NonInterventional, Multicenter, Prospective, European Study to Describe the Effectiveness of Trabectedin + PLD in the Treatment of Relapsed Ovarian Cancer (ROC) Patients According to SmPC Regardless of Previous Use of an Antiangiogenic Drug
Conditions: Relapsed Ovarian Cancer
Sponsor: PharmaMar

 
PharmaMar SA, Sociedad Unipersonal 
(mentioned as the Sponsor in this Protocol) 
Avda. de los Reyes, 1. 
Polígono Industrial “La Mina”. 
28770 Colmenar Viejo. 
Madrid, Spain. 
Phone: + 34 91 846 6000 
Fax: + 34 91 846 6003 
 
 
 
 
CLINICAL TRIAL PROTOCOL 
 
Non-interventional, multicenter, prospective, European study to describe the 
effectiveness of trabectedin + PLD in the treatment of relapsed ovarian cancer (ROC) 
patients by previous usage of an antiangiogenic drug 
 
 
INVESTIGATIONAL MEDICINAL PRODUCTS: Trabectedin 
Protocol No.: ET-D-031-14 
Version No.: 4 - Amendment 2 
Date Issued: 18 September 2018 
NCT Code: 02825420 
 
 
 
 
 

PharmaMar 
Page 1 
Protocol ID: ET-D-031-14 
Version 4- Amendement 2  
18 September 2018 
Confidential 
Trabectedin + PLD 
 
Clinical Protocol 
 
Title: 
Non-interventional, multicenter, prospective, European study to 
describe the effectiveness of trabectedin + PLD in the treatment of 
relapsed ovarian cancer (ROC) patients by previous usage of an 
antiangiogenic drug 
 
 
Sponsor: 
PharmaMar SA, Sociedad Unipersonal 
(mentioned as the Sponsor in this Protocol) 
Avda. de los Reyes, 1. 
Polígono Industrial “La Mina”. 
28770 Colmenar Viejo. 
Madrid, Spain. 
Phone: + 34 91 846 6000 
Fax: + 34 91 846 6003 
 
 
 
 
Tested Product: Trabectedin 
 
 
Protocol ID: 
ET-D-031-14 
 
 
Version No.: 
4 - Amendment 2 
 
 
Date Issued: 
18 September 2018 
 
 
 
CONFIDENTIAL 
The information and data included in this protocol contain trade secrets and privileged or confidential 
information which is the property of the Sponsor. No person is authorized to make it public without 
written permission of the Sponsor. These restrictions on disclosure will apply equally to all future 
information supplied to you which is indicated as privileged or confidential. This material may be 
disclosed to and used by your staff and associates as it may be necessary to conduct the clinical study. 

PharmaMar 
Page 2 
Protocol ID: ET-D-031-14 
Version 4- Amendement 2  
18 September 2018 
Confidential 
Trabectedin + PLD 
Protocol/Amendment Approval Page(s) 
 
Authored by: 
 
Co-Authored by: 
All Mapi signatures and approvals (Mapi, an ICON Plc company) are on file in the Electronic 
Project Master File (ePMF). 
 
Céline Faure 
 
 
Printed Name 
 
Printed Name 
 
 
 
 
 
Signature 
 
Signature 
+33 4 72 13 59 92 
 
 
 
Telephone Number 
 
Telephone Number 
 
Celine.Faure@iconplc.com 
 
 
 
E-mail Address 
 
E-mail Address 
 
 
 
 
Date [dd/mmm/yyyy] 
 
Date [dd/mmm/yyyy] 
 
Approved by: 
The undersigned attest to the following: 
1. Reviewed the Protocol /Amendment 
2. Agrees to its contents 
 
Maria José Pontes Valero 
 
 
Hervé Dhellot 
Printed Name 
 
Printed Name 
 
 
 
 
 
Signature 
 
Signature 
 
+ 34 91 846 6000 
 
 
+ 34 91 823 46 33 
Telephone Number 
 
Telephone Number 
 
mjpontes@pharmamar.com  
 
 
hdhellot@pharmamar.com 
E-mail Address 
 
E-mail Address 
 
 
 
 
 
Date [dd/mmm/yyyy] 
 
Date [dd/mmm/yyyy] 

PharmaMar 
Page 3 
Protocol ID: ET-D-031-14 
Version 4- Amendement 2  
18 September 2018 
Confidential 
Trabectedin + PLD 
Important Study Contacts 
 
Study Contact 
Name 
Address 
Telephone/Fax No. 
Sponsor 
PharmaMar SA 
Avda. de los Reyes, 1. 
Polígono Industrial “La Mina”. 
28770 Colmenar Viejo. 
Madrid, Spain. 
Tel: + 34 91 846 6000 
Fax: + 34 91 846 6003 
Sponsor Responsible 
Person 
Maria José Pontes Valero  
Medical Affairs Manager 
International Associate Director 
Avda. de los Reyes, 1. 
Polígono Industrial “La Mina”. 
28770 Colmenar Viejo. 
Madrid, Spain. 
Tel: + 34 91 846 6000  
Fax: + 34 91 846 6003 
Email: mjpontes@pharmamar.com  
Pharmacovigilance 
Contacts 
Pharmacovigilance Department. 
Product Safety, PharmaMar 
 
Avda. de los Reyes, 1. 
Polígono Industrial “La Mina”. 
28770 Colmenar Viejo. 
Madrid, Spain. 
Tel (24-hours): + 34 91 823 4556 
Tel: + 34 91 846 6055 
Fax: + 34 91 846 6004 
Email:  phv@pharmamar.com 
 
 
Alicia Rodríguez 
Pharmacovigilance 
Technician 
Phone: +34 91 823 45 89 
Email: arrodriguez@pharmamar.com 
Dr. Mirela Cartoafa 
EEA QPPV Deputy and Drug 
Safety Physician 
Phone: +34 91 846-61 43 
Email: mcartoafa@pharmamar.com 
Dr. Liliana Navarro 
Drug Safety Physician 
Phone: +34 91 846 61 47 
Email: lnavarro@pharmamar.com 
 
Dr. Hervé Dhellot, MD 
EEA Qualified Person for 
Pharmacovigilance and Senior 
Pharmacovigilance Manager 
Tel (Madrid, Spain): + 34 91 823 46 33 
Tel (24-hours): +34 91 823 47 49 
Fax: +34 91 846 60 04 
Email: hdhellot@pharmamar.com 
 

PharmaMar 
Page 4 
Protocol ID: ET-D-031-14 
Version 4- Amendement 2  
18 September 2018 
Confidential 
Trabectedin + PLD 
Study Contact 
Name 
Address 
Telephone/Fax No. 
Contract Research 
Organization (CRO) 
Mapi, an ICON Plc Company 
(hereafter referred as Mapi) 
27 rue de la Villette 
69003 Lyon France 
Phone: +33 4 72 13 66 66 
Mapi Project Director 
Dr. Dieter Komossa 
Konrad Zuse Platz 11 
81829 Munich, Germany. 
Phone: +49 89 666 105 123 
Email: dieter.komossa@iconplc.com 
Mapi Project Manager 
Dr. Petra Hellmann 
Konrad Zuse Platz 11 
81829 Munich, Germany  
Phone: +49 203 455 776 91 
Email: petra.hellmann@iconplc.com 
Coordinating 
Investigator 
Dr. Sandro Pignata  
Istituto Nazionale Tumori Pascale 
Napoli Italy 
Email: sandro.pignata@gmail.com 
 
 

PharmaMar 
Page 5 
Protocol ID: ET-D-031-14 
Version 4- Amendement 2  
18 September 2018 
Confidential 
Trabectedin + PLD 
Synopsis 
Study Title:
Non-interventional, multicenter, prospective, European study to describe the 
effectiveness of trabectedin + PLD in the treatment of relapsed ovarian cancer 
(ROC) patients by previous usage of an antiangiogenic drug 
Protocol ID:
ET-D-031-14 
Trial Centers:
Approximately 70 centers will be identified across 5 European countries (Italy, 
Spain, Germany, France, Belgium) 
Study Objectives:
Primary Objective:
To assess the progression-free survival (PFS) according to investigator criteria in 
relapsed ovarian cancer patients treated with trabectedin + pegylated liposomal 
doxorubicin (PLD) according to standard local clinical practice following approved 
Summary of Product Characteristics (SmPC) indication and dose, overall and by 
previous usage of antiangiogenic drug. 
 
Secondary Objectives:
• 
To evaluate the response rates (complete response [CR] + partial response 
[PR]), and disease control rate (DCR; CR + PR + stable disease [SD]) 
• 
Overall survival (OS)  
• 
To evaluate patient’s performance status (PS) 
• 
To assess treatment duration and number of cycles, treatment exposure, 
and time to next treatment 
• 
To evaluate the safety of the combination of trabectedin + PLD 
Secondary objectives will be assessed overall and by previous usage of 
antiangiogenic drug. 
Study Rationale:
To assess the PFS after trabectedin + PLD therapy for the treatment of relapsed 
ovarian cancer according to standard local clinical practice following approved 
SmPC indication and dose, while describing patients who were pretreated with an 
antiangiogenic drug and those not pretreated, in real-life clinical practice. 
Study Design: 
Non-interventional, multicenter, prospective study of trabectedin + PLD 
administered according to standard local clinical practice following approved 
SmPC indication and dose. 

PharmaMar 
Page 6 
Protocol ID: ET-D-031-14 
Version 4- Amendement 2  
18 September 2018 
Confidential 
Trabectedin + PLD 
Study Population: 
Patients with platinum-sensitive relapsed ovarian cancer who are receiving 
trabectedin + PLD according to standard local clinical practice following approved 
SmPC indication and dose. 
Selection Criteria: 
• 
Women aged 18 years or older. 
• 
Presence of platinum-sensitive relapsed ovarian cancer. 
• 
Treatment indication according to local label SmPC and reimbursement for 
trabectedin and PLD treatment. 
• 
Prior treatment with a minimum of 1 cycle of trabectedin + PLD before 
inclusion in the study. 
• 
Written informed consent indicating that patients understand the purpose 
and procedures and are willing to participate in the study. 
Study Drug: 
Trabectedin (Yondelis®) 
Administration: 
Trabectedin administered according to standard local clinical practice following 
approved SmPC indication and dose.  
The recommended dose of trabectedin for the treatment of relapsed platinum-
sensitive ovarian cancer is 1.1 mg/m2 body surface area (BSA), administered every 
3 weeks as a 3-hour infusion immediately after PLD 30 mg/m2. Pretreatment with 
corticosteroids (e.g., dexamethasone) is required; additional anti-emetics may be 
administered in accordance with local practice, as needed, and as specified in the 
SmPC. 

PharmaMar 
Page 7 
Protocol ID: ET-D-031-14 
Version 4- Amendement 2  
18 September 2018 
Confidential 
Trabectedin + PLD 
Study Procedures: 
Patients will be managed by their treating clinician without any additional 
instructions. The study will require no additional treatment procedures during 
patient visits. 
Patients meeting the selection criteria will be invited to participate in the study. 
Before any study-specific data are recorded, patients will be provided with all the 
study details prior to their decision to participate and will be requested to sign an 
informed consent form (ICF) prior to their participation in the study. 
Patient’s baseline data, safety, and PS (evaluation according to the Eastern 
Cooperative Oncology Group [ECOG] score) will be collected during the 
Observation Period (treatment with trabectedin + PLD). Even though baseline data 
will be collected when patient is under treatment with trabectedin + PLD, it 
corresponds to data prior to treatment initiation. Response and survival 
assessments will be collected during the study and include symptomatic response 
and overall tumor response according to investigator criteria. The preferred method 
to measure overall response is Response Evaluation Criteria in Solid Tumors 
(RECIST) version 1.1 as it is the generally accepted standard criteria; however 
other criteria used by the investigators will be accepted. 
Safety, response, reason for discontinuation of treatment and survival will be 
assessed during the follow-up period (1 month after the end the Observation Period 
and, for patients who discontinued trabectedin before the end of the 12-month 
Observation Period, 12 months after the Index date). Subsequent non-trabectedin 
treatments that the patient received during the follow-up period will also be 
described. 
Study Endpoints: 
Study endpoints will be assessed overall and by previous usage of antiangiogenic 
drug. 
Primary endpoint: 
PFS measured as time from first dose of trabectedin to disease progression as 
reported by the investigator or death regardless of cause. 
Secondary endpoints: 
• 
Response rate (CR+PR) 
• 
DCR (CR+PR+SD) 
• 
OS  
• 
Evolution of the patient’s performance status 
• 
Treatment duration  and number of cycles 
• 
Treatment exposure 
• 
Time to next treatment 
• 
Safety of the combination of trabectedin + PLD 

PharmaMar 
Page 8 
Protocol ID: ET-D-031-14 
Version 4- Amendement 2  
18 September 2018 
Confidential 
Trabectedin + PLD 
Safety Evaluation:
A solicited reporting system of adverse events (serious and non-serious, related or 
non-related) on trabectedin. 
Pharmacokinetic 
Considerations: 
This is a non-interventional, prospective study and no pharmacokinetic or 
pharmacodynamic evaluations are planned. 
Planned Study 
Periods: 
• 
Recruitment: 36 months 
• 
Observation Period: up to 12 months 
• 
Follow-up visits: 1 month after patient last on-study cycle and, for patients 
who discontinued treatment with trabectedin before the end of the 12-
month Observation Period, 12 months after the index date. 
• 
Data Base Lock: Nov 2019 
• 
Study Final Report: Jan 2020 
Date Issued:
18 Nov 2014 
Date Amended:
18 September 2018 
 
 
 
 
 

PharmaMar 
Page 9 
Protocol ID: ET-D-031-14 
Version 4- Amendement 2  
18 September 2018 
Confidential 
Trabectedin + PLD 
List of Abbreviations 
 
Abbreviation 
Description 
ADL 
Activities of Daily Living 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BSA 
Body Surface Area 
CI 
Confidence Interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CR 
Complete Response 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CT  
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
Disease Control Rate 
DNA 
Deoxy ribonucleic acid 
ECOG 
Eastern Cooperative Oncology Group 
ESMO 
European Society for Medical Oncology 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EU 
European Union 
FAS 
Full Analysis Set 
FIGO 
International Federation of Gynecology and Obstetrics 
GCP 
Good Clinical Practice 
GVP 
Good Pharmacovigilance Practices 
h 
Hour 
HR 
Hazard Ratio 

PharmaMar 
Page 10 
Protocol ID: ET-D-031-14 
Version 4- Amendement 2  
18 September 2018 
Confidential 
Trabectedin + PLD 
Abbreviation 
Description 
IARC 
International Agency for Research in Cancer 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization  
ID 
Patient identification number for study participation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
iv 
Intravenous 
kg 
Kilogram 
KM 
Kaplan-Meier 
m2 
Square Meter 
MAH 
Marketing Authorization Holder 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
MR 
Magnetic Resonance 
NCCN 
National Comprehensive Cancer Network 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PD 
Progression of Disease 
PFS 
Progression-Free Survival 
PR 
Partial Response 
PS 
Performance Status 
q 
Every 
REB 
Research Ethics Board 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RNA 
Ribonucleic acid 
SADR 
Serious Adverse Drug Reaction 
SAE 
Serious Adverse Event 
SD 
Stable Disease 

PharmaMar 
Page 11 
Protocol ID: ET-D-031-14 
Version 4- Amendement 2  
18 September 2018 
Confidential 
Trabectedin + PLD 
Abbreviation 
Description 
SmPC 
Summary of Product Characteristics 
US/USA 
United States of America 
VEGF 
Vascular Endothelial Growth Factor 
vs 
Versus 
WHO 
World Health Organization 
wk 
Week 
 

PharmaMar 
Page 12 
Protocol ID: ET-D-031-14 
Version 4- Amendement 2  
18 September 2018 
Confidential 
Trabectedin + PLD 
Table of Contents 
Protocol/Amendment Approval Page(s) ....................................................................................................... 2 
Important Study Contacts ............................................................................................................................. 3 
Synopsis ........................................................................................................................................................ 5 
List of Abbreviations .................................................................................................................................... 9 
List of Tables .............................................................................................................................................. 15 
1 
INTRODUCTION .............................................................................................................................. 16 
1.1 
Background ................................................................................................................................. 16 
1.1.1 
Ovarian Cancer ................................................................................................................... 16 
1.1.2 
Angiogenesis ....................................................................................................................... 17 
1.1.3 
Trabectedin + Pegylated Liposomal Doxorubicin (PLD) ................................................... 17 
1.1.3.1 
Efficacy ....................................................................................................................... 18 
1.1.3.2 
Safety .......................................................................................................................... 19 
1.2 
Rationale for the Study ............................................................................................................... 20 
2 
GOALS AND OBJECTIVES ............................................................................................................ 20 
2.1 
Primary Objective ....................................................................................................................... 20 
2.2 
Secondary Objectives .................................................................................................................. 20 
3 
METHODS ........................................................................................................................................ 21 
3.1 
Study Design Overview .............................................................................................................. 21 
3.2 
Estimated Duration of the Study ................................................................................................. 21 
4 
STUDY POPULATION .................................................................................................................... 21 
4.1 
General Considerations ............................................................................................................... 21 
4.2 
Number of Patients ..................................................................................................................... 22 
4.3 
Selection Criteria ........................................................................................................................ 22 
4.3.1 
Selection Criteria................................................................................................................. 22 
4.3.2 
Failure of Patient Enrollment .............................................................................................. 22 
4.4 
Discontinuation Criteria .............................................................................................................. 22 
4.4.1 
Patient Discontinuation ....................................................................................................... 22 
4.4.2 
Study Discontinuation ......................................................................................................... 22 
5 
STUDY MEDICATION AND TREATMENTS ............................................................................... 23 
5.1 
Study Drugs ................................................................................................................................ 23 
5.1.1 
Duration of Treatment ......................................................................................................... 23 
5.1.2 
Storage, Dispensing, and Reconciliation of Study Drug ..................................................... 23 
5.1.3 
Warnings and Precautions ................................................................................................... 23 
5.2 
Concomitant Medication ............................................................................................................. 23 

PharmaMar 
Page 13 
Protocol ID: ET-D-031-14 
Version 4- Amendement 2  
18 September 2018 
Confidential 
Trabectedin + PLD 
5.3 
Other Treatments ........................................................................................................................ 23 
5.3.1 
Medical Care ....................................................................................................................... 23 
5.3.2 
Pre-Existing Medical Conditions ........................................................................................ 23 
5.3.3 
Treatment of Emergent Adverse Drug Reaction ................................................................. 23 
5.3.4 
Laboratory Abnormalities ................................................................................................... 23 
6 
STUDY PROCEDURES.................................................................................................................... 24 
6.1 
Qualification Period .................................................................................................................... 24 
6.2 
Observation Period ...................................................................................................................... 24 
6.2.1 
First Study Visit .................................................................................................................. 24 
6.2.2 
Subsequent Visits during Observation Period ..................................................................... 25 
6.3 
Follow-up Period ........................................................................................................................ 25 
6.4 
Study Drug Treatment Procedures .............................................................................................. 26 
6.5 
Clinical Laboratory Procedures .................................................................................................. 26 
7 
STUDY ASSESSMENTS .................................................................................................................. 26 
8 
SAFETY REPORTING ..................................................................................................................... 28 
8.1 
Definitions ................................................................................................................................... 28 
8.1.1 
Adverse Event (AE) ............................................................................................................ 28 
8.1.2 
Serious Adverse Event (SAE) ............................................................................................. 28 
8.1.3 
Adverse Drug Reaction (ADR) ........................................................................................... 28 
8.1.4 
Serious Adverse Drug Reaction (SADR) ............................................................................ 29 
8.1.5 
Misuse of a Medicinal Product ........................................................................................... 29 
8.1.6 
Occupational Exposure to a Medicinal Product .................................................................. 29 
8.1.7 
Off-label Use ....................................................................................................................... 29 
8.1.8 
Overdose ............................................................................................................................. 29 
8.1.9 
Abuse .................................................................................................................................. 29 
8.1.10 
Lack of Efficacy/Effect ....................................................................................................... 29 
8.1.11 
Medication Error ................................................................................................................. 29 
8.2 
Collection and Reporting of Safety Information for Study Investigators ................................... 29 
8.2.1 
Reporting of Safety Information to Pharmacovigilance Department .................................. 31 
8.2.1.1 
Pregnancy Reporting ................................................................................................... 31 
8.2.1.2 
Exemptions from Reporting ........................................................................................ 32 
8.2.2 
Collection of Safety Information in the eCRF .................................................................... 32 
8.3 
Reporting to the Competent Regulatory Authorities .................................................................. 32 
9 
DATA MANAGEMENT ................................................................................................................... 33 
9.1 
Data Collection ........................................................................................................................... 33 
9.1.1 
Data Monitoring .................................................................................................................. 33 

PharmaMar 
Page 14 
Protocol ID: ET-D-031-14 
Version 4- Amendement 2  
18 September 2018 
Confidential 
Trabectedin + PLD 
9.2 
Site Monitoring ........................................................................................................................... 33 
9.3 
Data Quality Assurance .............................................................................................................. 33 
9.4 
Site Inspection ............................................................................................................................. 34 
9.5 
Database Quality Assurance and Data Protection ....................................................................... 34 
9.6 
Data Retention ............................................................................................................................ 34 
10 
STATISTICAL ANALYSIS .............................................................................................................. 35 
10.1 
Sample Size/Power Considerations ............................................................................................ 35 
10.2 
Interim Analysis .......................................................................................................................... 35 
10.3 
Study Endpoints .......................................................................................................................... 35 
10.4 
Data Analysis .............................................................................................................................. 35 
10.4.1 
Disposition .......................................................................................................................... 35 
10.4.2 
Analysis of Baseline and Demographic Data ...................................................................... 36 
10.4.3 
Analysis of the Primary Endpoint ....................................................................................... 36 
10.4.4 
Analysis of Secondary Endpoints ....................................................................................... 36 
10.4.5 
Safety Analysis ................................................................................................................... 37 
10.4.6 
Other Data ........................................................................................................................... 37 
10.4.7 
Pharmacokinetic / Pharmacodynamic Analysis .................................................................. 37 
11 
ETHICAL, ADMINISTRATIVE, AND REGULATORY REQUIREMENTS ................................ 37 
11.1 
Conduct of Study ........................................................................................................................ 37 
11.2 
Patient Information and Informed Consent ................................................................................. 38 
11.3 
Confidentiality ............................................................................................................................ 38 
11.4 
Ethics Committee Review ........................................................................................................... 38 
11.5 
Protocol Adherence and Modifications ....................................................................................... 39 
11.6 
Records Retention ....................................................................................................................... 39 
11.7 
Insurance ..................................................................................................................................... 39 
11.8 
Use of Study Information and Publications ................................................................................ 39 
12 
Investigator Agreement ...................................................................................................................... 40 
13 
References .......................................................................................................................................... 41 
14 
Appendices ......................................................................................................................................... 44 
14.1 
Appendix – Study Period Design ................................................................................................ 45 
14.2 
Appendix – Performance Status .................................................................................................. 46 
14.3 
Appendix – Response Criteria: RECIST Version 1.1 ................................................................. 47 
 
 
 

PharmaMar 
Page 15 
Protocol ID: ET-D-031-14 
Version 4- Amendement 2  
18 September 2018 
Confidential 
Trabectedin + PLD 
List of Tables 
 
Table 1. Study Schedule of Events ............................................................................................................. 27 
Table 2.  ECOG Performance Status .......................................................................................................... 46 
 
 
 

PharmaMar 
Page 16 
Protocol ID: ET-D-031-14 
Version 4- Amendement 2  
18 September 2018 
Confidential 
Trabectedin + PLD 
1 INTRODUCTION 
1.1 Background 
1.1.1 
Ovarian Cancer 
Ovarian cancer is a serious, clinically challenging malignancy with the majority of ovarian malignancies 
(85%-95%) developing from epithelial cells. Ovarian cancer represents a significant challenge in 
oncology, being a malignancy that has a mortality rate disproportionate to its incidence. According to the 
World Health Organization (WHO) International Agency for Research in Cancer (IARC) GLOBOCAN 
database, ovarian cancer comprised 3.6% of all incident cancer types reported worldwide in 2012, and 
4.1% of cancer types across Europe. Yet despite its low incidence, ovarian cancer has the sixth highest 
cancer-related mortality rate in European women, and is associated with the highest mortality-to-case 
ratio of all gynecologic malignancies (Holschneider and Berek, 2000; World Health Organization, 2014).  
A contributing factor to high mortality rates is the late disease diagnosis. Most women are asymptomatic 
until the disease has spread, with the majority of cases diagnosed at the advanced stage. In European 
countries, population-based data indicate that, of the subset of patients with known disease severity, 60% 
to 74% of cases of ovarian cancer are diagnosed at a FIGO (International Federation of Gynecology and 
Obstetrics) stage of III or IV (Maringe et al, 2012). Unfortunately, approximately 80% of patients will 
relapse after first-line platinum-based and taxane-based chemotherapy (National Cancer Institute, 2014). 
Given that relapsed ovarian cancer is not curable, most women who relapse die from their disease (Della 
Pepa and Banerjee, 2014). Consequently, developing new therapies for relapsed ovarian cancer is critical. 
According to treatment guidelines from the National Comprehensive Cancer Network (NCCN) and 
European Society for Medical Oncology (ESMO), primary treatment for advanced ovarian cancer (FIGO 
stage II, III, IV) consist of surgical staging and cytoreductive surgery followed by a combination of 
platinum-based chemotherapy, including paclitaxel/carboplatin or docetaxel/carboplatin combination 
therapies, or bevacizumab-containing regimens (Colombo et al, 2010; National Comprehensive Cancer 
Network, 2014). According to ESMO clinical practice guidelines, the appropriate therapy for patients 
with relapsed ovarian cancer is guided by the time to progression since the last platinum-based treatment 
(referred to as the platinum-free interval). Patients who progress during platinum-based treatment are 
considered to have platinum-refractory disease, while patients who develop recurrence within 6 months 
from the completion of first-line platinum chemotherapy are considered to have platinum-resistant disease 
(Colombo et al, 2010). The prognosis for these patients is poor, with a median overall survival (OS) 
typically under 12 months. Treatment options include paclitaxel, pegylated liposomal doxorubicin (PLD), 
topotecan, and gemcitabine (Della Pepa and Banerjee, 2014). However, since response rates are only 
about 10%, the primary goal of therapy in these patients is palliative care (Colombo et al, 2010). 
Patients with relapsed ovarian cancer who progress following an interval greater than 6 months since the 
last platinum-based treatment (platinum sensitive disease) have 2 categorizations: partially platinum-
sensitive patients are those who progress between 6 and 12 months, while fully platinum-sensitive 
patients progress with a platinum-free interval of more than 12 months (Ledermann et al, 2013). Both 
types are likely to benefit from further platinum-based therapy. The ESMO clinical practice guidelines 
recommend that for partially platinum-sensitive and fully platinum-sensitive patients, carboplatin 
combination therapies are the treatment of choice (Ledermann et al, 2013). Platinum-containing regimens 
that are effective for these patients include carboplatin with paclitaxel, carboplatin with PLD, carboplatin 
with gemcitabine, and a combination of carboplatin with gemcitabine and the antiangiogenic agent 
bevacizumab (see Section 1.1.2) (Della Pepa and Banerjee, 2014; Gonzalez Martin et al, 2013). Surgical 
resection is also an option in platinum-sensitive patients with prolonged (over 24 months) treatment free-

PharmaMar 
Page 17 
Protocol ID: ET-D-031-14 
Version 4- Amendement 2  
18 September 2018 
Confidential 
Trabectedin + PLD 
interval, especially with isolated recurrence and good performance status (Colombo et al, 2010). 
However, no single therapeutic agent is recommended for relapsed ovarian cancer, and recurrence 
therapies may include drugs, radiation, or other treatments aimed at reducing tumor burden, control 
symptoms, or increase length and/or quality of life patients (National Comprehensive Cancer Network, 
2014). 
Compared with fully platinum-sensitive patients, partially platinum-sensitive patients have a lower 
response to platinum-based regimens, with shorter progression-free survival (PFS) and OS. Thus, 
different strategies beyond carboplatin-based regimens are needed. Based on a subgroup analysis of the 
open-label, multinational, multicenter, phase III OVA-301 study (see Section 1.1.3.1 for additional study 
details), both ESMO and The Spanish Research Group for Ovarian Cancer (GEICO) recommend the non-
platinum-based regimen of trabectedin + PLD for patients with partially platinum-sensitive relapsed 
ovarian cancer (Gonzalez Martin et al, 2013; Ledermann et al, 2013).  
1.1.2 
Angiogenesis 
Angiogenesis is a key factor contributing to tumor growth and metastases. Since neoplasms are 
dependent, in part, on the formation of adequate vascular support, there is a focus on therapies targeting 
angiogenesis to reduce the growth and spread of ovarian cancer. For patients with ovarian cancer, the 
clinical utility of antiangiogenic therapies is apparent, since the extent of angiogenesis correlates inversely 
with prognosis (Huang et al, 2000).  
Studies have demonstrated a complex relationship underlying angiogenesis and vascular endothelial 
growth factor (VEGF), a family of ligands that are often overexpressed in women with ovarian cancer, 
and is an independent prognostic factor for OS (Aravantinos and Pectasides, 2014). Thus, many current 
therapeutic approaches target the inhibition of VEGF and its receptors (Eisenhauer et al, 2012). Current 
VEGF-mediated antiangiogenic therapies include biologics that target the ligand, including bevacizumab 
and aflibercept, and tyrosine kinase inhibitors that target VEGF receptors, such as pazopanib, cediranib, 
sorafenib, and vandetanib (Slomovitz et al, 2011).  
1.1.3 
Trabectedin + Pegylated Liposomal Doxorubicin (PLD) 
Trabectedin combined with PLD is approved in the EU for the treatment of relapsed platinum-sensitive 
ovarian cancer. Trabectedin (Yondelis®) is a novel antitumor agent derived from a marine source, the 
Caribbean tunicate Ecteinascidia turbinata and currently produced synthetically (Pommier et al, 1996). 
Trabectedin is a first-in-class antitumor agent with a complex mechanism of action at the level of gene 
transcription. Trabectedin binds covalently to the minor deoxyribonucleic acid (DNA) groove and 
alkylates the N2 amino group of a guanine residue, which bends towards the major groove (Pommier et 
al, 1996). Cytotoxic concentrations of trabectedin delay cell cycle progression through the S phase and 
produces arrest at G2/M, ultimately resulting in p53-independent apoptosis (Carter and Keam, 2007; Erba 
et al, 2001; Martinez et al, 2001; Martinez et al, 2005).  
Trabectedin also has selective anti-inflammatory and immunomodulatory properties that affect the tumor 
microenvironment. Emerging evidence suggests trabectedin has selective cytotoxicity on tumor stroma 
macrophages, inhibits VEGF, and selectively inhibits inflammatory mediators. These actions collectively 
inhibit tumor growth, invasion and metastases, while also providing an antiangiogenic effect (Poveda et 
al, 2014). 
PLD is available as doxorubicin hydrochloride in a pegylated liposomal formulation. Pegylation involves 
encapsulated doxorubicin hydrochloride in liposomes with surface-bound methoxypolyethylene glycol. 
This process protects liposomes from an immune response, thereby increasing its blood circulation time. 

PharmaMar 
Page 18 
Protocol ID: ET-D-031-14 
Version 4- Amendement 2  
18 September 2018 
Confidential 
Trabectedin + PLD 
The active ingredient of PLD—doxorubicin hydrochloride—is a cytotoxic anthracycline antibiotic 
obtained from Streptomyces peucetius var. caesius. Although the exact mechanism of action is not 
known, it is generally believed that inhibition of DNA, ribonucleic acid (RNA), and protein synthesis is 
responsible for the majority of antitumor effects of PLD. This is probably the result of intercalation of the 
anthracycline between adjacent base pairs of the DNA double helix thus preventing their unwinding for 
replication. (Caelyx SmPC, 2006) 
The recommended dosage for trabectedin in relapsed ovarian cancer is 1.1 mg/m2 administered as a 3-
hour infusion every 3 weeks (3h_q3w), immediately after infusion of 30 mg/m2 PLD. 
1.1.3.1 
Efficacy 
Several phase I trials extensively evaluated the safety and antitumor activity of trabectedin in patients 
with advanced solid malignancies using different rates of intravenous (iv) infusion on every-3-week 
(q3w) schedules (Ryan et al, 2001; Taamma et al, 2001; Twelves et al, 2003; van Kesteren et al, 2000; 
van Kesteren et al, 2002). In these phase I trials, trabectedin produced objective antitumor responses in 
heavily-pretreated patients with diverse tumor types. 
A retrospective pooled analysis of 3 phase II studies evaluated the efficacy and safety profile of 
trabectedin monotherapy as a second- and third-line therapy in patients with relapsed ovarian cancer (del 
Campo et al, 2013). Three trabectedin dose schedules were investigated: 1.3 mg/m2 3h_q3w administered 
to 94 patients , 0.58 mg/m2 given to 147 patients as a 3-hour weekly infusion for 3 weeks of a 4-week 
cycle (3h_qw x 3_q4w), and 1.5 mg/m2 over 24 h every 3 weeks (24h_q3w) administered to 54 patients. 
Of the combined total of 295 patients, 189 (64%) had platinum-sensitive disease. The primary endpoint in 
all 3 trials was the overall response rate (ORR, complete response [CR] + partial response [PR]). Among 
the secondary endpoints was the disease control rate (DCR), defined as the percentage of patients with a 
CR or PR and/or stable disease (SD) lasting 3 months or more. Compared with the weekly schedule, both 
q3w regimens showed a significantly higher ORR (36% vs 16%, P < 0.001) and DCR (66% vs 46 %, 
P < 0.001), and a longer median PFS (5.6 vs 2.8 months, P < 0.0001). Patients with platinum-sensitive 
disease treated with either q3w schedule had a longer median PFS (24h, 6.2 months; 3h, 6.8 months) 
versus (vs) the weekly schedule (5.1 months). The median OS for the q3w schedules was also comparable 
(24h, 20.4 months; 3h, 17.1 months) and longer than the weekly regimen (13.7 months). Patients with 
platinum-sensitive disease also had a higher median OS (20.4 months) compared with platinum-resistant 
patients (11.1 months). The analysis demonstrated that trabectedin was an effective monotherapy for the 
treatment of relapsed ovarian cancer, with better outcomes in patients with platinum-sensitive disease. 
Given the better safety profile regarding neutropenia, fatigue, and vomiting for the 3h_q3w vs the 
24h_q3w schedule, the 3h_q3w schedule (associated with shorter infusion times) was considered the most 
appropriate regimen. 
The key evidence of efficacy of trabectedin + PLD in relapsed ovarian cancer is based on an open-label, 
multicenter, randomized, phase III study (OVA-301) in 672 patients who experienced either persistent or 
recurrent disease, or disease progression following a prior platinum-based chemotherapy. Patients also 
had measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) and an 
Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2 or less. The randomization 
was stratified according to whether the patient had platinum-sensitive disease or platinum-resistant 
disease (Poveda et al, 2014). Treatment groups included trabectedin 1.1 mg/m2 administered as a 3-hour 
infusion and PLD 30 mg/m2 administered as a 1.5-hour infusion every 3 weeks, or PLD 50 mg/m2 
administered as a 1.5-hour infusion every 4 weeks. The primary analysis of PFS by independent radiology 
review was performed on 645 patients. Median PFS for the trabectedin + PLD group (7.3 months) vs PLD 
alone (5.8 months) translated to a 21% risk reduction for disease progression (Hazard ratio [HR] = 0.79, 

PharmaMar 
Page 19 
Protocol ID: ET-D-031-14 
Version 4- Amendement 2  
18 September 2018 
Confidential 
Trabectedin + PLD 
95% CI: 0.65-0.96). Secondary analyses of ORR also favored the combination arm (HR = 1.65, 95% CI: 
1.14-2.37). In patients with platinum-sensitive relapsed ovarian cancer (65% in trabectedin + PLD; 63% 
in PLD arm), median PFS was 9.7 months in the trabectedin + PLD arm compared with 7.2 months in the 
PLD monotherapy arm (HR = 0.66, 95% CI: 0.52-0.85).  
A secondary analysis of 214 partially platinum-sensitive patients from the OVA-301 study demonstrated 
a 35% risk reduction of disease progression or death that significantly favored the trabectedin + PLD 
combination (HR, 0.65. 95% CI, 0.45-0.92). The trabectedin + PLD group had a median PFS of 7.4 
months vs 5.5 months for PLD monotherapy. When PFS results were compared across subsets of patients 
according to patients’ platinum-free interval, the largest benefit with trabectedin + PLD treatment was 
obtained with partially platinum-sensitive patients (Poveda et al, 2011). 
The protocol-defined analysis of OS for OVA-301 did not demonstrate differences across treatment 
groups: the median OS was 22.2 months for trabectedin + PLD and 18.9 months for PLD (HR = 0.86, 
P = 0.08). However, a significant imbalance of the platinum-free interval across treatment groups 
(trabectedin + PLD, mean PFI = 10.6 months; PLD, mean PFI = 13.3 months; P < 0.01) spurred an 
exploratory multivariate analysis that considered platinum-free interval and other prognostic factors as 
covariates, which demonstrated a significant OS advantage in favor of trabectedin + PLD (22.6 vs 19.4 
months; HR = 0.82, 95% CI: 0.69-0.98). Further analysis with 430 platinum-sensitive patients showed a 
median OS of 27.0 months for trabectedin + PLD and 24.1 months for PLD (HR = 0.83; 95% CI: 0.67-
1.04). For partially platinum-sensitive patients, the median OS of 22.4 months in the trabectedin + PLD 
group was significantly longer than in the PLD group at 16.4 months (HR = 0.64; 95% CI: 0.47-0.86) 
(Monk et al, 2012; Poveda et al, 2014).  
Further advantages to OS were demonstrated in a subgroup of 94 patients with partially platinum-
sensitive disease from the OVA-301 trabectedin + PLD arm who subsequently received platinum-based 
chemotherapy at progression. Compared with PLD alone, trabectedin + PLD (followed by subsequent 
platinum-based therapy) induced a 9-month longer median OS (27.7 vs 18.7 months) and a significant 
42% decrease in the risk of death (HR = 0.58; P= 0.0153) (Poveda et al, 2014). 
Thus, the OVA-301 trial demonstrated a clinical benefit of trabectedin + PLD compared with PLD alone 
in patients with platinum-sensitive relapsed ovarian cancer. 
1.1.3.2 
Safety 
Myelosuppression, elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and 
fatigue were the primary dose-limiting toxicities in the dose-finding phase I studies. 
Adverse events from the OVA-301 trial, 1 dose-ranging randomized control trial, and 2 nonrandomized 
trials reported rates of grade 3 (severe) and 4 (life-threatening) adverse events of 89% vs 58% for 
trabectedin + PLD compared to PLD alone, respectively. The rates of discontinuation due to adverse 
events were 17% vs 9%, for patients who received trabectedin + PLD vs patients receiving PLD alone 
(Papaioannou et al, 2011).  Adverse events from OVA-301 were collected from 333 patients receiving 
trabectedin + PLD and 330 patients receiving PLD alone. The most frequent grade 4 hematologic adverse 
events at least possibly related to treatment with trabectedin + PLD vs PLD included neutropenia (34% vs 
8.5%), leukopenia (8.4% vs 2.4%), thrombocytopenia (8.1% vs 0.6%), anemia (3.0% vs 0.3%), and 
febrile neutropenia (2.4% vs 0.3%). The most frequent grade 4 nonhematologic adverse events that were 
more common with trabectedin + PLD therapy included increases in ALT (2.4% vs 0%) and AST (0.9% 
vs 0.3%). The most common adverse events leading to treatment termination or dose adjustment was 
neutropenia for trabectedin + PLD and hand-foot syndrome for PLD (Monk et al, 2010). 

PharmaMar 
Page 20 
Protocol ID: ET-D-031-14 
Version 4- Amendement 2  
18 September 2018 
Confidential 
Trabectedin + PLD 
All patients must receive corticosteroids (e.g., 20 mg dexamethasone iv) 30 minutes prior to PLD (in 
combination therapy) or Yondelis (in monotherapy); not only as anti-emetic prophylaxis, but also because 
it appears to provide hepatoprotective effects. Additional anti-emetics may be administered as needed 
(Yondelis SmPC). 
1.2 Rationale for the Study 
Based on the outcomes of study OVA-301, this non-interventional study will investigate the clinical 
utility of a platinum-free trabectedin + PLD regimen in patients with progressive ovarian cancer relapsing 
6 months or more following the previous platinum-based chemotherapy. This study will assess the value 
of palliative care by collecting real-life data on the response to trabectedin + PLD, which can be related to 
the principal objectives of re-treatment for patients with relapsed platinum-sensitive ovarian cancer—to 
prolong survival, improve quality of life, and alleviate cancer-related symptoms (Poveda et al, 2014). 
The aim of this non-interventional, European, multicenter, prospective study is to assess the PFS after 
trabectedin + PLD therapy for the treatment of relapsed ovarian cancer according to standard local 
clinical practice following approved SmPC indication and dose, describing patients who were pretreated 
with an antiangiogenic drug and those not pretreated, in real-life clinical practice. 
Patients must have received a minimum of 1 cycle of trabectedin + PLD before their inclusion in the 
study (Appendix 14.1, Figure 1). 
Clinical evidence of PFS, response rate, DCR, survival, treatment parameters, and safety will be obtained 
in order to evaluate the effectiveness of trabectedin + PLD in patients with relapsed ovarian cancer in 
Europe. 
2 GOALS AND OBJECTIVES 
2.1 Primary Objective 
To assess the progression-free survival (PFS) according to investigator criteria in relapsed ovarian cancer 
patients treated with trabectedin + pegylated liposomal doxorubicin (PLD) according to standard local 
clinical practice following approved Summary of Product Characteristics (SmPC) indication and dose, 
overall and by previous usage of antiangiogenic drug. 
2.2 Secondary Objectives 
The secondary objectives will be to determine the following based on real-life clinical data overall and by 
previous usage of antiangiogenic drug: 
• 
Response rate (CR + PR) and DCR (CR + PR + SD) 
• 
Overall survival (OS) 
• 
Evolution of the patient’s performance status (PS)  
• 
Treatment duration and number of cycles, treatment exposure, and time to next treatment 
• 
Safety of the combination of trabectedin + PLD.  

PharmaMar 
Page 21 
Protocol ID: ET-D-031-14 
Version 4- Amendement 2  
18 September 2018 
Confidential 
Trabectedin + PLD 
3 METHODS 
3.1 Study Design Overview 
This will be a non-interventional, prospective, multicenter study in which trabectedin + PLD will be 
administered according to standard local clinical practice following approved SmPC indication and dose. 
There will be no involvement with any treatment decisions for the patients included in the study. The 
choice of therapy must be made prior to the patient’s inclusion in the study. Treatment administration will 
be independent of, and dissociated from participation in the study. 
For each patient, the study will consist of a Qualification Period (see Section 6.1), an Observation Period 
(see Section 6.2) and a Follow-up Period (see Section 6.3). Once treatment with trabectedin is 
discontinued, patients may be treated with subsequent anticancer therapies or supportive care as per the 
treating clinician's best clinical judgment. The study design is summarized in Appendix 14.1, Figure 1. 
3.2 Estimated Duration of the Study 
The study will begin with the enrollment of the first patient. The individual patient study duration will be 
up to 13 months (12-month Observation Period + 1-month Follow-up Period). Enrollment of patients in 
the study is expected to be completed within 36 months. This target however, is dependent upon the 
enrollment rate of each individual study center participating in the study. If the targeted enrollment rate of 
each individual site participating in the study is lower than expected, additional sites may be added. 
The total duration of the study will be 49 months, including the 36-month enrollment period and the 13-
month study duration of the last patient enrolled in the study. 
The planned study periods are as follows: 
• 
Entire study period: September 2014-January 2020 
• 
First patient in: July 2015 
• 
Last patient in: 31 July 2018 
• 
Last patient last visit: August 2019 
Given the variation of clinical practice not only across, but also within countries, a good geographical 
representation of patients with relapsed ovarian cancer will be attempted by targeting study centers spread 
across the regions of each of the countries. This variation in clinical practices will contribute to more 
representative results for each country. 
4 STUDY POPULATION 
4.1 General Considerations 
The study population will include patients with platinum-sensitive relapsed ovarian cancer who are 
receiving trabectedin + PLD according to standard local clinical practice following approved SmPC 
indication and dose. 
To be enrolled in this study, the patients must meet all inclusion criteria and have none of the exclusion 
criteria. 

PharmaMar 
Page 22 
Protocol ID: ET-D-031-14 
Version 4- Amendement 2  
18 September 2018 
Confidential 
Trabectedin + PLD 
4.2 Number of Patients 
At least 300 patients will be selected across approximately 70 European sites. Study sites will be located 
in Germany, Italy, Spain, France, and Belgium. 
4.3 Selection Criteria 
If patients meet the selection criteria, they will be invited to participate in the study. Before any study-
specific data are recorded, patients will be provided with all the study details prior to their decision to 
participate and will be requested to sign an informed consent form (ICF) prior to their participation in the 
study. 
4.3.1 
Selection Criteria 
Patients must comply with all of the following criteria in order to be enrolled into the study:  
• 
Patients must be aged 18 years or older. 
• 
Patients must have platinum-sensitive relapsed ovarian cancer, defined as disease relapse that 
occurs 6 months or more after completion of last platinum-containing therapy. 
• 
Treatment indication according to local label SmPC and reimbursement for trabectedin and PLD 
treatment. 
• 
Patients must have received a minimum of 1 cycle of trabectedin + PLD before their inclusion in 
the study. 
• 
Patients must have signed an informed consent document indicating that they understand the 
purpose and procedures required for the study and are willing to participate in the study. 
4.3.2 
Failure of Patient Enrollment 
The reason(s) for not enrolling a patient in the study (patient declined, no reply, patient not fulfilling the 
selection criteria) will be recorded in a patient qualification log at each site. This will enable subsequent 
assessment of potential selection bias necessary for quality assurance of the data collected. 
4.4 Discontinuation Criteria 
4.4.1 
Patient Discontinuation 
Patients are free to discontinue the anticancer treatment at any time. Discontinuation of anti-cancer 
treatment is not considered a study discontinuation and treating clinicians are encouraged to follow the 
patient as long as possible. Whenever feasible, patients will be followed until death or until end of study. 
Patients may request discontinuation from the study at any time. The date and the reason for withdrawal 
or discontinuation must be recorded in the electronic Case Report Form (eCRF). 
4.4.2 
Study Discontinuation 
The Sponsor has the right to terminate the participation of either an individual site or the study at any 
time. Reasons for terminating an individual site or the study include, but are not limited to the following: 
• 
Treating clinician does not adhere to the protocol or applicable regulatory guidelines in 
conducting the study. 

PharmaMar 
Page 23 
Protocol ID: ET-D-031-14 
Version 4- Amendement 2  
18 September 2018 
Confidential 
Trabectedin + PLD 
5 STUDY MEDICATION AND TREATMENTS 
This is a non-interventional, prospective study and no study medication will be provided as part of the 
study. 
5.1 Study Drugs 
Trabectedin is administered every 3 weeks as a 3-hour infusion at a dose of 1.1 mg/m2, immediately after 
PLD 30 mg/m2 (see also the SmPC for specific administration advice). To minimize the risk of PLD 
infusion reactions, PLD infusion should be in accordance with the SmPC. Any dose modifications and/or 
change in dosing interval should be in accordance with the SmPC and the treating clinician’s best clinical 
judgment. 
5.1.1 
Duration of Treatment 
There is no predefined limit as to the number of cycles of treatment with trabectedin. Treatment may 
continue as long as the treating physician feels there is benefit, even in the presence of apparent disease 
progression. 
5.1.2 
Storage, Dispensing, and Reconciliation of Study Drug 
Detailed information on dosing, preparation, handling, storage, and disposal of trabectedin may be found 
in the SmPC. 
5.1.3 
Warnings and Precautions 
Detailed information regarding warnings and precautions for trabectedin may be found in the SmPC. 
5.2 Concomitant Medication 
Patients will be allowed to continue with any concomitant medication throughout the duration of this 
study in accordance with the SmPC and the treating clinician’s best clinical judgment. 
5.3 Other Treatments 
5.3.1 
Medical Care 
Standard of care will be provided to patients as per their treating clinician’s best clinical judgment. 
5.3.2 
Pre-Existing Medical Conditions 
Treatment of any pre-existing medical conditions will be provided according to the SmPC and the treating 
clinician’s best clinical judgment. 
5.3.3 
Treatment of Emergent Adverse Drug Reaction 
Treatment of any emergent adverse drug reaction (ADR) will be provided according to the SmPC and the 
treating clinician’s best clinical judgment. 
5.3.4 
Laboratory Abnormalities 
According to the SmPC and the treating clinician’s best clinical judgment, all laboratory tests associated 
with ADRs and serious adverse drug reactions (SADRs) will be assessed and any necessary medical 
intervention provided. When available, these will be collected on electronic case report forms (eCRFs). 

PharmaMar 
Page 24 
Protocol ID: ET-D-031-14 
Version 4- Amendement 2  
18 September 2018 
Confidential 
Trabectedin + PLD 
6 STUDY PROCEDURES 
This is a non-interventional study. Prior to the initiation of the qualification process or any study 
procedures, patients must sign an ICF indicating that they understand the purpose and procedures required 
for the study and that they are willing to participate in the study. The ICF must be signed 1 or more days 
following completion of the initial trabectedin + PLD administration (1st treatment cycle). The Study 
Schedule of Events is noted in Table 1 and Appendix 14.1, Figure 1. 
6.1 Qualification Period 
The patient’s inclusion/exclusion criteria will be evaluated before the patient signs the ICF. The 
Qualification Period will begin following the signing of the ICF and end with the first on-study 
trabectedin + PLD administration cycle.  
The first on-study trabectedin + PLD administration must follow, but may be on the same day as the 
signing of the ICF and the evaluation of the patient's inclusion/exclusion criteria 
6.2 Observation Period 
The Observation Period will begin with the first trabectedin + PLD dose administered after the signing of 
the ICF and will continue for up to a total of 12 months after that or until trabectedin treatment 
discontinuation, patient discontinuation for any reason or patient’s death. PLD discontinuation is not a 
reason for Observation Period discontinuation. There are no predefined limits to the number of cycles 
administered. Trabectedin + PLD treatment can continue at the treating clinician’s discretion. 
Methods and timing of the imaging procedures will be determined by the treating clinician. 
6.2.1 
First Study Visit 
On the first day of the Observation Period (Index Date) the following data, if available, will be collected: 
1. Medical history including baseline imaging evaluation. The patient’s baseline tumor imaging 
evaluation will be the last available imaging evaluation performed prior to the initial trabectedin 
+ PLD administration (1st treatment cycle) or the earliest imaging study following the 1st 
treatment cycle. 
2. Complete physical examination (including weight, height, and body surface area [BSA]). 
3. Evaluation of performance status using ECOG /World Health Organization (WHO) PS score 
(Appendix 14.2 Table 2). 
4. Date of first trabectedin + PLD administration. 
5. Any previous cycles of trabectedin + PLD therapy. If patient enrollment occurs after the second 
administration of trabectedin + PLD or later, all information should also be retrospectively 
collected from the time of first administration, when available. 
6. Symptomatic response and overall tumor response will be collected for each cycle of treatment 
with trabectedin + PLD, starting with cycle 2 (except for patients with confirmed progression of 
disease (PD) at discontinuation or who had started a new treatment). The preferred method to 
measure overall response is Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 
as it is the generally accepted standard criteria; however other criteria used by the investigators 
will be accepted. 

PharmaMar 
Page 25 
Protocol ID: ET-D-031-14 
Version 4- Amendement 2  
18 September 2018 
Confidential 
Trabectedin + PLD 
7. Safety assessment (all AEs including ADRs and SADRs) at the visit. 
8. Laboratory tests will be collected when available and based on the treating clinician’s usual 
practice procedures. Laboratory tests associated with ADRs and SADRs will be collected when 
available (at the visit and/or any prior cycles of trabectedin +PLD). 
9. Description of prior anticancer therapy, including nature of the prior systemic treatment, previous 
lines of therapy, date of first and last cycles of prior treatment, best response and/or date of 
progression with prior treatment. 
10. BRCA-1/2 status. 
Even though baseline data will be collected when patient is under treatment with trabectedin + PLD, it 
corresponds to data prior to treatment initiation. 
6.2.2 
Subsequent Visits during Observation Period 
Subsequent visits will occur at the treating clinician’s typical schedule. On each subsequent visit during 
the Observation Period, the following data, if available, will be collected: 
1. Complete physical examination (including weight, height, and BSA). 
2. Evaluation of performance status using ECOG/WHO PS score. 
3. Safety assessment (all AEs including ADRs and SADRs). 
4. Imaging procedures and results of imaging response evaluations will be collected, if they are 
available, during each cycle of the Observation Period of the study. Symptomatic response will 
also be collected. 
5. Laboratory tests will be collected when available and based on the treating clinician’s usual 
practice procedures. When available, those laboratory tests associated with ADRs and SADRs 
will be collected. 
6. Data on trabectedin + PLD treatment administration. 
6.3 Follow-up Period 
A follow-up visit will take place 1 month after the end of the Observation Period. For patients who 
discontinued trabectedin before 12 months after the Index date, an additional follow-up visit will be 
performed 12 months after the Index date, except for patients who are dead or have withdrawn consent. 
Follow-up information may be collected through phone calls with the patient or site visits by the patient. 
For each follow-up visit, the following data will be collected, if available: 
• 
Safety assessment (all AEs including ADRs and SADRs). Laboratory tests associated with ADRs 
and SADRs will be collected when available. 
• 
Reason for discontinuation of treatment with chemotherapy, if applicable. Reason will include the 
following: treatment completed, PD, toxicity including grade, patient refusal, patient lost to 
follow-up, withdrawal of consent, inter-current illness of sufficient severity (specify), withdrawal 
for pregnancy, death (specify the cause), or other (specify). 

PharmaMar 
Page 26 
Protocol ID: ET-D-031-14 
Version 4- Amendement 2  
18 September 2018 
Confidential 
Trabectedin + PLD 
• 
Best symptomatic response and best response (except for patients with confirmed PD at 
discontinuation or who had started a new treatment) and evaluation of treatment duration. 
• 
Survival status. 
• 
Subsequent non-trabectedin anti-cancer treatments that the patient received during the follow-up 
period, including regimen number, type of therapy, start and stop date, and best response 
observed for each regimen.  
6.4 Study Drug Treatment Procedures 
As per the primary objective of the study, patients may or may not have been pretreated with an 
antiangiogenic regimen. No pretreatment procedures will be specified for this non-interventional study. 
Patients will continue to be managed by their treating clinician without any additional instructions. No 
additional treatment procedures will be undertaken during patient visits. 
6.5 Clinical Laboratory Procedures 
Any laboratory tests necessary to diagnosis and/or monitor the patient’s condition will be performed at 
the discretion of the treating clinician. Laboratory test results associated with ADRs or SADRs will be 
collected for the study when available. 
7 STUDY ASSESSMENTS 
Observations and measurements collected, if available, during each study cycle are described in Table 1 
located below and in Appendix 14.1, Figure 1.

PharmaMar 
 
 
 
Page 27 
Protocol ID: ET-D-031-14 
Version 4- Amendement 2 
18 September 2018 
Confidential 
Trabectedin + PLD 
Table 1. Study Schedule of Events 
Assessment/Activity 
Qualification Period 
Observation Period 
Follow-up 
Period 
Patient 
Qualification 
ICF Signature 
Date  
Baseline and 
Cycle 1 Visit 
Subsequent 
Visits 
Review of inclusion/exclusion criteria 
X1 
 
 
 
 
Signed Informed Consent Form (ICF) 
 
X 
 
 
 
Medical history 
 
 
X2 
 
 
Prior therapies 
 
 
X 
 
 
Initial imaging 
 
 
X3 
 
 
Physical examination (BSA, weight, and height) 
 
 
X 
X4 
 
Performance status (ECOG/WHO score) 
 
 
X 
X4 
 
Date of first trabectedin + PLD administration 
 
 
X5 
 
 
Prior trabectedin + PLD therapy 
 
 
X 
 
 
Safety assessment (AEs including ADRs and SADRs) 
 
 
X 
X4 
X 
Laboratory tests  
 
 
X 
X4 
X6 
Reporting of symptomatic and best response 
 
 
X8 
X4 
X 
Additional imaging7  
 
 
X 
X4 
X7 
Reason for ending treatment with trabectedin + PLD 
 
 
X 
X 
 
Survival status 
 
 
X 
X 
X 
Abbreviations:  ADRs, adverse drug reactions; AE, Adverse Event; BSA, body surface area; ECOG, Eastern Cooperative Oncology Group; SADRs, serious adverse drug 
reactions; WHO, World Health Organization. 
1Information must be collected prior to first on-study trabectedin administration (Cycle 2 or later) but may occur on the same day. 
2This includes relevant prior history, the description of key features of the disease and disease histology. 
3The patient’s baseline tumor imaging assessment will be considered the imaging assessment performed prior to the initial trabectedin + PLD administration (1st treatment 
cycle) or the earliest imaging study following the 1st treatment cycle. 
4Repeat at the treating clinician’s typical schedule. 
5If patient enrollment occurs after the second administration of trabectedin + PLD or later, information on physical examination (BSA) and performance status should also be 
collected for Cycle 1 trabectedin + PLD administration, when available. 
6Safety assessments include laboratory tests associated with ADRs and SADRs and will be collected when available. 
7The final imaging assessment will be the imaging assessment performed closest to the Follow-up Visit and prior to initiation of any other chemotherapy treatments. 
8Collected from cycle 2 and onward. 
 

PharmaMar 
Page 28 
Protocol ID: ET-D-031-14 
Version 4- Amendement 2 
18 September 2018 
Confidential 
Trabectedin + PLD 
8 SAFETY REPORTING 
8.1 Definitions 
8.1.1 
Adverse Event (AE) 
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product that does not necessarily have a causal relationship with treatment 
[Directive 2001/20/EC Art 2(m)]. An adverse event can therefore be any unfavorable and unintended sign 
(e.g., an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not it is considered related to the medicinal product. 
8.1.2 
Serious Adverse Event (SAE) 
An adverse event is SERIOUS when the event fulfills 1 of the following criteria: 
• 
Results in DEATH 
• 
Is LIFE-THREATENING (see clarification below) 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant DISABILITY or INCAPACITY 
• 
Is a CONGENITAL ANOMALY or BIRTH DEFECT [Directive 2001/83/EC Art 1(12)] 
• 
Is MEDICALLY SIGNIFICANT (see clarification below) 
• 
Is a suspected transmission via a medicinal product of an infectious agent  
Life-threatening in this context refers to a reaction in which the patient was at risk of death at the time of 
the reaction; it does not refer to a reaction that hypothetically might have caused death if more severe (see 
Annex IV, ICH-E2D Guideline).  
For medically significant criteria, medical and scientific judgment should be exercised in deciding 
whether other situations should be considered serious reactions, such as important medical events that 
might not be immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 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 dependency or abuse (see 
Annex IV, ICH-E2D Guideline). 
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. 
8.1.3 
Adverse Drug Reaction (ADR) 
An ADR is defined as a response to a medicinal product that is noxious and unintended [Directive 
2001/83/EC Art 1(11)]. Response in this context means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility (see Annex IV, ICH-E2A Guideline).  

PharmaMar 
Page 29 
Protocol ID: ET-D-031-14 
Version 4- Amendement 2 
18 September 2018 
Confidential 
Trabectedin + PLD 
ADRs may arise from use of the product within or outside the terms of the marketing authorization or 
from occupational exposure [Directive 2001/83/EC Art 101(1)]. Conditions of use outside the Marketing 
Authorization include off-label use, overdose, misuse, abuse and medication errors. 
For the purpose of this study, an ADR is defined as any undesirable medical occurrence (sign, symptoms, 
or diagnosis) or worsening of a pre-existing medical condition that occurs after initiation of trabectedin 
that the treating clinician considers to be associated with the use of trabectedin. 
8.1.4 
Serious Adverse Drug Reaction (SADR) 
An adverse reaction is SERIOUS when the event is considered related to the drug and also fulfills 1 of the 
criteria described in section 8.1.2. 
8.1.5 
Misuse of a Medicinal Product 
Misuse of a medicinal product is defined as any situation where the medicinal product is intentionally and 
inappropriately used not in accordance with the authorized product information. 
8.1.6 
Occupational Exposure to a Medicinal Product 
For the purpose of reporting cases of suspected adverse reactions, is an exposure to a medicinal product as 
a result of one’s professional or non-professional occupation. 
8.1.7 
Off-label Use 
Off-label use is defined as any situation where a medicinal product is intentionally used for a medical 
purpose not in accordance with the authorized product information. 
8.1.8 
Overdose 
Administration of a quantity of a medicinal product given per administration or cumulatively that is above 
the maximum recommended dose according to the authorized product information. Clinical judgment 
should always be applied. 
8.1.9 
Abuse 
This corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, which is 
accompanied by harmful physical or psychological effects [Directive Art 1]. 
8.1.10 Lack of Efficacy/Effect 
Evidence of less than the expected effect of a product (Online Medical dictionnary for regulatoy 
activities; Whetzel et al, Epub 2011). 
8.1.11 Medication Error 
Medication error refers to any unintentional error in the prescribing, dispensing, administration [including 
preparation for administration] or monitoring of a medicinal product while in control of the healthcare 
professional, patient or consumer. 
8.2 Collection and Reporting of Safety Information for Study Investigators 
A solicited reporting system of all Adverse Events (serious and non-serious, related and not-related) will 
be used during this study, from the beginning of trabectedin + PLD treatment. Whenever possible the 
investigator will record the diagnosis instead of the signs and symptoms. 

PharmaMar 
Page 30 
Protocol ID: ET-D-031-14 
Version 4- Amendement 2 
18 September 2018 
Confidential 
Trabectedin + PLD 
To properly classify each adverse event, the treating physician should assess seriousness, causal 
relationship to study drugs (trabectedin + PLD), and severity (grade). 
Seriousness assessment will take into account criteria described in Section 8.1.2. 
The investigators must provide an assessment of the causal relationship for all AEs with the study 
treatment according to the following scale: 
• 
Related (Y): there is a reasonable possibility that the study treatment caused the AE (i.e., an 
ADR). 
• 
Not related (N): there is no reasonable possibility that the study treatment caused the AE and 
other causes are more probable. 
• 
Unknown (Unk): Only to be used in exceptional situations where the investigator has insufficient 
information (i.e., the patient was not seen at his/her center) and if none of the above can be used 
The grade will be assessed by the investigator according to the Common Terminology Criteria for 
Adverse Events (CTCAE Version 4.0) in force at time of study database development. The CTCAE 
displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this 
general guide: 
• 
Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
• 
Grade 2 = moderate; minimal, local or non-invasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL)1 
• 
Grade 3 = severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL2 
• 
Grade 4 = life-threatening consequences; urgent intervention indicated 
• 
Grade 5 = death related to AE 
                                                     
 
1  Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
2  Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and 
not bedridden. 

PharmaMar 
Page 31 
Protocol ID: ET-D-031-14 
Version 4- Amendement 2 
18 September 2018 
Confidential 
Trabectedin + PLD 
8.2.1 
Reporting of Safety Information to Pharmacovigilance Department 
The investigators will notify to PharmaMar Pharmacovigilance Department: 
1. ALL serious ADRs (SADRs). For the other drugs the reporting will be performed by the investigator 
to the applicable Marketing Authorization Holder (MAH). When possible, diagnosis should be 
reported instead of the signs and symptoms. 
2. ALL SPECIAL SITUATIONS included below, leading or not to an ADR (serious or non-serious): 
• 
Use during pregnancy or breastfeeding 
• 
Lack of efficacy 
• 
Overdose 
• 
Misuse 
• 
Medication errors 
• 
Off-label use 
• 
Abuse 
• 
Occupational exposure 
The information will be reported immediately by the investigator and always within 24 hours of 
awareness on the electronically available PharmaMar´s “Adverse Event Report form” or the 
“Pregnancy form for spontaneous and non-interventional studies”. The forms should be reported in 
English to the PharmaMar Pharmacovigilance Department by e-mail (phv@pharmamar.com) and a copy 
sent to the Mapi site monitor.  
In the case that electronic reporting is not possible, a paper “Adverse Event Report form” and 
“Pregnancy form for spontaneous and non-interventional studies” will be handed out at the beginning 
of the non-interventional study and remain at doctors’ disposal at the investigator's file for notification by 
conventional fax (PharmaMar fax number: 00 34 91 846 6004) or e-mail (phv@pharmamar.com). 
Additional information have to be provided when PharmaMar Pharmacovigilance Department request it 
and also if new significant information on the case is available. This additional information should always 
be provided in a serious adverse event (SAE) form (“follow-up” field of the SAE form should be ticked). 
8.2.1.1 
Pregnancy Reporting 
No sufficient clinical data on exposed pregnancies are available. However, based on its known 
mechanism of action, trabectedin may cause serious birth defects when administered during pregnancy. 
Trabectedin should not be used during pregnancy unless clearly necessary. If it is used during pregnancy, 
the patient must be informed of the potential risk to the fetus and be monitored carefully. If trabectedin is 
used at the end of pregnancy, potential adverse reactions should be monitored carefully in the newborns. 
To ensure patient safety, each pregnancy in a female patient or in a female partner of a male subject 
diagnosed during the Observation Period or within 6 months after last trabectedin administration must be 
reported to the sponsor within 24 hours of learning of its occurrence. 
The pregnancy should be followed up to determine outcome, including spontaneous or voluntary 
termination, details of the birth, and the presence or absence of any birth defects, congenital 

PharmaMar 
Page 32 
Protocol ID: ET-D-031-14 
Version 4- Amendement 2 
18 September 2018 
Confidential 
Trabectedin + PLD 
abnormalities, or maternal and/or new-born complications. The new-born will be followed at least up to 1 
year after the delivery. 
8.2.1.2 
Exemptions from Reporting 
The event of “disease progression” and events due to “disease progression”, even though these fulfill any 
seriousness criterion (i.e., fatal, requiring hospitalization, etc.), are exempted from reporting to 
PharmaMar Pharmacovigilance Department and will only be collected in the applicable CRF page. Death, 
as such, is the outcome of an ADR and should not be reported as the ADR itself. Instead the cause of 
death should be recorded as the ADR term. 
Hospitalizations that do not meet criteria for SADR reporting are: 
• 
Hospitalization or prolonged hospitalization for technical, practical or social reasons, in 
absence of an AE. 
• 
Pre-planned hospitalizations: Any pre-planned surgery or procedure must be documented in 
the source documentation. Only if the pre-planned surgery needs to be performed earlier due 
to a worsening of the condition, should this event (worsened condition) be reported as a 
SADR. 
• 
An emergency visit due to an accident where the patient is treated and discharged. 
• 
When the patient is held 24 hours for observation and finally is not admitted. 
• 
Planned treatments at sites not associated to a hospital and generally considered as minor 
surgical procedures (i.e., laser eye surgery, arthroscopy, etc.). 
8.2.2 
Collection of Safety Information in the eCRF 
The investigators are responsible for ensuring that all AEs (serious and non-serious, related and not-
related) that occur after first dose of trabectedin until 30 days after last dose administered are reported 
using the applicable eCRF page within 15 calendar days from its knowledge. Beyond this period of time, 
only ADRs suspected to be related to trabectedin will be reported to the PharmaMar Pharmacovigilance 
Department. 
All SADR with the study treatment must be followed after discontinuation until the event or its sequelae 
resolve or stabilize at an acceptable level to the treating physician. 
Non-serious ADRs also will be collected in the pharmacovigilance database. The non-serious ADR will 
be retrieved by the Contract Research Organization (CRO) from the CRF and will be provided in a line 
listing on a monthly basis. 
8.3 Reporting to the Competent Regulatory Authorities 
PharmaMar is responsible for all applicable reporting and notifications to the competent Regulatory 
Authorities, if required. 

PharmaMar 
Page 33 
Protocol ID: ET-D-031-14 
Version 4- Amendement 2 
18 September 2018 
Confidential 
Trabectedin + PLD 
9 DATA MANAGEMENT 
9.1 Data Collection 
The CRO (Mapi) will be required to have a web-based electronic data capture (EDC) system and provide 
an integrated, transparent tool to facilitate subject selection and study progress at country, center and 
subject level. The EDC system will include eCRFs, which will be developed by the CRO in conjunction 
with the Sponsor to allow the capture of all study data. Local center staff will be trained to enter study 
data into the eCRFs. Paper CRFs will not be provided. Alternatively, CRO staff could perform this 
function, subject to any additional informed consent, patient confidentiality, and data protection 
requirements. 
The study will be monitored by monthly telephone calls to the treating clinicians and on-site visits (if 
required) by the clinical study monitor from the CRO. During the telephone calls the monitor will discuss 
study status as well as any potential problems with data completeness or practical study conduct. 
9.1.1 
Data Monitoring 
All data entered into the EDC system by site study staff will be pseudonymized to ensure patient 
confidentiality and compliance with country ethical and data regulations. No patient-identifying 
information will be available to the Sponsor or the CRO. There will be no formal source data verification. 
However, the structure and programming of the EDC system will permit remote monitoring of the 
pseudonymized data by the Sponsor or the CRO as the study data accrue in real time, allowing data 
queries to be raised with sites. 
Where feasible, given the limitations of non-interventional data collection, queries will be reconciled 
prior to database acceptance. Data will be clarified with the sites by phone, fax, email or completion of data 
clarification and/or quality control reconciliation forms. All queries and their reconciliations will be 
documented and an audit trail of any changes will be kept on file. Sites with high query rates will be 
identified and provided additional training. A quality control plan will be documented prior to the go-live 
date. 
9.2 Site Monitoring 
During the site visit, the study monitor should review source documents (including original patient 
records) and document retention (study file). Additionally, the monitor will discuss any problem with the 
treating clinicians. 
Adequate time for these visits should be allocated by the treating clinicians. The treating clinicians should 
also ensure that the monitor is given direct access to source documents (i.e., hospital or private charts, 
original laboratory records, appointment books, etc.) of the patient, which support data recorded on 
eCRFs. 
9.3 Data Quality Assurance 
Systems with procedures will be implemented to ensure the quality of every aspect of the study. 
The CRO maintains high data quality standards and utilizes processes and procedures to repeatedly ensure 
that the data are as clean and as accurate as possible when presented for analysis. Data quality is enhanced 
through a series of programmed data quality checks that automatically detect and prevent the entry of out-

PharmaMar 
Page 34 
Protocol ID: ET-D-031-14 
Version 4- Amendement 2 
18 September 2018 
Confidential 
Trabectedin + PLD 
of-range or anomalous data. A remote data quality audit will be performed at various times throughout the 
study on collected data. 
9.4 Site Inspection 
During the course of the study, the Quality Assurance Department of the Sponsor or external auditors 
contracted by the Sponsor may conduct an on-site audit visit. 
Participation in this study implies acceptance of potential inspection by national or foreign health 
authorities. 
9.5 Database Quality Assurance and Data Protection 
The EDC system meets approved established standards for the security of health information and is 
validated. The system also meets the International Conference on Harmonization (ICH; 
http://www.ich.org) guideline E6R1 regarding electronic study data handling and is available for audit 
upon request. Patient confidentiality will be strictly maintained. 
Access to the EDC system will be controlled via a hierarchical user-name and password control. Subject 
data will be pseudonymized through design of data entry fields that do not permit the entry of identifying 
information such as initials, date of birth, or center-assigned patient identifiers. Site staff only will enter 
data into eCRFs. Subject’s ages in whole years, but not date of birth, will be entered. No patient 
identifiers used by centers will be entered; rather the EDC program will automatically assign a study 
identification number (ID) to each case. The pseudonymized data as entered into the EDC system will be 
visible to the CRO and the Sponsor, but only center staff will be able to trace a case ID back to a patient 
identity, a necessary measure to allow center staff to respond to data queries raised by the CRO later. 
Detailed explanation of data protection and patient confidentiality measures will be included in each 
application for local ethics approval. Where necessary, these will include country-specific measures. 
9.6 Data Retention 
All treating clinician’s completed forms, original ICFs, and essential documents will be maintained at the 
study site according to pertinent regulations. 
 

PharmaMar 
Page 35 
Protocol ID: ET-D-031-14 
Version 4- Amendement 2 
18 September 2018 
Confidential 
Trabectedin + PLD 
10 STATISTICAL ANALYSIS 
10.1 Sample Size/Power Considerations 
At least 300 patients are to be selected. With this number it is judged that PFS after treatment with 
trabectedin + PLD will be estimated with sufficient accuracy. 
10.2 Interim Analysis 
An interim analysis after 50% (i.e., ~150 patients) of the recruitment will be performed in order to obtain 
a first approach of the results. 
10.3 Study Endpoints 
The primary endpoint is the PFS measured as time from first dose of trabectedin to disease progression as 
reported by the investigator or death regardless of cause. 
The secondary endpoints include the following: 
1. Response rate (CR + PR) 
2. Disease control rate (CR + PR + SD) 
3. OS  
4. ECOG/WHO PS 
5. Treatment duration (number of cycles) 
6. Treatment exposure 
7. Time to next treatment 
8. Safety of the combination of trabectedin + PLD 
10.4 Data Analysis 
All analyses will be based on the full analysis set (FAS), consisting of all the patients enrolled into the 
study and who have at least one administration of trabectedin. The FAS will be the primary analysis set 
for the safety analyses and for analyses assessing effectiveness. All endpoints will be summarized overall 
and by prior antiangiogenic drug usage. 
Frequency tables will be prepared for categorical variables. Continuous variables will be described by 
median, mean, standard deviation, minimum and maximum.  
For the analyses of time-to-event data, methods that take into account censored observations will be used 
(Kaplan-Meier estimates). Non-informative censoring will be assumed.  
10.4.1 Disposition 
Number and percentage of patients enrolled, reasons for non-participation in the study, patient disposition 
over the course of the study, inclusion/exclusion criteria, the number of patients included in the FAS, 
number of trabectedin cycles received before ICF was signed, reasons for treatment discontinuation and 

PharmaMar 
Page 36 
Protocol ID: ET-D-031-14 
Version 4- Amendement 2 
18 September 2018 
Confidential 
Trabectedin + PLD 
for not completing the study will be summarized. In addition survival status at end of study, number of 
deaths including cause of death will also be presented. 
10.4.2 Analysis of Baseline and Demographic Data 
Descriptive statistics will be presented for the information specified and will include the following: 
1. Relevant prior patient history and general patient characteristics (age, gender, disease status, co-
morbidity). 
2. Clinical evaluation. 
10.4.3 Analysis of the Primary Endpoint 
PFS and their fixed-time estimations will be analyzed using the Kaplan-Meier (KM) method. KM 
estimates and 95% CIs will be calculated based on estimated variance for log-log transformation of the 
estimate. 
10.4.4 Analysis of Secondary Endpoints 
Response 
Response rate will be summarized. Response is defined as a best tumor response of complete or partial 
response as reported by the investigator. Patients without an assessment of disease response will be 
treated as non-responders. Descriptive statistics will be provided for best overall tumor response and 
response rate (CR + PR) and two-sided exact binomial 95% confidence intervals will be presented. 
Disease Control 
It is defined as a best tumor response assessment of CR, PR, or SD. Patients without a post-baseline 
tumor disease assessment will be considered to not have disease control. The disease control rate will be 
presented along with two-sided exact binomial 95% confidence intervals.   
Overall Survival  
OS will be descriptively analyzed as done for the primary endpoint PFS. 
ECOG  
ECOG/WHO performance status scores will be summarized at baseline, worst/best scores under 
treatment, and scores at end of treatment. The change in scores from baseline to best/worst and end of 
treatment scores will also be summarized presenting categories: <0 (indicating an improvement), 0-2, >2-
4, and >4 (indicating worst deterioration). 
Treatment Exposure 
Trabectedin and PLD administration history will be summarized presenting the number of previous cycles 
received prior to IC. Descriptive statistics will be calculated for total number of cycles started, 
administration setting (inpatient/ outpatient), administered dose per infusion (mg), cycle duration (days), 
and treatment duration. Cumulative dose administered, dose intensity (mg) / week, relative weekly dose 
intensity (%), and total dose administered (mg) per cycles will also be presented. The number and 
percentage of patients with modifications (including dose missed, reductions, dose delays, or doses 
withheld) from the investigator reported schedule will be summarized by type of dose modification and 

PharmaMar 
Page 37 
Protocol ID: ET-D-031-14 
Version 4- Amendement 2 
18 September 2018 
Confidential 
Trabectedin + PLD 
reason for the dose modification. The number of dose missed/reductions/interruptions/delays per patient 
will also be summarized. 
Subsequent Anti-Cancer Treatment 
Exposure to subsequent anticancer drugs will be described. Time from last dose of trabectedin, type of 
therapy, setting (single, combo), number of cycles, and best response will be described by regimen 
number, including number and percentage of patients in each regimen.   
10.4.5 Safety Analysis 
Descriptive summaries presenting all AEs (serious and non-serious, related and not related) reported from 
Day 1 of study treatment to 30 days post last dose of study treatment. Patient incidence of adverse drug 
reactions related to trabectedin and related to PLD, respectively, will be summarized by system organ 
class, preferred term and severity grade for all drug reactions and serious drug reactions. The 
corresponding summaries will also be presented for ADRs and SADRs grade 3 or higher. 
10.4.6 Other Data 
The number and percentage of patients with clinically significant laboratory results, symptomatic 
response, concomitant medications, physical examination, and exposure to subsequent surgery will also 
be summarized. 
10.4.7 Pharmacokinetic / Pharmacodynamic Analysis 
No pharmacokinetic or pharmacodynamic evaluations are planned. 
 
11 ETHICAL, ADMINISTRATIVE, AND REGULATORY 
REQUIREMENTS 
This study will comply with ethical and regulatory requirements for each participating country. 
11.1 Conduct of Study 
This study will comply with the definition of the non-interventional study provided in Article 2(c) of 
Directive 2001/20/EC and the Guideline on good pharmacovigilance practices (GVP) Annex I - 
Definitions (EMA/876333/2011) and GVP Module VI (EMA/873138/2011). 
This study will be conducted in compliance with this protocol and in accordance with the ethical 
principles that have their origin in the Declaration of Helsinki (located at 
http://www.wma.net/en/30publications/10policies/b3/) and will be consistent with the International 
Ethical Guidelines for Biomedical Research Involving Human Subjects (Council for International 
Organizations of Medical Sciences [CIOMS], 2002; located at 
http://www.cioms.ch/publications/layout_guide2002.pdf) and the Good Clinical Practices (GCP; located 
at http://www.emea.europa.eu) guidelines. The study will also follow the International Society of 
Pharmacoepidemiology, Guidelines for Good Pharmacoepidemiology Practices (2008), the International 
Ethical Guidelines for Epidemiological Studies (CIOMS, 2009), as well as all other applicable regulatory 
requirements. 
Study personnel involved in conducting this trial will be qualified by education, training, and experience 
to perform their respective task(s). 

PharmaMar 
Page 38 
Protocol ID: ET-D-031-14 
Version 4- Amendement 2 
18 September 2018 
Confidential 
Trabectedin + PLD 
11.2 Patient Information and Informed Consent 
The rights, safety, and well-being of the trial patients are the most important considerations and should 
prevail over interests of science and society. 
The Patient Information Sheet will include all elements required according to the GCP guidelines and 
applicable regulatory requirements. 
The treating clinicians or their designee must provide the patients with a copy of the consent form and 
written full information about the study in a language that is non-technical and easily understood. The 
treating clinicians should allow enough time for the patients or their legally acceptable representative to 
inquire about the details of the study. Then, the ICF must be freely signed and personally dated by the 
patients and by the person who conducted the informed consent discussion before the beginning of the 
study. The patients should receive a copy of the signed ICF and any other written information prior to 
participation in the trial. 
During their participation in the trial, any updates to the consent form and to the written information have 
to be provided to the patients. 
If a new consent needs to be obtained from the patients, the treating clinicians or their designee should 
inform the patient of any new information relevant to his/her willingness to continue participation in the 
study before obtaining the new written consent. 
11.3 Confidentiality 
The collection and processing of personal data from patients enrolled into this study will be limited to 
those data that are necessary to investigate the effectiveness, safety, quality, and utility of trabectedin or 
any other active treatment for ovarian cancer. It is the treating clinician’s responsibility that sufficient 
information related to the identity of the patients will be retained. The clinical trial monitor, the Sponsor 
auditor, the EC or the regulatory authorities should have direct access to all requested trial-related records 
and should agree to keep the identity of study patients confidential. 
The data must be collected and processed with adequate precautions to ensure confidentiality and 
compliance with applicable data privacy protection laws and regulations. 
Explicit consent for the processing of personal data will be obtained from the participating patients before 
collection of data, and such consent should also address the transfer of the data to other entities and to 
other countries. 
The Sponsor will comply with Directive 95/46/EEC of the European Parliament and the Council dated 24 
October 1995 on the protection of individuals with regard to the processing of personal data and on the 
free movement of such data for all data collected before 25 May 2018. After this date, the Sponsor will 
comply with Regulation (EU) 2016/679 dated 27 April 2016, repealing Directive 95/46/EEC. 
11.4 Ethics Committee Review 
The protocol, any amendments, and the ICF will receive Independent Ethics Committee ([IEC] or 
Institutional Review Board [IRB] or Research Ethics Board [REB]) approval/favorable opinion prior to 
initiation of the study. Treating clinicians under the jurisdiction of a local IEC must obtain approval of the 
protocol, ICF, and patient enrollment materials prior to initiating the study at the site. 

PharmaMar 
Page 39 
Protocol ID: ET-D-031-14 
Version 4- Amendement 2 
18 September 2018 
Confidential 
Trabectedin + PLD 
The CRO in charge of the study management will coordinate the submissions to the IECs and any other 
necessary authorities, as per international and local requirements. 
The decision of the IEC concerning the conduct of the study will be made in writing to the treating 
clinicians. A copy of the IEC approval letter, IEC committee member roster, and the IEC approved ICF 
must be submitted to the Sponsor prior to initiating any study procedures at a site and retained in the site 
files. 
The treating clinicians and/or the Sponsor is/are responsible for keeping the IEC informed of significant 
new information about study drug. 
11.5 Protocol Adherence and Modifications 
The study will be conducted in accordance with the current protocol or protocol amendments. All 
protocol and protocol amendments will be agreed upon by the Sponsor and the treating clinicians. 
Amendments to the protocol may only be made by the Sponsor. All protocol amendments must be signed 
and dated by the treating clinicians, and submitted and approved by the IEC and any other local authority 
as necessary, prior to implementation of the amendment. 
Administrative changes of the protocol are minor corrections and/or clarifications that have no impact on 
the way the study is to be conducted. 
11.6 Records Retention 
The treating clinicians must maintain all essential documents until notified by the Sponsor and in 
accordance with all local laws and regulations. The Sponsor and the CRO in charge of the study will 
follow their applicable standard operating procedures regarding retention of records. 
11.7 Insurance 
The Sponsor will provide insurance or indemnity in accordance with pertinent regulatory requirements. 
11.8 Use of Study Information and Publications 
Results of this clinical study will be disclosed by posting a summary online at 
www.clinicaltrialsregister.eu within 12 months of the last patient last visit.  
Before the treating clinicians of this study submit a manuscript/paper or abstract for publication or 
otherwise publicly disclose information concerning trabectedin, the Sponsor must be provided with at 
least 60 days to review and approve the proposed publication or disclosure in order to ensure that 
confidential and proprietary data are protected. If the Sponsor determines that patentable matters are 
disclosed in the proposed, it shall be withheld for a period of time considered convenient. If the study is 
part of a multicenter study, publications of the study shall be prepared in conjunction with the treating 
clinicians and the institutions from all appropriate sites contributing data, analysis, and comments. 
 
 

PharmaMar 
Page 40 
Protocol ID: ET-D-031-14 
Version 4- Amendement 2 
18 September 2018 
Confidential 
Trabectedin + PLD 
12 Investigator Agreement 
I have read the foregoing protocol “Non-interventional, multicenter, prospective, European study to 
analyze if the effectiveness of trabectedin + PLD in the treatment of relapsed ovarian cancer (ROC) 
patients regardless of previous use of an antiangiogenic drug”, Version 4 Amendment 2, dated 18 
September 2018, and agree to abide by all provisions set forth therein. 
I agree to comply with the ICH Tripartite Guideline on Good Clinical Practice and applicable national or 
regional regulations/guidelines. 
I agree to ensure that Financial Disclosure Statements will be completed by: 
1. Me (including, if applicable, my spouse [or legal partner,] and dependent children), 
2. My sub-investigators (including, if applicable, their spouses [or legal partners], and dependent 
children) 
at the start of the study and for up to 1 year after the study is completed, if there are changes that affect 
my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be used for any 
purpose other than the evaluation or conduct of the clinical investigation without the prior written consent 
of the Sponsor. 
 
 
 
 
Investigator’s name (block letters) 
 
 
 
Investigator’s signature 
 
 
Date (dd/mmm/yyyy) 
 
 
 

PharmaMar 
Page 41 
Protocol ID: ET-D-031-14 
Version 4- Amendement 2 
18 September 2018 
Confidential 
Trabectedin + PLD 
13 References 
Aravantinos G, Pectasides D. Bevacizumab in combination with chemotherapy for the treatment of 
advanced ovarian cancer: a systematic review. J Ovarian Res. 2014;7:57. 
Caelyx® (pegylated liposomal doxorubicin hydrochloride) [summary of product characteristics]. Belgium: 
Janssen-Cilag International NV; 2006. 
Carter NJ, Keam SJ. Trabectedin : a review of its use in the management of soft tissue sarcoma and 
ovarian cancer. Drugs. 2007;67(15):2257-2276. 
Colombo N, Peiretti M, Parma G, Lapresa M, Mancari R, Carinelli S, et al. Newly diagnosed and 
relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and 
follow-up. Ann Oncol. May 2010;21 Suppl 5:v23-30. 
Del Campo JM, Sessa C, Krasner CN, Vermorken JB, Colombo N, Kaye S, et al. Trabectedin as single 
agent in relapsed advanced ovarian cancer: results from a retrospective pooled analysis of three phase II 
trials. Med Oncol. 2013 Mar;30(1):435. 
Della Pepa C, Banerjee S. Bevacizumab in combination with chemotherapy in platinum-sensitive ovarian 
cancer. Onco Targets Ther. 2014;7:1025-1032. 
Eisenhauer EA, Kaye SB, Sessa C, De Vries EGE, van Dam GM, Glaudemans AWJM, et al. Emerging 
diagnostic and therapeutic targets in gynecological cancers: from science to clinical practice. Ann Oncol. 
September 1, 2012 2012;23(suppl 9):ix40-ix41. 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation 
criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. Jan 2009;45(2):228-247. 
Erba E, Bergamaschi D, Bassano L, Damia G, Ronzoni S, Faircloth GT, et al. Ecteinascidin-743 (ET-
743), a natural marine compound, with a unique mechanism of action. Eur J Cancer. Jan 2001;37(1):97-
105. 
González Martín A, Redondo A, Jurado M, De Juan A, Romero I, Bover I, et al. GEICO (Spanish Group 
for Investigation on Ovarian Cancer) treatment guidelines in ovarian cancer 2012. Clin Transl Oncol. 
2013 Jul;15(7):509-525. 
Holschneider CH, Berek JS. Ovarian cancer: epidemiology, biology, and prognostic factors. Semin Surg 
Oncol. Jul-Aug 2000;19(1):3-10. 
Huang S, Robinson JB, Deguzman A, Bucana CD, Fidler IJ. Blockade of nuclear factor-kappaB signaling 
inhibits angiogenesis and tumorigenicity of human ovarian cancer cells by suppressing expression of 
vascular endothelial growth factor and interleukin 8. Cancer Res. Oct 1 2000;60(19):5334-5339. 
Ledermann JA, Raja FA, Fotopoulou C, Gonzalez-Martin A, Colombo N, Sessa C, ESMO Guidelines 
Working Group. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice 
Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24:vi24-vi32. 

PharmaMar 
Page 42 
Protocol ID: ET-D-031-14 
Version 4- Amendement 2 
18 September 2018 
Confidential 
Trabectedin + PLD 
Luis F. Phase 2 clinical trial of ET-743 as 2nd and 3rd line treatment in patients with advanced stage and 
/or metastatic soft tissue sarcoma. Clinical Study Report (ET-B-010- 9). Madrid: PharmaMar; December 
2005. EDMS-PSDB- 4279949. 
Maringe C, Walters S, Butler J, Coleman MP, Hacker N, Hanna L, et al. Stage at diagnosis and ovarian 
cancer survival: evidence from the International Cancer Benchmarking Partnership. Gynecol Oncol. Oct 
2012;127(1):75-82. 
Martinez EJ, Corey EJ, Owa T. Antitumor activity- and gene expression-based profiling of ecteinascidin 
Et 743 and phthalascidin Pt 650. Chem Biol. Dec 2001;8(12):1151-1160. 
Martinez N, Sanchez-Beato M, Carnero A, Moneo V, Tercero JC, Fernandez I, et al. Transcriptional 
signature of Ecteinascidin 743 (Yondelis, Trabectedin) in human sarcoma cells explanted from chemo-
naive patients. Mol Cancer Ther. May 2005;4(5):814-823. 
Monk BJ, Herzog TJ, Kaye SB, Krasner CN, Vermorken JB, Muggia FM, et al. Trabectedin plus 
pegylated liposomal Doxorubicin in recurrent ovarian cancer. J Clin Oncol. 2010 Jul 1;28(19):3107-3114. 
Monk BJ, Herzog TJ, Kaye SB, Krasner CN, Vermorken JB, Muggia FM, et al. Trabectedin plus 
pegylated liposomal doxorubicin (PLD) versus PLD in recurrent ovarian cancer: Overall survival 
analysis. Eur J Cancer. 2012 Oct;48(15):2361-2368. 
National Cancer Institute. Recurrent or persistent ovarian epithelial cancer treatment. 2014; 
http://www.cancer.gov/cancertopics/pdq/treatment/ovarianepithelial/HealthProfessional/page6. Accessed 
13 August, 2014. 
National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN 
Guidelines). Ovarian cancer, including fallopian tube cancer and primary peritoneal cancer. Fort 
Washington, PA: National Comprehensive Cancer Network; 2014. Version 3.2014. 
Online Dictionary for Regulatory Activities Terms Summary - 
http://bioportal.bioontology.org/ontologies/42280?p=terms&conceptid=20000032. Accessed 06 
September, 2016. 
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response 
criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. Dec 1982;5(6):649-655. 
Papaioannou D, Rafia R, Stevenson MD, Stevens JW, Evans P. Trabectedin for the treatment of relapsed 
ovarian cancer. Health Technol Assess. May 2011;15 Suppl 1:69-75. 
Pommier Y, Kohlhagen G, Bailly C, Waring M, Mazumder A, Kohn KW. DNA sequence- and structure-
selective alkylation of guanine N2 in the DNA minor groove by ecteinascidin 743, a potent antitumor 
compound from the Caribbean tunicate Ecteinascidia turbinata. Biochemistry. Oct 15 1996;35(41):13303-
13309. 
Poveda A, Ray-Coquard I, Romero I, Lopez-Guerrero JA, Colombo N. Emerging treatment strategies in 
recurrent platinum-sensitive ovarian cancer: focus on trabectedin. Cancer Treat Rev. Apr 2014;40(3):366-
375. 

PharmaMar 
Page 43 
Protocol ID: ET-D-031-14 
Version 4- Amendement 2 
18 September 2018 
Confidential 
Trabectedin + PLD 
Poveda A, Ray-Coquard I, Romero I, Lopez-Guerrero JA, Colombo N. Emerging treatment strategies in 
recurrent platinum-sensitive ovarian cancer: focus on trabectedin. Cancer Treat Rev. 2014 Apr;40(3):366-
375. 
Poveda A, Vergote I, Tjulandin S, Kong B, Roy M, Chan S, et al. Trabectedin plus pegylated liposomal 
doxorubicin in relapsed ovarian cancer: outcomes in the partially platinum-sensitive (platinum-free 
interval 6-12 months) subpopulation of OVA-301 phase III randomized trial. Ann Oncol. 2011 
Jan;22(1):39-48. 
Roett MA, Evans P. Ovarian cancer: an overview. Am Fam Physician. Sep 15 2009;80(6):609-616. 
Ryan DP, Supko JG, Eder JP, Seiden MV, Demetri G, Lynch TJ, et al. Phase I and pharmacokinetic study 
of ecteinascidin 743 administered as a 72-hour continuous intravenous infusion in patients with solid 
malignancies. Clin Cancer Res. Feb 2001;7(2):231-242. 
Slomovitz BM, Worley MJ, Markman M, Coleman RL. Emerging therapeutics for primary peritoneal 
cancer. Expert Opin Emerg Drugs. Mar 2011;16(1):71-84. 
Taamma A, Misset JL, Riofrio M, Guzman C, Brain E, Lopez Lazaro L, et al. Phase I and 
pharmacokinetic study of ecteinascidin-743, a new marine compound, administered as a 24-hour 
continuous infusion in patients with solid tumors. J Clin Oncol. Mar 1 2001;19(5):1256-1265. 
Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to 
evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of 
Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer 
Inst. Feb 2 2000;92(3):205-216. 
Twelves C, Hoekman K, Bowman A, Vermorken JB, Anthoney A, Smyth J, et al. Phase I and 
pharmacokinetic study of Yondelis (Ecteinascidin-743; ET-743) administered as an infusion over 1 h or 
3 h every 21 days in patients with solid tumours. Eur J Cancer. Sep 2003;39(13):1842-1851. 
van Kesteren C, Cvitkovic E, Taamma A, Lopez-Lazaro L, Jimeno JM, Guzman C, et al. 
Pharmacokinetics and pharmacodynamics of the novel marine-derived anticancer agent ecteinascidin 743 
in a phase I dose-finding study. Clin Cancer Res. Dec 2000;6(12):4725-4732. 
van Kesteren C, Twelves C, Bowman A, Hoekman K, Lopez-Lazaro L, Jimeno J, et al. Clinical 
pharmacology of the novel marine-derived anticancer agent Ecteinascidin 743 administered as a 1- and 3-
h infusion in a phase I study. Anticancer Drugs. Apr 2002;13(4):381-393. 
Whetzel PL, Noy NF, Shah NH, Alexander PR, Nyulas C, Tudorache T, et al. BioPortal: enhanced 
functionality via new Web services from the National Center for Biomedical Ontology to access and use 
ontologies in software applications. Nucleic Acids Res. Jun 14 Epub 2011;39(Web Server Issue):W541-
545. 
World Health Organization. GLOBOCAN 2012: Estimated cancer incidence , mortality and prevalence 
worldwide in 2012. 2014; http://globocan.iarc.fr/Pages/online.aspx. Accessed August 12, 2014. 
Yondelis® (trabectedin) [summary of product characteristics]: Pharma Mar SA; 2014. 
 

PharmaMar 
Page 44 
Protocol ID: ET-D-031-14 
Version 4- Amendement 2 
18 September 2018 
Confidential 
Trabectedin + PLD 
14 Appendices 
 
Appendix 14.1 
Study Period Design 
Appendix 14.2 
Performance Status 
Appendix 14.3 
Response Criteria: RECIST version 1.1 
 

PharmaMar 
Page 45 
Protocol ID: ET-D-031-14 
Version 4- Amendement 2 
18 September 2018 
Confidential 
Trabectedin + PLD 
14.1 Appendix – Study Period Design 
Figure 1: Study design schematic 
 
1.
The informed consent must be signed at least 1 day following completion of the first trabectedin + PLD 
administration. 
2.
There are no predetermined numbers of study cycles. 
3.
A study cycle will be determined according to trabectedin SmPC and treating physician's practice. 
4.
There may be additional trabectedin + PLD administrations following the first administration prior to 
signing the informed consent. Patients must have received a minimum of 1 cycle of trabectedin + PLD 
before their inclusion in the study. 
5.
The signing of the informed consent, screening, and index date (administration of the second or subsequent 
dose of trabectedin + PLD) may all be on the same day. 
6.
Final data collection for an individual patient will coincide with the study’s last follow-up visit (at 13 
months for a patient who completed the 12-month Observation Period or at 12 months for patients who had 
their last dose of trabectedin before the end of the 12-month Observation Period), or at the end of 
Observation Period for patients who died or who discontinued the study. 
First Trabectedin + PLD administration
Index Date (First administration of trabectedin + PLD while on study) 
Additional trabectedin + PLD administrations 
End of Observation Period (12 month s after index date, end of treatment with trabectedin, 
patient discontinuation for any reason, progression of disease (PD) or patient’s death 
Last trabectedin + PLD administration 
Informed consent signature 
End of Study - 13 months after Index date 
End of Study - 12 months after Index date 
 
Qualification 
Period 
Observation Period 
 12 month 
Follow-up 
Period 
1 month
Follow-up Period 
Up to 12 months after Index 
date
 

PharmaMar 
Page 46 
Protocol ID: ET-D-031-14 
Version 4- Amendement 2 
18 September 2018 
Confidential 
Trabectedin + PLD 
14.2 Appendix – Performance Status 
Performance status evaluated according to the Eastern Cooperative Oncology Group (ECOG) score (also 
known as the World Health Organization [WHO] score) is shown in Table 2.  
Table 2.  ECOG Performance Status 
Grade 
ECOG Score Description* 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light house work, office work 
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 
5 
Dead 
* As published in American Journal of Clinical Oncology: Oken MM, Creech RH, Tormey DC, Horton 
J, Davis TE, McFadden ET, et al. Toxicity and response criteria of the Eastern Cooperative Oncology 
Group. Am J Clin Oncol. Dec 1982;5(6):649-655. 
 
The ECOG Performance Status is in the public domain therefore available for public use. Credit is given to the 
Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair. 
 
 

PharmaMar 
Page 47 
Protocol ID: ET-D-031-14 
Version 4- Amendement 2 
18 September 2018 
Confidential 
Trabectedin + PLD 
14.3 Appendix – Response Criteria: RECIST Version 1.1