
time) occurs in setting  
 
 
- 
Monitor and evaluate liver function test: AST, ALT, ALP, and TB. 
- 
Evaluate for alternative etiologies (e.g., viral hepatitis, disease progression, concomitant 
medications, worsening of liver cirrhosis [e.g., portal vein thrombosis]). 
- 
For hepatitis B (HBV)+ patients: evaluate quantitative HBV viral load, quantitative Hepatitis B 
surface antigen (HBsAg), or Hepatitis B envelope antigen (HBeAg). 
- 
For hepatitis C (HCV)+ patients: evaluate quantitative HCV viral load. 
- 
Consider consulting Hepatology or Infectious Diseases specialists regarding changing or 
starting antiviral HBV medications if HBV viral load is >2000 IU/ml. 
- 
Consider consulting Hepatology or Infectious Diseases specialists regarding changing or 
starting antiviral HCV medications if HCV viral load has increased by ≥2-fold. 
- 
For HCV+ with Hepatitis B core antibody (HBcAb)+: Evaluate for both HBV and HCV as 
above. 
Isolated AST or ALT 
>ULN and ≤5.0×ULN, 
whether normal or 
elevated at baseline  
 
No dose modifications. 
 
If ALT/AST elevations represents 
significant worsening based on 
investigator assessment, then 
treat as described for elevations in 
the row below. 
For all  transaminase elevations , see 
instructions at bottom of shaded area 
if transaminase rise is not isolated but 
 
THIS 
shaded 
area is guidance 
only 
for 
management of 
“Hepatitis 
(elevated LFTs)” 
in HCC patients  

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Hepatitis  
(elevated LFTs) 
Any Elevations of AST, 
ALT, or TB as 
Described Below 
General Guidance 
For Any Elevations Described 
 
of either increasing 
bilirubin or signs of 
DILI/liver 
decompensation 
(at any time) occurs in setting of 
either increasing bilirubin or signs 
of DILI/liver decompensation 
Isolated AST or ALT 
>5.0×ULN and 
≤8.0×ULN, if normal at 
baseline 
 
Isolated AST or ALT 
>2.0×baseline and 
≤12.5×ULN, if elevated 
>ULN at baseline 
 
Hold study drug/study regimen 
dose until resolution to AST or 
ALT ≤5.0×ULN. 
 
If toxicity worsens, then treat as 
described for elevations in the 
rows below.If toxicity improves to 
AST or ALT ≤5.0×ULN, resume 
study drug/study regimen after 
completion of steroid taper. (<10 
mg prednisone, or equivalent) 
Permanently 
discontinue 
study 
drug/study regimen for any case 
meeting Hy’s law criteria, in the 
absence of any alternative cause.b 
- 
Regular and frequent checking of LFTs (e.g., every 1 to 3 days) until elevations of these are 
improving or resolved. 
- 
Recommend consult hepatologist; consider abdominal ultrasound, including Doppler 
assessment of liver perfusion. 
- 
Consider, as necessary, discussing with Clinical Study Lead. 
- 
If event is persistent (>2 to 3 days) or worsens, and investigator suspects toxicity to be an 
imAE, start prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
- 
If still no improvement within 2 to 3 days despite 1 to 2 mg/kg/day of prednisone PO or IV 
equivalent, consider additional workup.  
- 
If still no improvement within 2 to 3 days despite 1 to 2mg/kg/day of IV methylprednisolone, 
consider additional abdominal workup (including liver biopsy) and imaging (i.e., liver 
ultrasound), and consider starting immunosuppressants (e.g., mycophenolate mofetil 0.5 – 1 
g every 12 hours then taper in consultation with hepatology consult or relevant practice 
guidelines).a Discuss with Clinical Study Lead if mycophenolate mofetil is not available. 
Infliximab should NOT be used 
Isolated AST or ALT 
>8.0×ULN and 
≤20.0×ULN, if normal at 
baseline 
 
Isolated AST or ALT 
>12.5×ULN and 
≤20.0×ULN, if  elevated 
>ULN at baseline 
 
Hold study drug/study regimen 
dose until resolution to AST or 
ALT ≤5.0×ULN Resume study 
drug/study regimen if elevations 
downgrade to AST or ALT 
≤5.0×ULN  within 14 days and 
after completion of steroid taper 
(<10 mg prednisone, or 
equivalent). 
 
Permanently discontinue study 
drug/study regimen if the 
elevations do not downgrade to  
AST or ALT ≤5.0×ULN within 
14 days 
- 
Regular and frequent checking of LFTs (e.g., every 1-2 days) until elevations of these are 
improving or resolved. 
- 
Consult hepatologist (unless investigator is hepatologist); obtain abdominal ultrasound, 
including Doppler assessment of liver perfusion; and consider liver biopsy. 
- 
Consider discussing with Clinical Study Lead, as needed. 
- 
If investigator suspects toxicity to be immune-mediated, promptly initiate empiric IV 
methylprednisolone at 1 to 2 mg/kg/day or equivalent. 
- 
If no improvement within 2 to 3 days despite 1 to 2 mg/kg/day methylprednisolone IV or 
equivalent, obtain liver biopsy (if it has not been done already) and promptly start treatment 
with an immunosuppressant (e.g, mycophenolate mofetil 0.5 – 1 g every 12 hours then taper 
in consultation with a hepatologist or relevant practice guidelines)). Discuss with study 
physician if mycophenolate is not available. Infliximab should NOT be used. 
Isolated AST or ALT 
>20×ULN,  whether 
normal or elevated at 
baseline 
Permanently 
discontinue 
study 
drug/study regimen. 
Same as above 
(except would recommend obtaining liver biopsy early) 
 
If transaminase rise is not isolated but (at any time) occurs in setting of either increasing total/direct bilirubin (≥1.5×ULN, if normal at baseline; or 
2×baseline, if >ULN at baseline) or signs of DILI/liver decompensation (e.g., fever, elevated INR): 
- 
Manage dosing for each level of transaminase rise as instructed for the next highest level of transaminase riseFor example, manage dosing for second 

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Hepatitis  
(elevated LFTs) 
Any Elevations of AST, 
ALT, or TB as 
Described Below 
General Guidance 
For Any Elevations Described 
 
level of transaminase rise (i.e., AST or ALT >5.0×ULN and ≤8.0×ULN, if normal at baseline, or AST or ALT >2.0×baseline and ≤12.5×ULN, if elevated 
>ULN at baseline) as instructed for the third level of transaminase rise (i.e., AST or ALT >8.0×ULN and ≤20.0×ULN, if normal at baseline, or AST or ALT 
>12.5×ULN and ≤20.0×ULN, if  elevated >ULN at baseline) 
- 
For the third and fourth levels of transaminase rises, permanently discontinue study drug/study regimen 
 
 
 
 

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Adverse 
Events 
Severity Grade of the Event 
(NCI CTCAE version 4.03) 
Dose Modifications 
Toxicity Management 
Nephritis 
or 
Renal 
Dysfunction 
(Elevated 
Serum 
Creatinine) 
Any Grade  
(Refer to NCI CTCAE applicable 
version in study protocol for 
defining the CTCAE 
grade/severity) 
General Guidance 
 
 
 
For Any Grade: 
- 
Consult Nephrologist 
- 
Monitor for signs and symptoms that may be related to changes in renal function (e.g. routine urinalysis, 
elevated serum BUN and creatinine, decreased creatinine clearance, electrolyte imbalance, decrease in urine 
output, or proteinuria)  
- 
Patients should be thoroughly evaluated to rule out any alternative etiology (e.g., disease progression  
infections, recent IV contrast, medications, fluid status) 
- Consider using steroids in the absence of clear alternative etiology even for low grade events (Grade 2), in 
order to prevent potential progression to higher grade event 
Grade 1  
 
No dose modification 
For Grade 1:  
- 
Monitor serum creatinine weekly and any accompanying symptom 
 If creatinine returns to baseline, resume its regular monitoring per study protocol. 
 If it worsens, depending on the severity , treat as Grade 2 or Grade 3 or 4  
- Consider symptomatic treatment including hydration, electrolyte replacement and diuretics 
- 
If baseline serum creatinine is elevated above normal, and there is a rise to > 1 to 1.5 × baseline, consider 
following recommendations in this row. 
Grade 2  
 
Hold study drug/study regimen 
until resolution to Grade ≤ 1 or 
baseline 
• If toxicity worsens then treat 
as Grade 3 or Grade 4 
• If toxicity improves to  Grade 
≤ 1 or baseline then resume 
study 
drug/study 
regimen 
after completion of steroid 
taper   
For Grade 2:  
- 
Consider symptomatic treatment including hydration, electrolyte replacement, diuretics,   
- 
Carefully monitor serum creatinine every 2 to 3 days and as clinically warranted 
- 
Consult Nephrologist and consider renal biopsy if clinically indicated 
- 
If event is persistent beyond  3 to 5 days or worsens, promptly start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent  
- 
If event is not responsive within 3 to 5 days or worsens despite prednisone at 1 to 2 mg/kg/day PO or IV 
equivalent, consider additional workup  
- 
When event returns to baseline, resume study drug/study regimen and routine serum creatinine monitoring 
per study protocol 
Grade 3 or 4  
  
Permanently discontinue study 
drug/study regimen 
For Grade 3 or 4: 
- 
Carefully monitor serum creatinine   
- 
Consult Nephrologist and consider renal biopsy if clinically indicated 
- 
Promptly start prednisone 1 to 2 mg/kg/day PO or IV equivalent  
- 
If event is not responsive within 3 to 5 days or worsens despite prednisone at 1 to 2 mg/kg/day PO or IV 
equivalent, consider additional workup and prompt treatment with  an immunosuppressant in consultation 
with a nephrologist 
Adverse 
Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Rash or 
dermatitis 
(including 
Any Grade  
 
(refer to NCI CTCAE v 5 for 
definition of severity/grade 
depending on type of skin 
General Guidance  
For Any Grade: 
- 
Monitor for signs and symptoms of dermatitis (rash and pruritus)  
- 
HOLD STUDY DRUG IF STEVENS-JOHNSON SYNDROME (SJS), TOXIC EPIDERMAL NECROLYSIS 
(TEN), OR OTHER  SEVERE CUTANEOUS ADVERSE REACTION (SCAR) IS SUSPECTED.  

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Pemphigoid) 
rash) 
- 
PERMANENTLY DISCONTINUE STUDY DRUG IF SJS, TEN, OR SCAR IS CONFIRMED. 
Grade 1  
No dose modification 
For Grade 1: 
- 
Consider symptomatic treatment including oral antipruritics (e.g., diphenhydramine or hydroxyzine) and 
topical therapy (e.g.,emolient, lotion, or institutional standard ) 
Grade 2 
For persistent (> 1  week) 
Grade 2 events, hold scheduled 
study drug/study regimen until 
resolution to Grade ≤ 1 or 
baseline  
 If toxicity worsens then treat 
as Grade 3  
 If toxicity improves to Grade 
≤1 or baseline, then resume 
drug/study 
regimen 
after 
completion of steroid taper 
(<10 
mg 
prednisone, 
or 
equivalent) 
For Grade 2 : 
- 
Obtain dermatology consult  
- 
Consider symptomatic treatment including oral antipruritics (e.g., diphenhydramine or hydroxyzine) and 
topical therapy  
- 
Consider moderate-strength topical steroid  
- 
If no improvement of rash/skin lesions occurs within 3 days or is worsening despite symptomatic treatment 
and/or use of moderate strength topical steroid, consider discussing with Clinical Study Lead as needed and 
promptly start systemic steroids such as prednisone 1 to 2 mg/kg/day PO or IV equivalent. If > 30% body 
surface area is involved, consider initiation of systemic steroids promptly. 
- 
Consider skin biopsy if the event persists for >1  week or recurs 
Grade 3 or 4 
For Grade 3: 
Hold study drug/study regimen 
until resolution to Grade ≤1 or 
baseline 
 If toxicity improves to Grade 
≤1 or baseline, then resume 
drug/study 
regimen 
after 
completion of steroid taper 
(<10 
mg 
prednisone, 
or 
equivalent). 
 If toxicity worsens, then treat 
as Grade 4. 
 
 
For Grade 4: 
Permanently discontinue study 
drug/study regimen 
For Grade 3 or 4: 
- 
Consult dermatology  
- 
Promptly initiate empiric IV methylprednisolone 1 to 2 mg/kg/day or equivalent  
- 
Consider hospitalization 
- 
Monitor extent of rash [Rule of Nines] 
- 
Consider skin biopsy (preferably more than 1) as clinically feasible. 
- 
Consider, as necessary, discussing with Clinical Study Lead.  
 

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Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Endocrinopathy 
(e.g., 
hyperthyroidism, 
thyroiditis, 
hypothyroidism, 
hypopituitarism, 
adrenal 
insufficiency, type I 
diabete mellitus, 
hypophysitis;) 
 
Any Grade  
(Depending on the type of 
endocrinopathy, refer to 
NCI CTCAE version 4.03 
for defining the CTCAE 
grade/severity)  
General Guidance 
For Any Grade: 
- 
Consult Endocrinologist for endocrine events. 
- 
Consider, as necessary, discussing with Clinical Study Lead,. 
- 
Monitor patients for signs and symptoms of endocrinopathies. Non-specific symptoms include 
headache, fatigue, behavior changes, mental status changes, photophobia, visual field cuts, vertigo, 
abdominal pain, unusual bowel habits, polydipsia, polyuria, hypotension and weakness. 
- 
Patients should be thoroughly evaluated to rule out any alternative etiology (e.g., disease progression 
including brain metastases, or infections) 
- 
Depending on the suspected endocrinopathy, monitor and evaluate thyroid function tests: thyroid 
stimulating hormone (TSH), free T3 and free T4 and other relevant endocrine and related labs (e.g., 
blood glucose and ketone levels, hemoglobin A1c (HgA1c). 
- 
If a patient experiences an AE that is thought to be possibly of autoimmune nature (e.g., thyroiditis, 
pancreatitis, hypophysitis, diabetes insipidus), the investigator should send a blood sample for 
appropriate autoimmune antibody testing  
- 
Investigators should ask subjects with endocrinopathies who may require prolonged or continued 
hormonal replacement, to consult their primary care physicians or endocrinologists about further 
monitoring and treatment after completion of the study. 
Grade 1 
 
No dose modification 
For Grade 1: 
- 
Monitor patient with appropriate endocrine function tests 
- 
For suspected hypophysitis/hypopituitarism, consider consultating of an endocrinologist to guide 
assessment of early-morning adrenocorticotropin hormone (ACTH), cortisol, TSH and free T4; also 
consider gonadotropins, sex hormones, and prolactin levels, as well as cosyntropin stimulation test 
(though it may not be useful in diagnosing early secondary adrenal insufficiency). 
- If TSH < 0.5x LLN, or TSH >2x ULN or consistently out of range in 2 subsequent measurements, 
include free T4 at subsequent cycles as clinically indicated and consider endocrinology consult. 
Grade 2, 3 or 4 
 
For Grade 2-4 
  endocrinopathies 
other 
than 
hypothyroidism 
and 
Type 
I 
Diabetes 
mellitus, 
consider 
holding study drug/study regimen 
dose until  acute symptoms 
resolve 
 Study drug/study regimen can be 
resumed once patient stabilizes 
and after completion of steroid 
taper (<10 mg prednisone, or 
equivalent) 
 
Patients with endocrinopathies who 
may require prolonged or continued 
steroid replacement (e.g. adrenal 
insufficiency) can be retreated with 
study drug/study regimen if patient 
For Grade 2, 3 or 4 : 
- 
Consult endocrinologist to guide evaluation of endocrine function, and as indicated by suspected 
endocrinopathy and as clinically indicated, consider pituitary scan 
- 
For all patients with abnormal endocrine work up, except those with isolated hypothyroidism or Type 1 
DM, and as guided by an endocrinologist, consider short-term, corticosteroids (e.g., 1 to 2mg/kg/day 
methylprednisolone or IV equivalent) and prompt initiation of treatment with relevant hormone 
replacement (e.g. hydrocortisone, sex hormones) 
- 
Isolated hypothyroidism may be treated with replacement therapy, without study drug/study regimen 
interruption, and without corticosteroids. 
- 
Isolated Type 1 diabetes mellitus (DM) may be treated with appropriate diabetic therapy, and without 
corticosteroids. Only hold study drug/study regimen in setting of hyperglycemia when diagnostic 
workup is positive for diabetic ketoacidosis. 
- 
For patients with normal endocrine work up (laboratory assessment or magnetic resonance imaging 
(MRI) scans), repeat laboratory assessment/MRI as clinically indicated. 

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is clinically stable as per Investigator 
or 
treating 
physician’s 
clinical 
judgement, If toxicity worsens, then 
treat based on severity 
If toxicity worsens, then treat based 
on severity 
 
 
 
Adverse 
Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Amylase/Lipase 
Increased  
 
Any Grade 
(Refer to NCI CTCAE 
applicable version in 
study protocol for 
defining the CTCAE 
grade/severity) 
 
 
For Any Grade 
- 
For modest asymptomatic elevations in serum amylase and lipase, corticosteroid treatment is not 
indicated as long as there are no other signs or symptoms of pancreatic inflammation.  
- 
Assess for signs/symptoms of pancreatitis  
- 
Consider appropriate diagnostic testing (e.g., abdominal CT with contrast, MRCP if clinical suspicion of 
pancreatitis and no radiologic evidence on CT) 
- 
If isolated elevation of enzymes without evidence of pancreatitis, continue immunotherapy.  Consider 
other causes of elevated amylase/lipase 
- 
If evidence of pancreatitis, manage according to pancreatitis recommendations 
Grade 1 
No dose modifications. 
 
Grade 2,3 or 4 
For Grade 2,3, or 4 
 In consultation with relevant pancreatic 
specialist 
consider 
continuing 
study 
drug/study regimen if no clinical/radiologic 
evidence of pancreatitis ± improvement in 
amylase/lipase. 
Acute 
Pancreatitis 
Any Grade 
 
For Any Grade 
Consider Gastroenterology referral 
Grade 1 
No dose modifications 
For Grade 1 
- 
IV hydration 
- 
Manage as per amylase/lipase increased (asymptomatic) 

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Grade 2, 3, or 4 
For Grade 2 
Hold study drug/study regimen dose until 
resolution to Grade ≤1. 
If toxicity improves to Grade <1 or 
baseline, then resume study drug/study 
regimen after completion of steroid taper 
(<10 mg prednisone, or equivalent). 
 
For Grade 3 or 4 
Permanently discontinue study drug/study 
regimen. 
 
For Grade 2, 3, or 4 
- 
Promptly start systemic steroids prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
- 
IV hydration 

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Adverse 
Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Neurotoxicity 
(to include but 
not limited to 
non-infection 
meningitis, non 
infectious 
encephalitis and 
. autonomic 
neuropathy, 
excluding 
Myasthenia 
Gravis and 
Guillain-Barre) 
Any Grade 
(Depending on the type 
of neurotoxicity, refer to 
NCI CTCAE version 4.03 
for defining the CTCAE 
grade/severity) 
General Guidance 
For Any Grade: 
- 
Patients should be evaluated to rule out any alternative etiology (e.g., disease progression, infections, 
metabolic syndromes and medications)  
- 
Monitor patient  for general symptoms (headache, nausea, vertigo, behavior change, or weakness) 
- 
Consider appropriate diagnostic testing (e.g. electromyogram and nerve conduction investigations) 
- Perform symptomatic treatment with neurological consult as appropriate 
- FOR TRANSVERSE MYELITIS, PERMANENTLY DISCONTINUE FOR ANY GRADE. 
Grade 1 
No dose modification 
For Grade 1: 
See “Any Grade” recommendations above. 
Treat mild signs/symptoms as Grade 1 (e.g.  loss of deep tendon reflexes or paresthesia) 
Grade 2 
For 
acute 
motor 
neuropathies 
or  
neurotoxicity, 
hold 
study 
drug/study 
regimen dose until resolution to Grade ≤ 1 
For sensory neuropathy/ neuropathic pain, 
consider holding study drug/study regimen 
dose until resolution to Grade ≤ 1 
Permanently discontinue study drug/study 
regimen if Grade 2 imAE does not resolve 
to Grade ≤1 within 30 days. 
If toxicity worsens then treat as Grade 3 
or Grade 4  
 
For Grade 2: 
- 
Consider, as necessary, discussing with the Clinical Study Lead  
- 
Obtain Neurology Consult  
- 
Sensory neuropathy/neuropathic pain may be managed by appropriate medications (e.g., gabapentin, 
duloxetine) 
- 
Promptly start systemic steroids prednisone 1 to 2mg/kg/day PO or IV equivalent  
- 
If no improvement within 2 to 3 days despite 1 to 2mg/kg/day prednisone PO or IV equivalent 
consider additional workup and promptly treat with an additional immunosuppressive therapy (e.g. IV 
IG or other immunosuppressant depending on the specific imAE).).  
 
Grade 3 or 4 
For Grade 3 or 4: 
 
Permanently discontinue study drug/study 
regimen 
For Grade 3 or 4: 
- 
Consider, as necessary, discussing with the Clinical Study Lead Obtain Neurology Consult 
- 
Consider hospitalization 
- 
Promptly initiate empiric IV methylprednisolone 1 to 2 mg/kg/day or equivalent  
- 
If no improvement within 2 to 3 days despite IV corticosteroids, consider additional workup and 
promptly treat with an additional immunosuppressant (e.g. IV IG or other immunosuppressant 
depending on the specific imAE)  
- Once stable, gradually taper steroids over ≥28 days  
 

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Adverse 
Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Peripheral 
neuromotor 
syndromes 
(such 
as 
Guillain-Barre 
and Myasthenia 
Gravis) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Any Grade 
(Refer to NCI CTCAE 
applicable version in study 
protocol for defining the 
CTCAE grade/severity) 
General Guidance  
For Any Grade: 
- 
The prompt diagnosis of immune-mediated peripheral neuromotor syndromes is important, since 
certain patients may unpredictably experience acute decompensations which can result in 
substantial morbidity or in the worst case, death. Special care should be taken for certain sentinel 
symptoms which may predict a more severe outcome, such as prominent dysphagia, rapidly 
progressive weakness, and signs of respiratory insufficiency or autonomic instability 
 
- 
Patients should be evaluated to rule out any alternative etiology (e.g., disease progression, 
infections, metabolic syndromes and medications). It should be noted that the diagnosis of immune-
mediated peripheral neuromotor syndromes can be particularly challenging in patients with 
underlying cancer, due to the multiple potential confounding effects of cancer (and its treatments) 
throughout the neuraxis. Given the importance of prompt and accurate diagnosis, it is essential to 
have a low threshold to obtain a neurological consult 
 
- 
Neurophysiologic diagnostic testing (e.g., electromyogram and nerve conduction investigations, and  
“repetitive stimulation” if myasthenia is suspected) are routinely indicated upon suspicion of such 
conditions and may be best facilitated by means of a neurology consultation  
 
- Important to consider that the use of steroids as the primary treatment of Guillain-Barre is not 
typically considered effective. Patients requiring treatment should be started  with IV IG and 
followed by plasmapheresis if not responsive to IV IG  
Grade 1 
 
No dose modification 
For Grade 1: 
- 
Consider discussing with the Clinical Study Lead, as needed.  
- 
Care should be taken to monitor patients for sentinel symptoms of a potential decompensation as 
described above 
- Consult a neurologist  
Grade 2 
 
Hold study drug/study regimen dose until 
resolution to  Grade ≤ 1 
Permanently discontinue study drug/study 
regimen if it does not resolve to ≤ Grade 1 
within 30 days or if there are signs of 
respiratory 
insufficiency 
or 
autonomic 
instability 
 
For Grade 2:  
- 
Consider discussing with the Clinical Study Lead, as needed. Care should be taken to monitor 
patients for sentinel symptoms of a potential decompensation as described above 
- 
Consult a neurologist 
- 
Sensory neuropathy/neuropathic pain may be managed by appropriate medications (e.g., 
gabapentin or duloxetine) 
 
MYASTHENIA GRAVIS: 
o Steroids may be successfully used to treat Myasthenia Gravis. Important to consider that steroid 
therapy (especially with high doses) may result in transient worsening of myasthenia and should 
typically be administered in a monitored setting under supervision of a consulting neurologist 
o Patients unable to tolerate steroids may be candidates for treatment with plasmapheresis or IVIG. 
Such decisions are best made in consultation with a neurologist, taking into account the unique 
needs of each patient. 
o If Myasthenia Gravis-like neurotoxicity is present, consider starting acetylcholine esterase (AChE) 
inhibitor therapy in addition to steroids. Such therapy, if successful, can also serve to reinforce the 
diagnosis 

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o Avoid medications that can worsen myasthenia gravis (e.g. some antibiotics, beta blockers, 
calcium channel blockers, muscle relaxants). 
GUILLAIN-BARRE:  
o It is important to consider here that the use of steroids as the primary treatment of Guillain-Barre 
is not typically considered effective.  
o Patients requiring treatment should be started with IVIG and followed by plasmapheresis if not 
responsive to IVIG 
Grade 3 or 4 
 
For Grade 3: 
Hold study drug/study regimen dose until 
resolution to Grade ≤1 
 
Permanently discontinue study drug/study 
regimen if Grade 3  
imAE does not resolve to Grade ≤ 1 within 
30 days or if there are signs of respiratory 
insufficiency or autonomic instability 
 
For Grade 4: 
Permanently discontinue study 
drug/study regimen 
For Grade 3 or 4 :  
- 
Consider discussing with Clinical Study Lead, as needed 
- 
Recommend hospitalization 
- 
Monitor symptoms and obtain neurological consult 
 
MYASTHENIA GRAVIS: 
o Steroids may be successfully used to treat Myasthenia Gravis. It should typically be administered 
in a monitored setting under supervision of a consulting neurologist. 
o Patients unable to tolerate steroids may be candidates for treatment with plasmapheresis or IVIG. 
o If Myasthenia Gravis-like neurotoxicity present, consider starting acetylcholine esterase (AChE) 
inhibitor therapy in addition to steroids. Such therapy, if successful, can also serve to reinforce the 
diagnosis. 
o Avoid medications that can worsen myasthenia gravis (e.g. some antibiotics, beta blockers, 
calcium channel blockers, muscle relaxants). 
GUILLAIN-BARRE: 
o It is important to consider here that the use of steroids as the primary treatment of Guillain-Barre 
is not typically considered effective.  
o Patients requiring treatment should be started with IVIG and followed by plasmapheresis if not 
responsive to IVIG 
 
 
 
 

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Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Myocarditis 
Any Grade 
(Refer to NCI CTCAE 
applicable version in 
study protocol for 
defining the CTCAE 
grade/severity) 
General Guidance  
Discontinue drug permanently if biopsy-
proven immune-mediated myocarditis 
For Any Grade: 
− The prompt diagnosis of immune-mediated myocarditis is important, particularly in patients with 
baseline cardiopulmonary disease and reduced cardiac function.  
− Consider discussing with the Clinical Study Lead, as needed. 
− Monitor patients for signs and symptoms of myocarditis (new onset or worsening chest pain, 
arrhythmia, shortness of breath, peripheral edema). As some symptoms can overlap with lung 
toxicities, simultaneously evaluate for and rule out pulmonary toxicity as well as other causes 
(e.g., pulmonary embolism, congestive heart failure, malignant pericardial effusion). Consult a 
cardiologist early, to promptly assess of whether and when to complete a cardiac biopsy, 
including any other diagnostic procedures. 
− Initial work-up should include clinical evaluation, B-type natriuretic peptide (BNP), cardiac 
enzymes, electrocardiogram (ECG), echocardiogram (ECHO), monitoring of oxygenation via pulse 
oximetry (resting and exertion), and additional laboratory work-up as indicated. Spiral CT or 
cardiac MRI can complement ECHO to assess wall motion abnormalities when needed. 
− Patients should be thoroughly evaluated to rule out any alternative etiology (e.g., disease 
progression, other medications, or infections) 
Grade 1 
 
No dose modifications required unless 
clinical suspicion is high, in which case 
hold study drug/study regimen dose 
during diagnostic work-up for other 
etiologies. If study drug/study regimen is 
held, resume after complete resolution to 
Grade 0. 
For Grade 1 : 
- Monitor and closely follow up in 2 to 4 days for clinical symptoms, BNP, cardiac enzymes, ECG, 
ECHO, pulse oximetry (resting and exertion), and laboratory work-up as clinically indicated. 
- Consider using steroids if clinical suspicion is high. 
Grade 2, 3 or 4 
 
 
 
 
 
 
 
If Grade 2 -- Hold study drug/study 
regimen dose until resolution to Grade 0. 
If toxicity rapidly improves to Grade 0, 
then the decision to reinitiate study 
drug/study regimen will be based upon 
treating physician’s clinical judgment and 
after completion of steroid taper. If 
toxicity 
does 
not 
rapidly 
improve, 
permanently. 
discontinue 
study 
For Grade 2-4: 
- Monitor symptoms daily, hospitalize. 
- Promptly start IV methylprednisolone 2 to 4 mg/kg/day or equivalent after Cardiology 
consultation has determined whether and when to complete diagnostic procedures including a 
cardiac biopsy. 
- Supportive care (e.g., oxygen). 
- If no improvement within 2 to 3 days despite IV methylprednisone at 2 to 4 mg/kg/day, promptly 
start immunosuppressive therapy such as TNF inhibitors (e.g., infliximab at 5 mg/kg IV, may be 
repeated at 2 and 6 weeks after initial dose at the discretion of the treating provider or relevant 
practice guidelines). Caution: It is important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab. 

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drug/study regimen. 
If Grade 3-4, permanently discontinue 
study drug/study regimen. 
- Infliximab is contraindicated for patients who have heart failure. 
 
 

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Adverse Events 
Severity Grade of the 
Event 
(NCI 
CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Myositis/ 
Polymyositis 
(“Poly/myositis”) 
 
Any Grade 
(Refer to NCI CTCAE 
applicable version in study 
protocol for defining the 
CTCAE grade/severity) 
General Guidance 
For Any Grade: 
− 
Monitor patients for signs and symptoms of poly/myositis. Typically, muscle weakness/pain 
occurs in proximal muscles including upper arms, thighs, shoulders, hips, neck and back, but 
rarely affects the extremities including hands and fingers; also difficulty breathing and/or trouble 
swallowing can occur and progress rapidly. Increased general feelings of tiredness and fatigue 
may occur, and there can be new-onset falling, difficulty getting up from a fall, and trouble 
climbing stairs, standing up from a seated position, and/or reaching up. 
− 
If poly/myositis is suspected, a Neurology consultation should be obtained early, with prompt 
guidance on diagnostic procedures. Myocarditis may co-occur with poly/myositis; refer to 
guidance under Myocarditis. Given breathing complications, refer to guidance under 
Pneumonitis/ILD.  
Given possibility of an existent (but previously unknown) autoimmune disorder, consider 
Rheumatology consultation. 
− 
Consider, as necessary, discussing with the Clinical Study Lead. 
− 
Initial work-up should include clinical evaluation, creatine kinase, aldolase, lactate 
Dehydrogenase (LDH), blood urea nitrogen (BUN)/creatinine, erythrocyte sedimentation rate or 
C-reactive protein (CRP) level, urine myoglobin, and additional laboratory work-up as indicated, 
including a number of possible rheumatological/antibody tests (i.e., consider whether a 
rheumatologist consultation is indicated and could guide need for rheumatoid factor, antinuclear 
antibody, anti-smooth muscle, antisynthetase [such as anti-Jo-1], and/or signal-recognition 
particle antibodies). Confirmatory testing may include electromyography, nerve conduction 
studies, MRI of the muscles, and/or a muscle biopsy. Consider Barium swallow for evaluation of 
dysphagia or dysphonia. 
Patients should be thoroughly evaluated to rule out any alternative etiology (e.g., disease 
progression, other medications, or infections). 
Grade 1 
 
No dose modifications. 
For Grade 1: 
− 
Monitor and closely follow up in 2 to 4 days for clinical symptoms and initiate evaluation as 
clinically indicated. 
− 
Consider Neurology consult. 
− 
Consider, as necessary, discussing with the Clinical Study Lead.. 
Grade 2 
 
Hold study drug/study regimen dose until 
resolution to Grade ≤1. 
Permanently 
discontinue 
study 
drug/study regimen if it does not resolve 
to Grade ≤1 within 30 days or if there are 
signs of respiratory insufficiency. 
For Grade 2: 
− 
Monitor symptoms daily and consider hospitalization. 
− 
Obtain Neurology consult, and initiate evaluation. 
− 
Consider, as necessary, discussing with the Clinical Study Lead.. 
− 
If clinical course is rapidly progressive (particularly if difficulty breathing and/or trouble 
swallowing), promptly start IV methylprednisolone 2 to 4 mg/kg/day systemic steroids along 
with receiving input from Neurology consultant  

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− 
If clinical course is not rapidly progressive, start systemic steroids (e.g., prednisone 1 to 
2 mg/kg/day PO or IV equivalent); if no improvement within 2 to 3 days, continue additional 
work up and start treatment with IV methylprednisolone 2 to 4 mg/kg/day 
− 
If after start of IV methylprednisolone at 2 to 4 mg/kg/day there is no improvement within 2 to 
3 days, consider start of immunosuppressive therapy such as TNF inhibitors (e.g., infliximab at 
5 mg/kg IV, may be repeated at 2 and 6 weeks after initial dose at the discretion of the treating 
provider or relevant practice guidelines). Caution: It is important to rule out sepsis and refer to 
infliximab label for general guidance before using infliximab. 
 
Grade 3 or 4 
 
Grade 4: life-threatening 
consequences; 
urgent 
intervention indicated) 
 
For Grade 3: 
Hold study drug/study regimen dose until 
resolution to Grade ≤1. 
Permanently 
discontinue 
study 
drug/study regimen if Grade 3 imAE does 
not resolve to Grade ≤1 within 30 days or 
if 
there 
are 
signs 
of 
respiratory 
insufficiency. 
 
For Grade 4: 
Permanently 
discontinue 
study 
drug/study regimen. 
For Grade 3 or 4: 
− 
Monitor symptoms closely; recommend hospitalization. 
− 
Obtain Neurology consult 
− 
Consider, as necessary, discussing with the Clinical Study Lead. 
− 
Promptly start IV methylprednisolone 2 to 4 mg/kg/day systemic steroids along with receiving 
input from Neurology consultant. 
− 
If after start of IV methylprednisolone at 2 to 4 mg/kg/day there is no improvement within 2 to 
3 days, consider starting another immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg IV, may be repeated at 2 and 6 weeks after intial dose at the 
discretion of the treating provider or relevant practice guidelines). Caution: It is important to rule 
out sepsis and refer to infliximab label for general guidance before using infliximab. 
− 
Consider whether patient may require IV IG, plasmapheresis. 
 
 
 
Other-Immune-Mediated reactions 
 
General guidelines 
Severity Grade of the 
Event (NCI CTCAE 
version 5.0) 
 
Dose Modifications Durvalumab 
Toxicity Management 
Any Grade 
 
Note: It is possible that events with an 
inflammatory or immune mediated 
mechanism could occur in nearly all organs, 
some of them are not noted specifically in 
these guidelines (e.g. immune 
thrombocytopenia, haemolytic anaemia, 
uveitis, and vasculitis). 
− 
The Clinical Study Leadmay be 
contacted for immune-mediated reactions 
not listed in the “specific immune-
mediated reactions” section 
− 
Thorough evaluation to rule out 
any alternative etiology (e.g., disease 
progression, concomitant medications, 
and infections) 
− 
Consultation with relevant 
specialist 
− 
Treat accordingly, as per 
institutional standard. 

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General guidelines 
Severity Grade of the 
Event (NCI CTCAE 
version 5.0) 
 
Dose Modifications Durvalumab 
Toxicity Management 
Grade 1 
 
No dose modification. 
Monitor as clinically indicated 
Grade 2 
 
• 
Hold study drug/study regimen until 
resolution to ≤Grade 1 or baseline. 
• 
If toxicity worsens, then treat as Grade 
3 or Grade 4. 
• 
Study drug/study regimen can be 
resumed once event stabilizes to Grade ≤1 after 
completion of steroid taper. 
Consider whether study drug/study regimen 
should be permanently discontinued in Grade 2 
events with high likelihood for morbidity and/or 
mortality when they do not rapidly improve to 
Grade <1 upon treatment with systemic steroids 
and following full taper 
For Grade 2, 3, or 4 
Treat accordingly, as per institutional 
standard, appropriate clinical practice 
guidelines, and other society guidelines 
(e.g., NCCN, ESMO) 
Grade 3 
 
Hold study drug/study regimen 
 
Grade 4 
 
Permanently discontinue study drug/study 
regimen 
 
 
 
 

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Infusion-Related Reactions 
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Any Grade 
 General Guidance 
For Any Grade: 
- 
Management per institutional standard at the discretion of investigator 
- 
Monitor patients for signs and symptoms of infusion-related reactions (e.g., fever 
and/or shaking chills, flushing and/or itching, alterations in heart rate and blood 
pressure, dyspnea or chest discomfort, or skin rashes) and anaphylaxis (e.g., 
generalized urticaria, angioedema, wheezing, hypotension, or tachycardia) 
Grade 1 or 2  
For Grade 1: 
The infusion rate of study drug/study regimen may be decreased by 50% or 
temporarily interrupted until resolution of the event 
 
For Grade 2: 
The infusion rate of study drug/study regimen may be decreased 50% or 
temporarily interrupted until resolution of the event 
Subsequent infusions may be given at 50% of the initial infusion rate 
For Grade 1 or Grade 2: 
- 
Acetaminophen and/or antihistamines may be administered per institutional 
standard at the discretion of the investigator 
- 
Consider premedication per institutional standard prior to subsequent doses 
- 
Steroids should not be used for routine premedication of Grade ≤2 infusion 
reactions  
Grade 3 or 4 
For Grade 3 or 4: 
 Permanently discontinue study drug/study regimen 
For Grade 3 or 4: 
- 
Manage severe infusion-related reactions per institutional standards appropriate 
clinical practice guidelines, and society guidelines (e.g., IM epinephrine, followed 
by IV diphenhydramine and famotidine, and IV glucocorticoid) 
 
 

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Non-immune Mediated Reactions 
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose Modification 
Toxicity Management 
Any Grade 
Note: dose modifications are not required for adverse events not deemed to be 
related to study treatment (i.e. events due to underlying disease) or for laboratory 
abnormalities not deemed to be clinically significant. 
Treat accordingly, as per institutional standard 
Grade 1 
No dose modifications 
Treat accordingly, as per institutional standard 
Grade 2 
Hold study drug/study regimen until resolution to ≤ Grade 1 or baseline 
Treat accordingly, as per institutional standard 
Grade 3 
Hold study drug/study regimen until resolution to ≤ Grade 1 or baseline 
For AEs that downgrade to ≤ Grade 2 within 7 days or resolve to ≤ Grade 1 or 
baseline within 14 days, resume study drug/study regimen administration. 
Otherwise, discontinue study drug/study regimen 
Treat accordingly, as per institutional standard 
Grade 4 
Discontinue Study drug/study regimen (Note for Grade 4 labs, decision to discontinue 
would be based on accompanying clinical signs/symptoms, the Investigator’s clinical 
judgment and consultation with the Sponsor) 
Treat accordingly, as per institutional standard 
 
 
a ASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow MD. 
b FDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical Evaluation. 
AChE  Acetylcholine esterase; ADL  Activities of daily living; AE  Adverse event; ALP  Alkaline phosphatase test; ALT  Alanine aminotransferase; AST  Aspartate aminotransferase; BUN  Blood urea nitrogen; 
CT  Computed tomography; CTCAE  Common Terminology Criteria for Adverse Events; ILD  Interstitial lung disease; imAEimAE  Immune-mediated adverse event; IG  Immunoglobulin; IV  Intravenous; 
GI  Gastrointestinal; LFT  Liver function tests; LLN  Lower limit of normal; MRI  Magnetic resonance imaging; NCI  National Cancer Institute; NCCN  National Comprehensive Cancer Network; PJP Pneumocystis 
jirovecii pneumonia (formerly known as Pneumocystis carinii pneumonia) ; PO  By mouth; T3  Triiodothyronine; T4  Thyroxine; TB  Total bilirubin; TNF  Tumor necrosis factor; TSH  Thyroid-stimulating 
hormone; ULN  Upper limit of normal. 
 
 
 
 

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APPENDIX 5: SERIOUS ADVERSE EVENT NOTIFICATION FORM 
 
 
 
 
 

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APPENDIX 6 : EVENT OF CLINICAL INTEREST NOTIFICATION 
FORM 
 

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APPENDIX 7 : PREGNANCY   NOTIFICATION FORM 
 
 

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APPENDIX 8 : DECLARATION OF HELSINKI 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 
and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of Clarification added) 
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
Preamble 
1.The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of 
ethical principles for medical research involving human subjects, including research on identifiable 
human material and data. 
The Declaration is intended to be read as a whole and each of its constituent paragraphs should be 
applied with consideration of all other relevant paragraphs. 
 
2. Consistent with the mandate of the WMA, the Declaration is addressed primarily to physicians. The 
WMA encourages others who are involved in medical research involving human subjects to adopt 
these principles.  
 
General Principles 
3. The Declaration of Geneva of the WMA binds the physician with the words, “The health of my 
patient will be my first consideration,” and the International Code of Medical Ethics declares that, “A 
physician shall act in the patient's best interest when providing medical care.” 
 
4. It is the duty of the physician to promote and safeguard the health, well-being and rights of 
patients, including those who are involved in medical research. The physician's knowledge and 
conscience are dedicated to the fulfilment of this duty. 
 
5. Medical progress is based on research that ultimately must include studies involving human 
subjects. 
 
6. The primary purpose of medical research involving human subjects is to understand the causes, 
development and effects of diseases and improve preventive, diagnostic and therapeutic interventions 
(methods, procedures and treatments). Even the best proven interventions must be evaluated 
continually through research for their safety, effectiveness, efficiency, accessibility and quality. 
 
7. Medical research is subject to ethical standards that promote and ensure respect for all human 
subjects and protect their health and rights. 
 
8. While the primary purpose of medical research is to generate new knowledge, this goal can never 
take precedence over the rights and interests of individual research subjects. 
 
9. It is the duty of physicians who are involved in medical research to protect the life, health, dignity, 
integrity, right to self-determination, privacy, and confidentiality of personal information of research 
subjects. The responsibility for the protection of research subjects must always rest with the physician 
or other health care professionals and never with the research subjects, even though they have given 
consent. 
 
10. Physicians must consider the ethical, legal and regulatory norms and standards for research 
involving human subjects in their own countries as well as applicable international norms and 
standards. No national or international ethical, legal or regulatory requirement should reduce or 
eliminate any of the protections for research subjects set forth in this Declaration. 
 
11. Medical research should be conducted in a manner that minimises possible harm to the 
environment. 

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12. Medical research involving human subjects must be conducted only by individuals with the 
appropriate ethics and scientific education, training and qualifications. Research on patients or healthy 
volunteers requires the supervision of a competent and appropriately qualified physician or other 
health care professional. 
 
13. Groups that are underrepresented in medical research should be provided appropriate access to 
participation in research. 
 
14. Physicians who combine medical research with medical care should involve their patients in 
research only to the extent that this is justified by its potential preventive, diagnostic or therapeutic 
value and if the physician has good reason to believe that participation in the research study will not 
adversely affect the health of the patients who serve as research subjects. 
 
15. Appropriate compensation and treatment for subjects who are harmed as a result of participating 
in research must be ensured. 
 
Risks, Burdens and Benefits  
16. In medical practice and in medical research, most interventions involve risks and burdens. 
Medical research involving human subjects may only be conducted if the importance of the objective 
outweighs the risks and burdens to the research subjects. 
 
17. All medical research involving human subjects must be preceded by careful assessment of 
predictable risks and burdens to the individuals and groups involved in the research in comparison 
with foreseeable benefits to them and to other individuals or groups affected by the condition under 
investigation. 
Measures to minimise the risks must be implemented. The risks must be continuously monitored, 
assessed and documented by the researcher.  
 
18. Physicians may not be involved in a research study involving human subjects unless they are 
confident that the risks have been adequately assessed and can be satisfactorily managed. 
When the risks are found to outweigh the potential benefits or when there is conclusive proof of 
definitive outcomes, physicians must assess whether to continue, modify or immediately stop the 
study.            
 
Vulnerable Groups and Individuals 
19. Some groups and individuals are particularly vulnerable and may have an increased likelihood of 
being wronged or of incurring additional harm. 
All vulnerable groups and individuals should receive specifically considered protection. 
 
20. Medical research with a vulnerable group is only justified if the research is responsive to the 
health needs or priorities of this group and the research cannot be carried out in a non-vulnerable 
group. In addition, this group should stand to benefit from the knowledge, practices or interventions 
that result from the research. 
 
Scientific Requirements and Research Protocols  
21. Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant sources of 
information, and adequate laboratory and, as appropriate, animal experimentation. The welfare of 
animals used for research must be respected. 
 
22. The design and performance of each research study involving human subjects must be clearly 
described and justified in a research protocol. 
The protocol should contain a statement of the ethical considerations involved and should indicate 
how the principles in this Declaration have been addressed. The protocol should include information 
regarding funding, sponsors, institutional affiliations, potential conflicts of interest, incentives for 
subjects and information regarding provisions for treating and/or compensating subjects who are 
harmed as a consequence of participation in the research study. 
In clinical trials, the protocol must also describe appropriate arrangements for post-trial provisions. 
 

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Research Ethics Committees 
23.The research protocol must be submitted for consideration, comment, guidance and approval to 
the concerned research ethics committee before the study begins. This committee must be 
transparent in its functioning, must be independent of the researcher, the sponsor and any other 
undue influence and must be duly qualified. It must take into consideration the laws and regulations 
of the country or countries in which the research is to be performed as well as applicable international 
norms and standards but these must not be allowed to reduce or eliminate any of the protections for 
research subjects set forth in this Declaration.  
The committee must have the right to monitor ongoing studies. The researcher must provide 
monitoring information to the committee, especially information about any serious adverse events. No 
amendment to the protocol may be made without consideration and approval by the committee. After 
the end of the study, the researchers must submit a final report to the committee containing a 
summary of the study’s findings and conclusions.  
 
Privacy and Confidentiality  
24. Every precaution must be taken to protect the privacy of research subjects and the confidentiality 
of their personal information. 
 
Informed Consent  
25.Participation by individuals capable of giving informed consent as subjects in medical research 
must be voluntary. Although it may be appropriate to consult family members or community leaders, 
no individual capable of giving informed consent may be enrolled in a research study unless he or she 
freely agrees. 
 
26.In medical research involving human subjects capable of giving informed consent, each potential 
subject must be adequately informed of the aims, methods, sources of funding, any possible conflicts 
of interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of the 
study and the discomfort it may entail, post-study provisions and any other relevant aspects of the 
study. The potential subject must be informed of the right to refuse to participate in the study or to 
withdraw consent to participate at any time without reprisal. Special attention should be given to the 
specific information needs of individual potential subjects as well as to the methods used to deliver 
the information. 
After ensuring that the potential subject has understood the information, the physician or another 
appropriately qualified individual must then seek the potential subject’s freely-given informed consent, 
preferably in writing. If the consent cannot be expressed in writing, the non-written consent must be 
formally documented and witnessed.       
All medical research subjects should be given the option of being informed about the general outcome 
and results of the study. 
 
27. When seeking informed consent for participation in a research study the physician must be 
particularly cautious if the potential subject is in a dependent relationship with the physician or may 
consent under duress. In such situations the informed consent must be sought by an appropriately 
qualified individual who is completely independent of this relationship. 
 
28. For a potential research subject who is incapable of giving informed consent, the physician must 
seek informed consent from the legally authorised representative. These individuals must not be 
included in a research study that has no likelihood of benefit for them unless it is intended to promote 
the health of the group represented by the potential subject, the research cannot instead be 
performed with persons capable of providing informed consent, and the research entails only minimal 
risk and minimal burden. 
 
29. When a potential research subject who is deemed incapable of giving informed consent is able to 
give assent to decisions about participation in research, the physician must seek that assent in 
addition to the consent of the legally authorised representative. The potential subject’s dissent should 
be respected. 
 
30. Research involving subjects who are physically or mentally incapable of giving consent, for 
example, unconscious patients, may be done only if the physical or mental condition that prevents 
giving informed consent is a necessary characteristic of the research  group. In such circumstances 

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the physician must seek informed consent from the legally authorised representative. If no such 
representative is available and if the research cannot be delayed, the study may proceed without 
informed consent provided that the specific reasons for involving subjects with a condition that 
renders them unable to give informed consent have been stated in the research protocol and the 
study has been approved by a research ethics committee. Consent to remain in the research must be 
obtained as soon as possible from the subject or a legally authorised representative. 
 
31. The physician must fully inform the patient which aspects of their care are related to the research. 
The refusal of a patient to participate in a study or the patient’s decision to withdraw from the study 
must never adversely affect the patient-physician relationship. 
 
32. For medical research using identifiable human material or data, such as research on material or 
data contained in biobanks or similar repositories, physicians must seek informed consent for its 
collection, storage and/or reuse. There may be exceptional situations where consent would be 
impossible or impracticable to obtain for such research. In such situations the research may be done 
only after consideration and approval of a research ethics committee. 
 
Use of Placebo 
33. The benefits, risks, burdens and effectiveness of a new intervention must be tested against those 
of the best proven intervention(s), except in the following circumstances: 
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or 
Where for compelling and scientifically sound methodological reasons the use of any intervention less 
effective than the best proven one, the use of placebo, or no intervention is necessary to determine 
the efficacy or safety of an intervention  
and the patients who receive any intervention less effective than the best proven one, placebo, or no 
intervention will not be subject to additional risks of serious or irreversible harm as a result of not 
receiving the best proven intervention.  
Extreme care must be taken to avoid abuse of this option. 
 
Post-Trial Provisions 
34. In advance of a clinical trial, sponsors, researchers and host country governments should make 
provisions for post-trial access for all participants who still need an intervention identified as beneficial 
in the trial. This information must also be disclosed to participants during the informed consent 
process. 
 
Research Registration and Publication and Dissemination of Results 
35. Every research study involving human subjects must be registered in a publicly accessible 
database before recruitment of the first subject. 
 
36. Researchers, authors, sponsors, editors and publishers all have ethical obligations with regard to 
the publication and dissemination of the results of research. Researchers have a duty to make publicly 
available the results of their research on human subjects and are accountable for the completeness 
and accuracy of their reports. All parties should adhere to accepted guidelines for ethical reporting. 
Negative and inconclusive as well as positive results must be published or otherwise made publicly 
available. Sources of funding, institutional affiliations and conflicts of interest must be declared in the 
publication. Reports of research not in accordance with the principles of this Declaration should not be 
accepted for publication. 
 
Unproven Interventions in Clinical Practice 
 
37. In the treatment of an individual patient, where proven interventions do not exist or other known 
interventions have been ineffective, the physician, after seeking expert advice, with informed consent 
from the patient or a legally authorised representative, may use an unproven intervention if in the 
physician's judgement it offers hope of saving life, re-establishing health or alleviating suffering. This 
intervention should subsequently be made the object of research, designed to evaluate its safety and 
efficacy. In all cases, new information must be recorded and, where appropriate, made publicly 
available.