Clinical trial NCT03164980
Conditions: Quality of Life Ovarian Cancer Recurrent Ovarian Carcinoma
Keywords: Quality of life ovarian cancer platinum sensitive recurrent
Sponsor: North Eastern German Society of Gynaecological Oncology
Start date: 2018-02-01; Completion date: 2023-08-08
Enrollment: 89 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multicenter, randomized, controlled, open-label study including patients with recurrent, platinum-sensitive, ovarian, peritoneal or fallopian tube cancer.

The main scope of the trial is to evaluate QoL during chemotherapy comparing trabectedin/PLD with other standard platinum-based chemotherapy in platinum-sensitive disease.

Detailed description:
This is a multicenter, randomized, controlled, open-label study including patients with recurrent, platinum-sensitive, ovarian, peritoneal or fallopian tube cancer.

The main scope of the trial is to evaluate QoL during chemotherapy comparing trabectedin/PLD with other standard platinum-based chemotherapy in platinum-sensitive disease.

Patients with recurrent, platinum-sensitive, ovarian, fallopian tube and peritoneal cancer will be stratified according to surgery for relapse (R0 vs. R1/2 resection) vs. no surgery in the same setting and age (\< 75 years vs. ≥ 75 years), and randomized 1:1 to receive either trabectedin/PLD (Arm A) or one of 3 platinum-based standard therapies without bevacizumab (Arm B, "other standard therapy"). In case of randomization to "other standard therapy", the investigator has the choice between carboplatin/PLD, carboplatin/gemcitabine and carboplatin/paclitaxel. Patients in both treatment arms will receive chemotherapy up for 6 cycles or until disease progression (PD), unacceptable toxicities or patient's wish to stop therapy, whichever occurs first.

Arms: arm 1: PLD followed by Trabectedin. Treatment is repeated every 3 weeks for 6 cycles or until disease progression. arm 2: * Carboplatin/PLD
* Carboplatin/Gemcitabine
* Carboplatin/Paclitaxel Patients will be treated for 6 cycles or until PD, unacceptable toxicity or patient's wish to discontinue, whichever occurs first.
Interventions: intervention 1: Trabectidin (Yondelis)
Intervention descriptions: intervention 1: To compare QoL in patients treated with trabectedin/PLD vs. other standard combination therapy of carboplatin/ PLD, carboplatin/ gemcitabine, or carboplatin/ paclitaxel

Protocol documents:
Prot_000.pdf: 
 
 
 
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“COMPASS” 
 
Comparison of QoL between Trabectedin / PLD and standard 
platinum-based therapy in patients with platinum sensitive 
recurrent ovarian, fallopian tube and peritoneal cancer 
Intergroup-Study of NOGGO and BNGO 
 
EudraCT:  
 
 
2016‐005029-36 
ClinicalTrials.gov ID:  
NCT03164980 
Sponsor’s Protocol Code:  NOGGO S16/COMPASS  
 
 
Protocol Version             3.0 
Protocol Date                  07Dec2020 
 
 
 
 
 
 
Sponsor of the Study according to AMG 
NOGGO e.V. 
Schwedenstraße 9 
13359 Berlin 
Tel.: +49 30 / 403 68 65 30 
Fax: +49 30 / 403 68 65 40 
Email: studies@noggo.de 
 
 
CONFIDENTIALITY STATEMENT 
This protocol is confidential information and is intended solely for the guidance of the clinical 
investigation. This protocol may not be disclosed to third parties not associated with the clinical 
investigation or used for any purpose without the prior written consent of the sponsor. 


 
 
 
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Lead Coordinating Investigator (LKP) 
Prof. Dr. med. Jalid Sehouli 
Charité-University Hospital of Berlin 
Campus Virchow-Klinikum 
Department of Gynecology 
Augustenburger Platz 1 
13353 Berlin 
Tel.: +49 30 / 450 564 002 
Fax: +49 30 / 450 564 900 
Email: Jalid.Sehouli@charite.de 
 
Clinical Trial Management 
Institut für Klinische Krebsforschung IKF 
GmbH am Krankenhaus Nordwest  
Steinbacher Hohl 2-26 
60488 Frankfurt am Main 
Tel.:  
+49 69 7601-4420 
Fax:  
+49 69 7601-3655 
Email: info@ikf-khnw.de 
 
Statistics  
Dario Zocholl 
Institut für Biometrie und Klinische Epidemiologie der 
Charité – Universitätsmedizin Berlin 
Charitéplatz 1 
10117 Berlin 
Tel.: +49 30 / 450 562 175 
Fax: +49 30 / 450 562 972 
Email: dario.zocholl@charite.de 
 
Monitoring & Data Management 
Institut für Klinische Krebsforschung IKF 
GmbH am Krankenhaus Nordwest  
Steinbacher Hohl 2-26 
60488 Frankfurt am Main 
Tel.: +49 69 7601-4420 
Fax: +49 69 7601-3655 
Email: info@ikf-khnw.de 
 
Study lead for BNGO 
PD. Dr. med. Christian M. Kurbacher, Bonn 
 
Institutional Review Board (Ethics Committee) 
Ethik-Kommission des Landes Berlin am Landesamt 
für Gesundheit und Soziales (LaGeSo) Berlin 
Fehrbelliner Platz 1 
10707 Berlin 
 
 
 
 
Steering committee 
Prof. Dr. med. Salah-Eddin Al-Batran, Frankfurt 
Dr. med. Radoslav Chekerov, Berlin 
Dr. rer. nat. Ute Goerling, Berlin 
PD. Dr. med. Christian M. Kurbacher, Bonn 
Priv.-Doz. Dr. med. Gülten Oskay-Öczelik  
Prof. Dr. med. Matthias Rose, Berlin 
Dr. Jörg Schilling, Berlin 
 
 
 
 




 
 
 
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Site / Principal Investigator / Deputy 
Principal Investigator’s Site: 
Site:  
 
________________________________ 
Address:  
________________________________ 
________________________________ 
or 
 
< stamp > 
 
 
Principal Investigator (Print name): _____________________________ 
I have read and checked the protocol diligently; I comply with the stated demands and requirements 
and agree to conduct the study according to the guidelines of Good Clinical Practice (GCP) and the 
requirements of the responsible authorities in regard to reconciliation of original data and to 
audits/inspections.  
I consent to report every serious clinical adverse event to the CRO within one working day, whether it 
is related to study medication or not.  
 
_______________________________  
______________________________________ 
Place and Date  
 
 
 
Signature Principal Investigator 
 
 
Deputy (Print name): ______________________________________ 
 
_______________________________  
______________________________________ 
Place and Date  
 
 
 
Signature Deputy 
 
 
If applicable: 2nd Deputy (Print name): ______________________________________ 
 
_______________________________  
______________________________________ 
Place and Date  
 
 
 
Signature 2nd Deputy 
 
 
 


 
 
 
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1 Table of contents 
1 
Table of contents ............................................................................................................................. 5 
2 
Abbreviations ................................................................................................................................... 8 
3 
Synopsis ............................................................................................................................................ 9 
4 
Background and Rationale ............................................................................................................. 17 
4.1 
Rationale .................................................................................................................................17 
4.2 
Pegylated liposomal doxorubicin (PLD) ................................................................................19 
4.3 
Trabectedin .............................................................................................................................19 
4.4 
Clinical safety and efficacy data of trabectedin/PLD .............................................................20 
4.5 
Quality of Life: EORTC QLQ-C30 and QLQ-OV28 .............................................................21 
4.6 
Justification for the selection of the control arm ....................................................................22 
4.7 
The relevance of this study to current care and benefit-risk assessment ................................23 
5 
Endpoints ....................................................................................................................................... 24 
5.1 
Efficacy objectives .................................................................................................................24 
5.2 
Safety objectives .....................................................................................................................24 
6 
Patient Selection ............................................................................................................................ 25 
6.1 
Inclusion Criteria ....................................................................................................................25 
6.2 
Exclusion Criteria ...................................................................................................................26 
7 
Patient Recruitment and Randomization ....................................................................................... 27 
8 
Therapy schema ............................................................................................................................. 28 
9 
Concomitant Therapy ..................................................................................................................... 29 
10 
Criteria for continuation, dose adjustment, overall duration, and termination ....................... 29 
10.1 
General remarks .....................................................................................................................29 
10.2 
Requirements for chemotherapy administration .....................................................................30 
10.3 
Chemotherapy dose adjustment ..............................................................................................31 
10.4 
Criteria for study termination .................................................................................................32 
10.4.1 
Individual criteria for treatment termination ................................................................. 32 
10.4.2 
General criteria for premature termination of the trial .................................................. 33 
10.4.3 
Handling premature treatment (whole treatment) termination ...................................... 33 
11 
Study drugs ................................................................................................................................ 33 
11.1 
Pegylated Liposomal Doxorubicin (PLD) ..............................................................................33 
11.2 
Trabectedin .............................................................................................................................33 
11.3 
Carboplatin .............................................................................................................................34 
11.4 
Gemcitabine ............................................................................................................................34 
11.5 
Paclitaxel ................................................................................................................................34 
12 
Treatment schedule and schedule of assessments ................................................................... 35 
12.1 
Screening/baseline examinations and randomization .............................................................37 
12.2 
Treatment in Arm A (Trabectedin/PLD) ................................................................................38 
12.3 
Treatment in Arm B (Carboplatin/PLD, carboplatin/gemcitabine, carboplatin/paclitaxel) ...38 


 
 
 
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12.4 
General examinations before start of a new chemotherapy cycle (cycle 1*-6) ......................38 
12.5 
End of study treatment (EOT) ................................................................................................39 
12.6 
Follow-up ...............................................................................................................................40 
12.7 
Patient’s care after end of study .............................................................................................41 
13 
Safety ......................................................................................................................................... 41 
13.1 
Definitions ..............................................................................................................................41 
13.1.1 
Adverse event (AE) ....................................................................................................... 41 
13.1.2 
Serious adverse event (SAE) ......................................................................................... 42 
13.2 
Relationship of an adverse event to the study drug(s) ............................................................44 
13.3 
Severity of an adverse event ...................................................................................................44 
13.4 
Unexpected adverse event / SUSAR ......................................................................................45 
13.5 
Reporting procedures .............................................................................................................46 
13.5.1 
Reporting of Adverse Events (serious and non-serious) ............................................... 46 
13.5.2 
Reporting of Serious Adverse Events ............................................................................ 46 
13.6 
Reporting Pregnancy Cases Occurred within the Clinical Trial .............................................48 
14 
Quality control and quality assurance ....................................................................................... 49 
14.1 
Quality assurance ...................................................................................................................49 
14.2 
Standardization and randomization ........................................................................................49 
14.3 
Audits / inspections ................................................................................................................49 
14.4 
Monitoring ..............................................................................................................................50 
14.5 
Plausibility check, data cleaning and coding ..........................................................................50 
14.6 
Data management ...................................................................................................................50 
14.7 
Information on study drugs to trial investigators....................................................................51 
15 
Regulatory and ethical obligations ............................................................................................ 51 
15.1 
Regulatory and ethical compliance ........................................................................................51 
15.2 
Registration and request for authorization of the trial ............................................................51 
15.3 
Institutional review board / ethics committee.........................................................................52 
15.4 
Informed consent ....................................................................................................................52 
15.5 
Insurance ................................................................................................................................52 
15.6 
Patient confidentiality .............................................................................................................52 
16 
Statistical design ........................................................................................................................ 53 
16.1 
General considerations ...........................................................................................................53 
16.2 
Sample size calculation ..........................................................................................................53 
16.3 
Study Duration .......................................................................................................................53 
16.4 
Efficacy parameters ................................................................................................................53 
16.5 
Analysis ..................................................................................................................................54 
16.5.1 
Study populations for the analysis ................................................................................. 55 
16.5.2 
Statistical methods for the analysis ............................................................................... 55 
16.6 
Methods against bias ..............................................................................................................56 
17 
Data management ..................................................................................................................... 56 
17.1 
Data collection ........................................................................................................................56 


 
 
 
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17.2 
Confidentiality ........................................................................................................................57 
17.3 
Investigator site file ................................................................................................................57 
18 
Funding of the study and responsibilities ................................................................................. 57 
18.1 
Financing ................................................................................................................................57 
18.2 
Responsibilities ......................................................................................................................57 
19 
Administrative and legal obligations ......................................................................................... 58 
19.1 
Protocol amendments .............................................................................................................58 
19.2 
Trial termination .....................................................................................................................58 
19.3 
Trial documentation and data storage .....................................................................................58 
19.4 
Publication and registration of the study ................................................................................59 
20 
References ................................................................................................................................. 60 
21 
Appendices ................................................................................................................................ 62 
21.1 
Charlson Score .......................................................................................................................62 
21.2 
ECOG-Classification ..............................................................................................................63 
21.3 
NRS ........................................................................................................................................64 
21.4 
EORTC QLQ-C30 version 3.0 (German Version) .................................................................65 
21.5 
EORTC QLQ-OV28 (German Version) ................................................................................67 
 
 
 
List of tables 
Table 1: Treatment Schedule. ................................................................................................................ 16 
Table 2: TOI-QLQ-OV with data from HECTOR study. ..................................................................... 22 
Table 3: TOI-QLQ-OV changes to different time points with data from HECTOR study- .................. 22 
Table 4: Arm A dose reduction due to toxicity ..................................................................................... 32 
Table 5: Treatment Schedule. ................................................................................................................ 35 
Table 6: SmPCs of reference products .................................................................................................. 45 
Table 7: Charlson Score with age points [36, 37] ................................................................................. 62 
Table 8: ECOG Performance Status as developed by the Eastern Cooperative Oncology Group[38]. 63 
 
List of figures 
Figure 1: Study Scheme. ....................................................................................................................... 36 
 
 


 
 
 
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2 Abbreviations 
AE  
 
Adverse Event 
AMG 
Arzneimittelgesetz (German Drug 
Law) 
ANC  
Absolute neutrophil count 
AP  
Alkaline Phosphatase 
AST/ALT 
Aspartate aminotransferase  
 
 
(=sGOT)/ Alanine  
 
 
Aminotransferase (=sGPT) 
BfArM  
Bundesinstitut für Arzneimittel  
 
 
und Medizinprodukte 
CI 
 
Confidence Interval 
CPK   
Creatine phosphokinase 
CR  
 
Complete Response 
CRF 
 
Case Report Form 
CRO 
 
Contract Research Organization 
CT  
 
Computer Tomography 
CTC/CTCAE  National Cancer Institute:  
 
 
Common Terminology Criteria  
for Adverse Events 
DNA  
Desoxyribonucleic Acid 
DSUR  
Developmental Safety Update  
 
 
Report 
ECG 
 
Electrocardiogram 
eCRF   
Electronic Case Report Form 
ECOG   
Eastern Cooperative Oncology  
 
 
Group 
EDC    
 Electronic Data Capture  
EORTC  
European Organisation for the  
 
 
Research and Treatment of  
 
 
Cancer 
EOT 
 
End Of Treatment 
EP  
 
Efficacy Population 
ESMO   
European Society for Medical  
 
 
Oncology 
FPI 
 
First Patient In 
FU 
 
Follow Up 
GCP   
Good Clinical Practice 
GGT   
Gamma Glutamyl Transpeptidase 
Hb 
 
Hemoglobin 
HR 
 
Hazard Ratio 
ICH  
 
International Conference on  
 
 
Harmonisation 
ITT  
 
Intent-To-Treat population 
IKF 
 
Institut für Klinische  
 
 
 
Krebsforschung IKF GmbH am 
                          Krankenhaus Nordwest       
IMP  
 
Investigational Medicinal Product 
IRB 
 
Institutional Review Board 
ISF  
 
Investigator Site File 
i.v. 
 
Intravenous 
IWRS  
Interactive Web Response System 
kg  
 
Kilogram 
 
 
LKP 
 
Leiter der Klin. Prüfung 
 
 
(Coordinating investigator) 
LPI 
 
Last Patient In 
LVEF  
Left Ventricular Ejection 
 
 
Fraction 
MASCC  
Multinational Association of 
 
 
Supportive Care in Cancer 
MDRD  
Modification of Diet in Renal 
 
 
Disease 
mg  
 
Milligram 
m2  
 
Square meter 
ml  
 
Milliliter 
MR 
 
Minor Response 
MRI  
 
Magnetic Resonance  
 
 
Imaging 
NaCl 
 
Sodium chloride 
NCI 
 
National Cancer Institute 
NRS 
 
Nutritional Risk Screening 
OS  
 
Overall Survival 
pCR 
 
Pathol. Complete Remission  
PD  
 
Progressive Disease  
PFS  
 
Progression-Free Survival 
PK 
 
Pharmacokinetic 
PLD 
 
Pegylated Liposomal  
 
 
Doxorubicin 
p.o. 
 
Per os; orally 
PP  
 
Per Protocol population 
PR  
 
Partial Response 
q 
 
every 
ROC 
 
Recurrent Ovarian Cancer 
SAE  
 
Serious Adverse Event 
SAP 
 
Statistical Analysis Plan 
SAR 
 
Serious Adverse Reaction 
SD  
 
Stable Disease 
SOP 
 
Standard Operating Procedure 
SmPC  
Summary of Product  
 
 
Characteristics 
SR 
 
Subtotal Response  
SUSAR  
Suspected Unexpected 
Serious  
 
 
Adverse Reaction 
QLQ 
 
Quality of Life Questionnaire 
QoL  
 
Quality of Life 
TEAE  
Treatment Emergent Adverse 
 
 
Events 
TOI-QLQ-OV Trial Outcome Index of the 
 
 
EORTC QLQ-C30 and QLQ-
 
 
OV28 
TNM   
Primary Tumor / Lymph 
 
 
Node / Distant Metastasis  
ULN 
 
Upper Limit of Normal 
WHO  
World Health Organization 
 
 


 
 
 
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3 Synopsis 
Study title 
Comparison of Quality of life (QoL) between trabectedin/PLD and 
standard platinum-based therapy in patients with platinum sensitive 
recurrent ovarian, fallopian tube and peritoneal cancer 
Study type 
Phase IV, open-label, prospective, multi centre randomized trial 
Objectives 
To compare QoL in patients treated with trabectedin/PLD vs. other standard 
combination therapy of carboplatin/ PLD, carboplatin/ gemcitabine, or 
carboplatin/ paclitaxel 
Endpoints 
Primary endpoints: 
Primary Endpoint is the observation of change in QoL. This is measured for 
every patient as the change from baseline (C1 D1) to end of treatment (EOT) 
visit (3-4 weeks after C6 D1 or, in case of progression/relapse, 3-4 weeks 
after day 1 of last treatment Cycle). The primary QoL measure is the mean 
score of the Trial Outcome Index (TOI). The TOI is based on selected items 
from the EORTC QLQ-C30 version 3.0 and QLQ-OV28 (TOI-QLQ-OV) 
and includes the C-30 functional scales physical and role functioning, the 
symptom scales constipation, diarrhea, nausea and vomiting, in addition to 
the first 24 items of the EORTC Ovar 28 (i.e. all items of the EORTC Ovar 
28, excluding sexual functioning). The primary endpoint will be analysed by 
general linear models for paired samples. 
Secondary endpoints: 
 Clinical benefit rate (CR, PR, SD), or PD in patients with measurable 
disease  
 Difference in QoL for all other time points not included in primary 
endpoint 
 Progression-free survival (PFS) 
 Overall survival (OS) 
 Time to next medical intervention 
 
 


 
 
 
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Study design 
This is a multicenter, randomized, controlled, open-label study including 
patients with recurrent, platinum-sensitive, ovarian, peritoneal or fallopian 
tube cancer.  
The main scope of the trial is to evaluate QoL during and after chemotherapy 
comparing 
trabectedin/PLD 
with 
other 
standard 
platinum-based 
chemotherapy in platinum-sensitive disease.  
Patients with recurrent, platinum-sensitive, ovarian, fallopian tube and 
peritoneal cancer will be stratified according to surgery for relapse (tumor 
free vs. not tumor free resection) vs. no surgery in the same setting and age 
(< 75 years vs. ≥ 75 years), and randomized 1:1 to receive either 
trabectedin/PLD (Arm A) or one of 3 platinum-based standard therapies 
without bevacizumab (Arm B, “other standard therapy”). In case of 
randomization to “other standard therapy”, the investigator has the choice 
between 
carboplatin/PLD, 
carboplatin/gemcitabine 
and 
carboplatin/paclitaxel. Patients in both treatment arms will receive 
chemotherapy up for 6 cycles or until disease progression (PD), unacceptable 
toxicities or patient’s wish to stop therapy, whichever occurs first. 
Arm A (Trabectedin/PLD) 
Patients randomized to Arm A will receive PLD 30 mg/m2 i.v. as a 1-hour 
infusion followed by trabectedin 1.1 mg/m2 as a 3-hour infusion immediately 
after the PLD infusion. Treatment is repeated every 3 weeks for 6 cycles or 
until disease progression.  
Arm B (carboplatin/ PLD, carboplatin/gemcitabine, or carboplatin/ 
paclitaxel) 
Patients randomized to Arm B will receive up to 6 cycles of the platinum-
based therapy as mentioned above and administered according to respective 
SmPC.  
In both of the arms, tumor assessments (CT or MRI) are performed as 
standard of care until progression / relapse, death or end of follow up. A 
CT/MRI before baseline is required, however, the timeframe in which a 
patient can be randomized in the trial after tumor assessment is left up to the 


 
 
 
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investigator. A change from CT into MRI in the follow up period is possible 
at any time.  
During treatment, clinical visits (blood cell counts, detection of toxicity) 
occur prior to every treatment dose. Safety will be monitored continuously 
by careful monitoring of all adverse events (AEs) and serious adverse events 
(SAEs).  
 
 
    
Figure 1: Study Scheme. 
 
About 20 sites will participate in this study to recruit 204 patients in 52 
months. 
 
 
 


 
 
 
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Rationale 
Ovarian cancer remains the second-most lethal gynecologic malignancy after 
cervical cancer, with approximately 125,000 deaths annually worldwide [2]. 
Most patients with this type of cancer are initially diagnosed in already 
advanced stages. Surgery including maximal debulking followed by 
chemotherapy with carboplatin and paclitaxel has become the standard 
treatment [3] in first line therapy.  
Although most patients achieve a complete response, the majority will suffer 
a relapse and eventually die from the disease.  Relapses occurring ≥ 6 months 
after end of first line platinum-based treatment are considered platinum 
sensitive and are advised to be re-treated with a platinum based regimen [4]. 
However, this definition has been widely discussed as the type of relapse 
treatment is determined by various factors. The sole definition of the 
recurrence populations exclusively via the platinum-free therapy interval is 
therefore insufficient [5]. 
Recurrent ovarian cancer represents a major clinical challenge; few 
compounds have shown activity in large randomized trials, including 
carboplatin/cisplatin, paclitaxel, pegylated liposomal doxorubicin (PLD), 
gemcitabine and trabectedin [6-8].  
Non-platinum monotherapy is the preferred treatment for patients who 
experience disease recurrence soon after completing first-line therapy 
(platinum-resistant disease). This so called platinum-resistant patients, 
represent a subgroup with a worse prognosis [9].  
For platinum-sensitive patients, the standard of care in Germany (according 
to the current S3-Guidelines) is carboplatin combined with e.g. gemcitabine, 
paclitaxel or PLD. These combination chemotherapies showed an 
improvement of PFS and OS compared with platinum monotherapy [10]. But 
similarly the combination of trabectedin/PLD also showed an improvement 
of PFS and OS in the favorable subgroup of platinum-sensitive patients with 
a relapse free interval of more than 6 months after platinum-based therapy 
[11]. As a result, trabectedin in combination with PLD is considered an 
option for patients with relapsed, platinum-sensitive, ovarian cancer [12]. 
Because most women with recurrent ovarian cancer ultimately die of their 
cancer, QoL and regimen convenience are objectives that are as important as 


 
 
 
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efficacy. In palliative cancer therapy, the QoL is one of the most important 
objectives; besides the prolongation of OS. Platinum-based combination 
chemotherapy is known to be intense and toxic and can therefore, be 
associated with impaired QoL. Therefore, there is a strong rational to 
compare the platinum-free combination trabectedin/PLD with other standard 
platinum-based combinations in terms of their impact on QoL.  
Procedures used in this study (such as the chemotherapy, the blood tests and 
the radiology investigations) are in line with those usually used in the 
treatment of patients with recurrent ovarian, peritoneal or fallopian tube 
cancer in routine clinical practice. In terms of the chemotherapy, 
carboplatin/PLD, 
carboplatin/gemcitabine, 
carboplatin/paclitaxel 
are 
recommended chemotherapy regimens by the S3 German Guideline 
(highest-level national guidelines in Germany) [12] for platinum-sensitive 
relapse, as just mentioned above.  
Taken together, the risks emerging from participation in this clinical trial are 
acceptable and the results of the study may have an impact on future 
treatment of patients in the given indication. 
Chemotherapy 
schedule 
Arm A: Trabectedin/PLD: 
 Dexamethasone 20 mg; PLD 30 mg/m2 D1, Trabectedin 1.1 mg/m2 
D1; qd22 
Arm B: Other standard treatment according to respective SmPC and 
published therapy algorithms [1]: 
 Carboplatin/PLD: Carboplatin AUC5 D1, PLD 30 mg/m2 D1; qd29 
 Carboplatin/Gemcitabine: Carboplatin AUC4 D1; Gemcitabine 
1.000 mg/m2 D1, D8; qd22 
 Carboplatin/Paclitaxel: Carboplatin AUC5 D1, Paclitaxel 175 mg/m2 
D1; qd22 
Patients will be treated for 6 cycles (or more in case of clinical benefit, but 
this extended treatment will not be part of the study) or until PD, 


 
 
 
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unacceptable toxicity or patient’s wish to discontinue, whichever occurs 
first. 
Inclusion criteria 
1. Women aged ≥ 18 years 
2. Patients with histologically confirmed diagnosis of epithelial ovarian 
cancer, primary peritoneal carcinoma or fallopian tube cancer who 
received ≥1 prior chemotherapy 
3. Patients must be eligible for platin-containing therapy; Patient is defined 
as platin-sensitive when considered for platin-containing therapy by the 
investigator. The time frame from end of prior therapy until disease 
progression alone is not pivotal for study participation. Patients without a 
platin-containing regimen in the previous line who are also eligible for 
platin-containing regime are also appropriate for participation 
4. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 
5. Adequate baseline organ function as defined as 
 
Leucocytes > 3.0 x 109/l 
 
Platelet count > 100 x 109/l 
 
Absolute neutrophil count (ANC) ≥1500/mm3 
 
Haemoglobin ≥ 9 g/dl 
 
Alkaline Phosphatase (AP) ≤ 2.5 × ULN (consider hepatic 
isoenzymes 5 nucleotidase or gamma glutamyl transpeptidase 
(GGT), if the elevation could be osseous in origin) 
 
Alanine aminotransferase (ALT) and aspartate aminotransferase 
(AST) ≤ 2.5 × ULN 
 
Creatinine-Clearance ≥ 60 ml/min (MDRD formula or Cockroft & 
Gault formula) 
 
Serum creatinine ≤ 1.5 mg/dl 
 
Creatine phosphokinase (CPK) ≤ 2.5 × ULN 
 
Total bilirubin < ULN 
6. Women of childbearing potential should use contraceptives or abstain 
from heterosexual activity for the course of the study through 6 months 
after the last dose of study medication or be surgically sterile. 


 
 
 
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7. Adequate cardiac function defined as left ventricular ejection fraction 
(LVEF) ≥ 50% as determined by echocardiogram 
Patients must provide written informed consent prior to performance of 
study specific procedures or assessments, and must be willing to comply 
with treatment and follow up assessments and procedures. 
Exclusion criteria 
1. Only malignancies, which influence the prognosis  
2. Any unstable or serious concurrent condition (e.g. active infection 
requiring systemic therapy). 
3. Chemotherapy or radiation therapy or tumor embolization within 2 weeks 
prior to the first dose of study drug or planned during study participation. 
4. Patients who have refractory disease. Refractory disease is defined if 
relapse occurs <4 months after beginning of platin-containing therapy.  
5. Hypersensitivity to the active substance or to any of the excipients of 
study drug 
6. Findings from ECG and/or assessment of LVEF which indicate an 
anthracycline-related 
cardiotoxic 
process 
which 
contradicts 
administration of liposomal doxorubicin or trabectedin in accordance 
with the requirements of the SmPCs. 
7. Biological therapy, immunotherapy, hormonal therapy or treatment with 
an investigational agent within 14 days (for bevacizumab, 30 days) prior 
to the first dose of study drug. 
8. Any condition that is unstable or could jeopardize the safety of the patient 
and their compliance in the study 
9. Participation in another clinical study with experimental therapy within the 
30 days before start of and during treatment. Participation in a non-
interventional study should be discussed with sponsor and NC 
beforehand. 
10. Patients in a closed institution according to an authority or court decision 
(AMG § 40, Abs. 1 No. 4) 
11. Patients who are depending on the sponsor/CRO or investigational site 
as well as on the investigator.  
12. Pregnancy or lactation period, or planning to become pregnant within 7 
months after the end of treatment. 


 
 
 
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Sample size 
204 patients (Arm A, 102; Arm B, 102) 
Duration of the  
study (planned) 
Enrolment start date (FPI): Q3 2017 
Recruitment period: 52 months 
Enrolment finish date (LPI): Q4 2022 
Treatment period: up to 6 cycles administered every 3 weeks or 4 weeks 
(depends on therapy regimen) 
Follow-up-period: starting from end of study treatment for 12 months after 
baseline for the last patient included.   
End of Follow-up: Q2 2024 
Table 1: Treatment Schedule. 
 
Screening (day) Treatment 
cycles 1-61 
End of study 
treatment 
FU 13 
 
- 14 to 0 
D15 
3-4 weeks after C6 D1 
or 3-4 weeks after last 
D1 (progression) 
Starting 6M after 
BL (C1 D1), every 
6 months14 
Informed consent 
X 
 
 
 
Body height 
X 
 
 
 
Concomitant diseases  
X 
 
 
 
ß-HCG-Pregnancy test (for women with 
childbearing potential) 
X 
 
 
 
Physical examination / ECOG 
X 
X 
X 
 
Charlson Score 
X 
 
X 
 
ECG11, Echocardiogram 2, 11, 6 
X 
 
X 
 
Weight 
X 
X 
X 
 
Randomization 
X 
 
 
 
Calculation of medication dose3 
 
X5 
 
 
Laboratory examinations8  
Blood count9 (before every cycle) 
X 
X12 
X 
 
Tumor evaluation (using always the same method), 
CA 12510 
X6 
TO BE PERFORMED AS STANDARD OF CARE 
Adverse events 
 
X 
X7 
 
Concomitant medication 
X 
X 
X 
 
Quality of Life4: 
EORTC QLQ-C30 and QLQ-OV28 
(X)15 
X15 
X 
X 
NRS 2002 
X 
 
X 
 
Documentation of Follow-up therapy, PFS and OS 
 
 
X 
X 
1Therapy will continue for 6 cycles or until one of the discontinuation criteria (Section 10.4.1) applies.  
2 In case of anomalies further examinations during therapy as clinically indicated.  
3 At day 1 of each therapy application 
4 Prior to first application of each therapy cycle 
5 For gemcitabine also D8 to be documented 
6  CT and Echocardiogram to be performed as standard of care and can be older than 14 days before treatment if investigator 
considers this as acceptable. 
7 AEs and SAEs to be documented until 30 days after EoT or until start of new antitumor therapy, whatever occurs first 


 
 
 
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8 Laboratory: Serum: Creatinine, ALT, AST, AP, total bilirubin, albumin, CPK 
9 Blood count: Haemoglobin, white blood cell count with differential (total neutrophil count including lymphocyte, 
monocyte, eosinophil and basophil counts), platelets 
10 Evaluation of CA 125 may not be required (Investigators decision) 
11 Findings from ECG and/or assessment of LVEF which indicate an anthracycline-related cardiotoxic process which 
contradicts administration of PLD or trabectedin in accordance with the requirements of the SmPC is an Exclusion criteria. 
12 Trabectedin: Additional monitoring of haematological parameters bilirubin, alkaline phosphatase, aminotransferases and 
CPK should occur weekly during the first two cycles of therapy, and at least once between treatments in subsequent cycles. 
13 If EOT or other visits are planned 6 month (± 4 weeks) after Baseline, a separate visit for first FU is not necessary as long 
as all examinations and QoL assessments were performed. 
14 until 5 years after Baseline or end of study 
15 Quality of Life Assessments can be obtained up to 15 days before Baseline Visit. 
4 Background and Rationale 
4.1 
Rationale 
Ovarian cancer remains the second-most lethal gynecologic malignancy after cervical cancer, 
with approximately 125,000 deaths annually worldwide [2]. Most patients present with disease 
in advanced stage. Surgery including maximal debulking followed by chemotherapy with 
carboplatin and paclitaxel has become the standard treatment [3].  
Although most patients achieve a complete response, the majority will suffer a relapse and 
eventually die from the disease. Relapses occurring ≥ 6 months after end of first line platinum-
based treatment are considered platinum sensitive and are advised to be re-treated with a 
platinum-based regimen [4].  However, this definition has been widely discussed as the type of 
relapse treatment is determined by various factors. The sole definition of the recurrence 
populations exclusively via the platinum-free therapy interval is therefore insufficient [5]. 
Recurrent ovarian cancer represents a major clinical challenge; few compounds have shown 
activity in large randomized trials, including carboplatin/cisplatin, paclitaxel, pegylated 
liposomal doxorubicin (PLD), gemcitabine, and trabectedin.  
Non-platinum monotherapy is the preferred treatment for patients who experience disease 
recurrence soon after completing first-line therapy (platinum-resistant disease). This so called 
platinum-resistant patients, represent a subgroup with a worse prognosis[9].  
For platinum-sensitive patients, the standard of care in Germany according to the current S3-
Guidelines is carboplatin combined with gemcitabine, paclitaxel or PLD. These combination 
chemotherapies showed an improvement of PFS and OS compared with platinum monotherapy 
[10]. But similarly the combination of trabectedin/PLD also showed an improvement of PFS 
and OS in the favorable subgroup of platinum-sensitive patients with a relapse free interval of 
more than 6 months after platinum-based therapy [11]. As a result, trabectedin in combination 


 
 
 
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with PLD is considered an option for patients with relapsed, platinum-sensitive, ovarian 
cancer[12]. 
As mentioned above the standard after surgical debulking at initial surgery is chemotherapy 
with carboplatin and paclitaxel. So, in the relapse situation, many women still suffer from 
persistent neuropathy from initial therapy, making re-treatment with taxanes, especially 
paclitaxel a difficult endeavor [13]. For instance, the ICON4/AGO-Ovar-2.2 study [14] 
demonstrated improved survival by adding paclitaxel to a platinum agent in patients with 
platinum-sensitive recurrent ovarian cancer. However, this combination was associated with 
significant neurotoxicity [15]. Studies have shown that patients report motor neuropathy as the 
most unpleasant adverse effect of treatment [16] and the development of neuropathy is a major 
factor impairing QoL [17], which can lead to early treatment discontinuation. 
Regarding platinum backbone of the doublet chemotherapy, carboplatin and cisplatin have a 
similar efficacy, although carboplatin has a more favorable toxicity profile and convenient 
administration [7, 10, 14]. Carboplatin exhibits considerably lower nephrotoxicity than 
cisplatin. However, renal function must be monitored when determining dosage regimens to 
avoid acute toxicity, because renal clearance is the primary means by which carboplatin is 
cleared from the body. Carboplatin causes dose-limiting and cumulative myelo-suppression, 
characterized by thrombocytopenia, granulocytopenia and anemia. Thrombocytopenia 
following carboplatin therapy is frequent and severe [18, 19]. Although cumulative 
myelosuppression is the main toxicity associated with carboplatin, there is also a significant 
risk of neurotoxicity and hypersensitivity reactions. A study at the Cleveland Clinic Cancer 
Center [20] reported that hypersensitivity to carboplatin developed in 12 % of carboplatin- 
treated patients. Because of the possibility of fatal cross-hypersensitivity, the use of cisplatin in 
patients who have developed hypersensitivity to carboplatin is not recommended [21]. Though 
platinum-based regimens are the current standard of care in first-line therapy of ovarian cancer, 
their long-term toxicities represent a challenge in the treatment of patients with relapsed ovarian 
cancer. Patients with ovarian cancer will often be retreated with multiple courses of recurrence 
therapy. Caution should be used in patients who receive multiple sequential courses of 
chemotherapy, because they may experience excessive toxicity and may not be able to tolerate 
doses used for first-line therapy; thus, clinical judgment should be used when selecting doses 
and regimens (NCCN). For this purpose, a non-platinum-based regimen such as 
trabectedin/PLD could be an alternative option.  


 
 
 
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Because most women with recurrent ovarian cancer ultimately die of their cancer, QoL and 
regimen convenience are objectives that are as important as efficacy. In palliative cancer 
therapy, the QoL is one of the most important objectives, besides the prolongation of OS. 
Platinum-based combination chemotherapy is known to be intense and toxic and can, therefore, 
be associated with impaired QoL. Therefore, there is a strong rational to compare the platinum-
free combination trabectedin/PLD with other standard platinum-based combinations in terms 
of their impact on QoL. 
4.2 
Pegylated liposomal doxorubicin (PLD) 
Doxorubicin is an anthracycline class with broad spectrum of antineoplastic activity. PLD is 
doxorubicin hydrochloride encapsulated in liposomes aimed at escaping recognition and uptake 
by the mononuclear phagocyte system. PLD safety profile is improved over doxorubicin, with 
less cardiotoxicity, nausea, vomiting and alopecia. 
The major toxicity is direct against the bone marrow, limiting the dose of PLD. Irreversible 
cumulative cardiac toxicity limits the total deliverable dose as well. Special attention must be 
given to the myocardial damage that may be associated with cumulative doses of doxorubicin 
and caution should be observed in patients who have received other anthracyclines. PLD is 
approved both in the United States (Doxil®) and in Europe (Caelyx®) for patients with 
recurrent ovarian cancer after initial standard chemotherapy. The approved dose of PLD as a 
single agent for the treatment of ovarian carcinoma is 50 mg/m2 administered every 4 weeks. 
4.3 
Trabectedin 
Trabectedin is an antineoplastic agent. It binds covalently to the minor groove of DNA, bending 
DNA towards the major groove, and disrupts transcription leading to G2-M cell cycle arrest 
and ultimately apoptosis [22].  
The clinical development program was focused primarily on ovarian cancer and soft tissue 
sarcoma, where trabectedin demonstrated activity at very low concentrations in both preclinical 
models and humans.  
Trabectedin received marketing authorization in the European Union (EU) in 2007 for the 
treatment of patients with advanced soft tissue sarcoma after failure of anthracyclines and 
ifosfamide, or who are unsuited to receive these agents. Also, trabectedin in combination with 
PLD was approved for patients with relapsed platinum-sensitive ovarian cancer by the 
European Medicines Agency (EMA) in 2009. Further information regarding trabectedin may 
be found in the Summary of Product Characteristics (SmPC). 


 
 
 
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4.4 
Clinical safety and efficacy data of trabectedin/PLD 
The efficacy of trabectedin in the treatment of patients with recurrent ovarian cancer is based 
primarily on clinical data from the phase III study ET-743-OVA-301 (OVA-301). This was an 
open-label, multicenter, randomized clinical trial designed to investigate the efficacy and safety 
of the combination of PLD 30 mg/m², followed by trabectedin 1.1 mg/m² every 3 weeks 
compared with the approved standard single-agent PLD 50 mg/m² every 4 weeks [11, 23]. In 
the primary analysis by independent radiology review, the combination resulted in a statistically 
significant 21% decrease in the risk of disease progression or death vs. PLD alone. For platinum 
sensitive patients (PFI ≥ 6 months) the median PFS was 9.2 months for trabectedin/ PLD vs. 
7.5 months for PLD (HR 0.73, p= 0.017) with even a 27 % reduction of risk.  
A subgroup analysis of OS by platinum sensitivity based on PFI (0 to 6 months, 6 to 12 months, 
and >12 months) showed greater benefit (HR <1) in OS in patients receiving trabectedin/PLD 
compared with PLD monotherapy. The effect was most prominent in the partially platinum-
sensitive (platinum-free interval 6-12 months) group. In the partially platinum-sensitive subset 
of patients, trabectedin/PLD induced a significant 36 % decrease in the risk of death compared 
with PLD alone (HR = 0.64; 95 % CI, 0.47–0.86; P = 0.0027). Median OS was 22.4 months in 
the trabectedin/PLD arm versus 16.4 months in the PLD arm [24].  
The results were supported further by three phase II trials in which trabectedin has been 
investigated as single-agent in 2nd or 3rd line therapy in patients with relapsed advanced 
ovarian cancer. Regimens assessed were: 0.58 mg/m² over 3-h weekly x 3 q4w, 1.3 mg/m² over 
3-h q3w and 1.5 mg/m² over 24-h q3w [8, 25, 26].  
The most common haematological toxicity observed during the study OVA-301 was 
neutropenia. The incidence of grade 3/4 neutropenia cases evaluated as drug-related adverse 
events was higher in the trabectedin/PLD arm compared with PLD alone although this 
neutropenia was reversible and non-cumulative. Grade 3/4 ALT elevations were also more 
common with the combination but were transient and non-cumulative. Hand-foot syndrome and 
mucositis were less frequent with trabectedin/PLD than with PLD alone. 
Trabectedin, as a single-agent or combined with PLD, does not usually show the symptomatic 
clinical toxicity (e.g., neurotoxicity, renal toxicity or skin/nail toxicity) associated with other 
chemotherapeutic agents of common use. 
Thus, these results of the most recent studies have shown that trabectedin, in combination with 
PLD, is effective for the treatment of patients with platinum-sensitive relapsed ovarian cancer 


 
 
 
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without substantially increased toxicity compared with PLD alone. Especially patients in long-
term treatment, having received 6 or more cycles, show a good tolerability, since the observed 
toxicities were transient and not cumulative [27]. 
4.5 
Quality of Life: EORTC QLQ-C30 and QLQ-OV28 
The European Organization for Research and Treatment of Cancer (EORTC) quality of life 
questionnaire (QLQ) is an integrated system for assessing the health-related QoL of cancer 
patients participating in international clinical trials. The core questionnaire, the EORTC QLQ-
C30 [28] is a 30-item questionnaire composed of multi-item scales and single items that reflect 
the multidimensionality of the quality-of-life construct [29]. It incorporates five functional 
scales (physical, role, cognitive, emotional, and social), three symptom scales (fatigue, pain, 
and nausea and vomiting), and a global health and quality-of-life scale. The remaining single 
items assess additional symptoms commonly reported by cancer patients (dyspnea, appetite 
loss, sleep disturbance, constipation, and diarrhea), as well as the perceived financial impact of 
the disease and treatment. 
Following its general release in 1993, the QLQ-C30 has been used in a wide range of cancer 
clinical trials, by a large number of research groups. The EORTC group has developed a 
modular approach to the assessment of QoL. A number of modules specific to e.g. tumor site 
or treatment modality have been developed to be administered in addition to the QLQ-C30. A 
module is defined as a set of items assessing QoL issues not (sufficiently) covered by the QLQ-
C30 and considered to be relevant for the target population and the research question on hand. 
Such a module is the ovarian cancer module (EORTC QLQ-OV28). It was developed to 
supplement the EORTC QLQ-C30 for issues of relevance to the QoL of patients with ovarian 
cancer. The QLQ-OV28 module assesses abdominal/gastrointestinal symptoms, peripheral 
neuropathy, other chemotherapy side-effects, hormonal/menopausal symptoms, body image, 
attitude to disease/treatment and sexual functioning [30]. 
The primary objective of this study is to evaluate the overall burden of the therapy. Based on 
experience from our study HECTOR (AGO Ovar 2.12 [31]), a score called “Trial Outcome 
Index” (TOI) was created. We wanted to develop a score similar to the FACIT TOI [32], which 
consists for the FACIT TOI in Physical Well-Being (PWB), Functional Well-Being (FWB), 
and "additional concerns" subscales. 


 
 
 
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For this trial the primary outcome is the mean TOI of items from the EORTC QLQ-C30 version 
3.0 and QLQ-OV28. This new score we called TOI-QLQ-OV. It is based on items from the C-
30 functional scales physical and role functioning, the symptom scales constipation, diarrhea, 
nausea and vomiting, in addition to the first 24 items of the QLQ-OV28 (i.e. all items of the 
EORTC QLQ-OV28 excluding sexual functioning). The sexual functioning items are excluded 
as those will not be answered by all patients. The new scale ranges from 0 (high level of 
functioning / no symptomatology) to 100 (low level of functioning / high symptomatology). 
This TOI-QLQ-OV was tested with patient data from the HECTOR study of the standard 
treatment arm. Reliability was tested for all time points with good results (Chronbach’s alpha 
>0.9, N=550 assessments including EOT and Follow up). A change of 3.9 points from Baseline 
to about 24 weeks (including a range from 20 to 27 weeks) resulted in a standard deviation of 
14.2 within 72 patients (see Table 2 for the assessments at different time points and Table 3 for 
the differences to Baseline values). 
Table 2: TOI-QLQ-OV with data from HECTOR study. 
Time point 
mean 
SD 
N 
Baseline 
32.7 
17.6 
232 
At 12 weeks 
36.4 
15.0 
152 
At 24 weeks 
40.7 
16.5 
14 
 
Table 3: TOI-QLQ-OV changes to different time points with data from HECTOR study- 
Change from Baseline to… 
mean 
SD 
N 
12 weeks 
4.5 
12.6 
135 
24 weeks 
5.9 
11.8 
13 
24 weeks or end of therapy 
(20 to 27 weeks) 
3.9 
14.2 
72 
 
4.6 
Justification for the selection of the control arm 
Carboplatin and paclitaxel therapy for patients with advanced ovarian carcinoma relapsing after 
six months of previous platinum-based chemotherapy has been evaluated in the ICON4/0VAR 
2.2 study [14], in which the addition of a taxane led to a longer PFS (hazard ratio [HR] 0.76, 
p= .0004) and OS (HR 0.82, p=.02) over a conventional platinum-based chemotherapy in 
patients with platinum-sensitive, recurrent ovarian cancer. 


 
 
 
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In another randomized study, Pfisterer et al. [7] confirmed that combination therapy, in this 
case carboplatin/gemcitabine, prolongs PFS over a platinum single agent. With a median 
follow-up of 17 months, median PFS was 8.6 months for gemcitabine plus carboplatin vs. 5.8 
months for carboplatin alone, HR 0.72, p=.0031. No survival differences were found in this 
trial. 
Also, PLD was proven to be an active agent in second-line therapy for ovarian carcinoma which 
obtained regulatory approval in both platinum-resistant and platinum-sensitive recurrent 
ovarian cancer [33]. The combination of PLD plus carboplatin was shown to be safe and active 
in a phase II trial [34]. A large phase III trial (CALYPSO), comparing carboplatin/PLD vs. 
carboplatin/paclitaxel showed non inferior PFS results (HR 0.82; median 11.3 months for 
carboplatin/PLD vs. 9.4 months for carboplatin/paclitaxel) [35] . With a median follow-up of 
49 months, also no statistically significant difference was observed between arms in OS (HR = 
0.99 (95% confidence interval 0.85, 1.16); log-rank P = 0.94). Median survival times were 30.7 
months (carboplatin/PLD) and 33.0 months (carboplatin/paclitaxel) [36].  
Therefore, according to the current German S3 Guidelines for treating ovarian cancer, the upon 
mentioned combination chemotherapies are regarded the standard of care in platinum-sensitive 
recurrent ovarian carcinomas [12]. 
4.7 
The relevance of this study to current care and benefit-risk assessment 
This trial investigates the QoL between trabectedin/PLD vs. the other standard of a carboplatin-
based chemotherapy in recurrent ovarian, fallopian tube or primary peritoneal platinum-
sensitive cancer. Although platinum-based combination therapies are considered the current 
standards of care in this setting, long-term toxicities represent huge challenges in platinum-
pretreated patients with relapsed cancer. Because most women with recurrent ovarian cancer 
ultimately die of their cancer, QoL and regimen convenience are as important as efficacy in 
assessing the role of a treatment combination.  
If the concept proves to be effective, this could potentially lead to a new standard of care and 
patients in the prognostically favorable situation of platinum-sensitive cancer will no further 
need burdening platinum-based therapy. In palliative cancer therapy, the QoL is one of the most 
important objectives, besides the prolongation of OS. 
Procedures used in this study (such as the chemotherapy, the blood tests and the radiology 
investigations) are in line with those usually used in the treatment of patients with recurrent 
ovarian, peritoneal or fallopian tube cancer in routine clinical practice. In terms of the 
chemotherapy, 
carboplatin/PLD, 
carboplatin/gemcitabine, 
carboplatin/paclitaxel 
are 


 
 
 
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recommended chemotherapy regimens by the S3 German Guidelines (highest-level national 
guidelines in Germany) [12] for platinum-sensitive relapse, as just mentioned above.  
Taken together, the risks emerging from participation in this clinical trial are acceptable and the 
impact of the study results on the future treatment of patients in the given indication. 
5 Endpoints 
5.1 
Efficacy objectives 
Primary Endpoint is the observation of change in QoL. This is measured for every patient as 
the change from Baseline to EOT (3-4 weeks after C6 D1 or, in case of progression, after last 
D1). The primary QoL measure is the mean score of the previously defined TOI-QLQ-OV 
(see Section 4.5) between the treatment arms.  
The main secondary efficacy objectives are as follows: 
• 
Clinical benefit rate (CR, PR, SD), or PD in patients with measurable disease 
• 
Difference in QoL for all other time points not included in primary endpoint  
• 
Progression-free survival (PFS) defined as the time from randomization to the first 
occurrence of progression or recurrence, as determined by the investigator using CT 
criteria, or death from any cause  
• 
Overall survival (OS), defined as the time from randomization to death from any cause 
• 
Time to next medical intervention (e.g. chemotherapy, immunotherapy) 
 
5.2 
Safety objectives 
The safety objective is to evaluate the safety and tolerability of trabectedin/PLD in patients with 
platinum sensitive recurrent ovarian, fallopian tube and peritoneal cancer, focusing on adverse 
events and serious adverse events according to National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE).  
 


 
 
 
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6 Patient Selection 
6.1 
Inclusion Criteria 
1. Women aged ≥ 18 years 
2. Patients with histologically confirmed diagnosis of epithelial ovarian cancer, primary 
peritoneal carcinoma or fallopian tube cancer who received ≥1 prior chemotherapy 
3. Patients must be eligible for platin-containing therapy; Patient is defined as platin-
sensitive when considered for platin-containing therapy by the investigator. The time 
frame from end of prior therapy until disease progression alone is not pivotal for study 
participation. Patients without a platin-containing regimen in the previous line who are 
also eligible for platin-containing regime are also appropriate for participation 
4. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 
5. Adequate baseline organ function as defined as 
6. Leucocytes > 3.0 x 109/l 
7. platelet count > 100 x 109/l 
8. Absolute neutrophil count (ANC) ≥1500/mm3 
9. Haemoglobin ≥ 9 g/dl 
10. Alkaline Phosphatase (AP) ≤ 2.5 × ULN (consider hepatic isoenzymes 5 nucleotidase 
or gamma glutamyl transpeptidase (GGT), if the elevation could be osseous in origin) 
11. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN 
12. Creatinine-Clearance ≥ 60 ml/min (MDRD formula or Cockroft & Gault formula) 
13. Serum creatinine ≤ 1.5 mg/dl 
14. Creatine phosphokinase (CPK) ≤ 2.5 × ULN 
15. Total bilirubin < ULN 
16. Women of childbearing potential should use contraceptives or abstain from 
heterosexual activity for the course of the study through 6 months after the last dose of 
study medication or be surgically sterile. 
17. Adequate cardiac function defined as left ventricular ejection fraction (LVEF) ≥ 50% 
as determined by echocardiogram 
18. Patients must provide written informed consent prior to performance of study specific 
procedures or assessments, and must be willing to comply with treatment and follow up 
assessments and procedures. 


 
 
 
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6.2 
Exclusion Criteria 
1. Only malignancies, which influence the prognosis  
2. Any unstable or serious concurrent condition (e.g. active infection requiring systemic therapy). 
3. Chemotherapy or radiation therapy or tumor embolization within 2 weeks prior to the first dose 
of study drug or planned during study participation. 
4. Patients who have refractory disease. Refractory disease is defined if relapse occurs <4 months 
after beginning of platin-containing therapy.  
5. Hypersensitivity to the active substance or to any of the excipients of study drug 
6. Findings from ECG and/or assessment of LVEF which indicate an anthracycline-related 
cardiotoxic process which contradicts administration of liposomal doxorubicin or trabectedin 
in accordance with the requirements of the SmPCs. 
7. Biological therapy, immunotherapy, hormonal therapy or treatment with an investigational 
agent within 14 days (for bevacizumab, 30 days) prior to the first dose of study drug. 
8. Any condition that is unstable or could jeopardize the safety of the patient and their compliance 
in the study 
9. Participation in another clinical study with experimental therapy within the 30 days before start 
of and during treatment.  Participation in a non-interventional study should be discussed with 
sponsor and NC beforehand. 
10. Patients in a closed institution according to an authority or court decision (AMG § 40, Abs. 1 
No. 4) 
11. Patients who are depending on the sponsor/CRO or investigational site as well as on the 
investigator.  
12. Pregnancy or lactation period, or planning to become pregnant within 7 months after the end 
of treatment. 
 
 
 
 


 
 
 
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7 Patient Recruitment and Randomization 
Investigators will recruit patients directly during regular clinical consultation visits in the 
respective center. All study related investigations and enrolment of patients will only be 
performed after written consent was collected using the ethics committee approved patient 
information and consent form (see also chapter 15.4). 
Patients fulfilling the inclusion-/exclusion criteria (see Chapter 6 Patient Selection) will be 
captured online in the eCRF as screening patients to obtain a screening number which is used 
for identification during the central evaluation process. 
Stratification and randomization is performed online in the EDC-System after capturing all 
necessary data. Only after complete registration of a patient and following randomization sites 
can start with study therapy. 
 
 


 
 
 
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8 Therapy schema 
Patients will receive the following treatment regimen in the study:
 
Arm A: Trabectedin / PLD: 
Dexamethasone 20 mg i.v. 30 minutes before PLD; D1 
PLD (30 mg/m2) in 250 ml G5% i.v. for 1h; D1 
Trabectedin (1.1 mg/m2) in 500 ml NaCl 0.9% i.v for 3h (administration after PLD); D1 
The use of central venous access is strongly recommended. To minimize the risk of PLD 
infusion reactions, the initial dose is administered at a rate no greater than 1 mg/minute. If no 
infusion reaction is observed, subsequent PLD infusions may be administered over a 1 hour 
period (see PLD SmPC for specific administration advice). 
Repeated every three weeks (qd22), following the treatment schedule. 
 
Arm B: Other standard treatment according to respective SmPC and current literature [1]:  
Carboplatin/PLD: 
Carboplatin AUC5 in 250 ml G5% i.v. for 1h, D1 
PLD (30 mg/m2) in 250 ml G5% i.v. for 1h, D1 
To minimize the risk of PLD infusion reactions, the initial dose is administered at a rate no 
greater than 1 mg/minute. If no infusion reaction is observed, subsequent PLD infusions may 
be administered over a 1 hour period (see PLD SmPC for specific administration advice). 
Repeated every four weeks (qd29), following the treatment schedule. 
–or- 
Carboplatin/Gemcitabine:  
Carboplatin AUC4 in 250 ml G5% i.v. for 1h, D1;  
Gemcitabine 1.000mg/m2 in 500 ml NaCl 0.9% i.v. as a 30min infusion D1, D8 
Repeated every three weeks (qd22), following the treatment schedule. 
  
 
–or- 
Carboplatin/ Paclitaxel:  
Carboplatin AUC5 in 250 ml G5% i.v. for 1h; D1  
Paclitaxel 175mg/ m2 in 500 ml NaCl 0.9% i.v for 3h D1 
Repeated every three weeks (qd22), following the treatment schedule. 
In both arms patients will be treated for 6 cycles (or more in case of clinical benefit, but this 
extended treatment will not be part of the study) or until PD, unacceptable toxicities or 
patients wish, whichever occurs first. 
 
 


 
 
 
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Note: The specifications regarding dilutions and used dilutions media mentioned in the therapy 
scheme are not mandatory to be followed and can be adjusted to local standard of care at sites. 
The dose of active substances must be observed in order to maintain comparability between sites. 
The sequence of medication administration in Arm A is binding but for Arm B it can be considered 
as suggestion.  
9 Concomitant Therapy 
The current chemotherapy regimens in the protocol are standard regimens, thus the 
investigators may administer antiemetic therapy according to local guidelines, SmPCs and the 
most recent MASCC/ESMO antiemetic Guideline. The administration of all types of pain 
killers and allergic reaction preventing drugs according local guidelines is also permitted.  
All patients in Arm A must receive corticosteroids e.g. 20 mg of dexamethasone intravenously 
30 minutes prior to PLD; not only as antiemetic prophylaxis, but also because it appears to 
provide hepatoprotective effects. Additional antiemetics (i.e.: 5-HT3-inhibitors) may be 
administered as needed, but avoid aprepitant, as potent CYP3A4 inhibitor. Intravenous 
administration through a central venous line is strongly recommended. Caution should be taken 
if medicinal products associated with rhabdomyolysis (e.g. statins), are administered 
concomitantly with trabectedin, since the risk of rhabdomyolysis may be increased. For more 
information about concomitant therapy and trabectedin, please see Section 4.4 (Special 
warnings and precautions for use) of the SmPC of trabectedin. 
10 Criteria for continuation, dose adjustment, overall duration, and 
termination 
10.1 General remarks 
Toxicity will be graded according to NCI CTCAE, version 4.0. The dose modification described 
below is performed according to this grading system. Toxicities of severity grade 1 only will 
not lead to any dose reduction or cycle delay. The same holds for adverse reactions without any 
potential of serious or life-threatening complications according to the judgment of the physician 
(e.g. alopecia). In case of toxicities requiring dose modification, the dose modification should 
reflect the causal relationship to the respective drug(s). E.g., if the toxicity is unequivocally 
caused by only one drug, a dose modification of the other drug is not required. If more than one 
different type of toxicity occurs concurrently, the most severe grade will determine the 
modification. If a dose reduction is performed, the reduced dose level is usually kept throughout 
the rest of the study without re-escalation. However, investigators can deviate from this 


 
 
 
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procedure and increase the dose to the previous level if they feel i) that this is in the best interest 
of the patient and if they ii) do not expect the toxicity to reoccur. 
Study treatment will be administered in a clinical treatment setting with emergency equipment 
and staff who are trained to monitor for and respond to medical emergencies. In case of acute 
allergic reactions of grade 3 or 4, the causative agent should be discontinued permanently. In 
case of grade 1 or 2, it is up to the physician to continue treatment without dose modification, 
if this is in the best interest of the patient. 
The study teams will document all actions of dose modifications or treatment delays in the 
eCRF, including the reason for each action.  
10.2 Requirements for chemotherapy administration  
Patients will remain on treatment for 6 cycles in the absence of confirmed progression or 
unacceptable toxicity that is not resolved after applying the appropriate dose reductions. Patients 
with clinical benefit may continue therapy beyond 6 cycles. 
In order to be treated on Day 1 of a new cycle, patients will have to fulfill these entry criteria:  
 Leucocytes > 3.0 x 109/l 
 Platelet count > 100 x 109/l 
 Absolute neutrophil count (ANC) ≥1500/mm3 
 Haemoglobin ≥ 9 g/dl 
 Alkaline Phosphatase (AP) ≤ 2.5 × ULN (consider hepatic isoenzymes 5 
nucleotidase or gamma glutamyl transpeptidase (GGT), if the elevation could be 
osseous in origin) 
 Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
≤ 2.5 × ULN 
 Creatinine-Clearance ≥ 60 ml/min (MDRD formula or Cockroft & Gault 
formula) 
 Serum creatinine ≤ 1.5 mg/dl 
 Creatine phosphokinase (CPK) ≤ 2.5 × ULN 
 Total bilirubin < ULN 
 
If these criteria are not met on Day 1 of a new cycle, treatment administration may be delayed 
for a maximum of the respective cycle length and reevaluated weekly. The new cycle will start 
upon recovery of these parameters, according to the same criteria. 


 
 
 
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A maximum delay of one cycle length is allowed for recovery from drug-related AEs. If 
toxicities have not recovered within the allowed timeframe, the patient should discontinue 
treatment. In the event of obvious clinical benefit, the patient may remain on treatment upon 
agreement with the Sponsor, provided that all parameters have recovered according to the 
aforementioned criteria.  
10.3 Chemotherapy dose adjustment  
Dose reductions will be based on the worst drug-related toxicity that occurred since the last 
dose administration. The criteria for dose delay/reduction in Arm A are defined in Table 4. For 
Arm B please refer to the respective SmPC. Once a dose has been reduced because of toxicity, 
there will be no dose re-escalation in subsequent cycles. A maximum of two dose reductions 
are allowed regardless of the type of toxicity. Study treatment will be permanently discontinued 
for any patient who requires a third dose reduction. 
 
Arm A: Trabectedin/PLD 
Prior to re-treatment, patients must fulfil the criteria defined above. If any of the following 
events occur at any time between cycles, the dose must be reduced one level, according to Table 
4 below, for subsequent cycles: 
 
 Neutropenia: Neutrophile count < 0.5 x 109/l lasting for more than 5 days or associated 
with fever or infections  
 Thrombocytopenia: Platelet count < 25 x 109/l 
 Increase of Bilirubin > ULN and/or alkaline Phosphatase > 2.5 x ULN 
 Increase of Aminotransferase (AST or ALT) > 5 x ULN, which has not recovered by 
D21  
 Any other grade 3 or 4 adverse reactions (such as nausea, vomiting, fatigue) 
 
Once a dose has been reduced because of toxicity, dose escalation in the subsequent cycles is 
not recommended. If any of these toxicities reappear in subsequent cycles in a patient exhibiting 
clinical benefit, the dose may be further reduced.  
 
 
 
 
 
 
 


 
 
 
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Table 4: Arm A dose reduction due to toxicity 
Dosing step 
PLD 
Trabectedin 
Dose Level 0 (Starting dose) 
30 mg/m2 
1.1 mg/ m2 
Dose Level -1 
25 mg/m2 
0.9 mg/ m2 
Dose Level -2 
20 mg/m2 
0.75 mg/ m2 
 
In case of recurrent toxicity after two dose reductions of one of the agents, the other non-reduced 
compound may be continued for patients with clinical benefit or stop the whole treatment (see 
section 10.4.3). Upon occurrence of hematologic toxicities as e.g. febrile neutropenia or 
infection during neutropenia, all center-specific therapeutic and prophylactic actions (e.g. 
administration of antibiotics and growth factors) should be applied. 
 
In case of acute allergic reactions of grade 3 or 4, the causative agent should be discontinued 
permanently. In case of grade 1 or 2, it is up to the physician to continue treatment without dose 
modification, if this is in the best interest of the patient. The study teams will document all 
actions of dose modifications or treatment delays in the eCRF, including the reason for each 
action. 
Each of the chemotherapeutic agents administered in the course of this study are market 
approved in Germany and all participating investigators will have broad experience with these 
medications. Therefore, investigators are permitted to deviate from the recommendations given 
above in reasonable cases.  
10.4 Criteria for study termination 
10.4.1 Individual criteria for treatment termination 
The reason for treatment termination has to be documented as follows (criteria for termination): 
- 
Treatment completed after 6 cycles 
- 
Progression or relapse of the disease during treatment 
- 
Unacceptable side effects (a maximum delay of one cycle length is allowed for recovery 
from drug-related AEs)  
- 
Patient’s decision/wish 
- 
Occurrence of other diseases which interfere with study participation (e.g. secondary 
malignant neoplasms) 
- 
Pregnancy 
- 
Post-operative nutritional problems or post-operative complications 


 
 
 
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- 
Other reasons* 
* Details will be documented in the eCRF 
 
10.4.2 General criteria for premature termination of the trial 
- 
Unexpected severe toxicity of the study medication  
- 
More effective therapies become available 
- 
Insufficient patient enrollment  
 
10.4.3 Handling premature treatment (whole treatment) termination 
If chemotherapy is prematurely discontinued, the patient will be removed from the active study 
part and will enter the follow-up until 5 years after baseline or end of study. 
11 Study drugs 
This section provides an overview on the study medication used. It is not intended to replace the 
careful reading of the summary of product characteristics (SmPC) for each component, which 
contains details on drug characteristics, storage, application, mode of action and adverse 
reactions. All substances are market approved in Germany for at least one kind of tumor. 
Moreover, the used regimens in both arms are standard of care for patients with ovarian recurrent 
cancer in Germany. Therefore, the protocol requires limited documentation of concomitant 
medication in the study. If patients receive concomitant medication, the product characteristics 
need to be checked by the investigator with respect to potential drug interactions. In case of any 
doubt, the lead principal investigator shall be consulted. The investigator or the pharmaceutical 
expert in delegation is responsible for the safe storage, preparation, release, and documentation 
of the study medication with respect to standard procedures and national guidelines. All 
medication shall be distributed according to the prescription of the investigator. 
11.1 Pegylated Liposomal Doxorubicin (PLD) 
Commercially available PLD (Caelix®) will be utilized in this study. See the Caelix® Package 
Insert and SmPC, for more details. 
11.2 Trabectedin 
Commercially available trabectedin (Yondelis®) will be utilized in this study. Trabectedin is 
available as a sterile lyophilized product in vials containing 1.0 mg of trabectedin (Yondelis®).  


 
 
 
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Before lyophilization, sufficient quantities of monopotassium phosphate and phosphoric acid 
were added to the process solution for pH adjustment. See the Yondelis® Package Insert and 
SmPC, for more details. 
11.3 Carboplatin 
Commercially available carboplatin will be utilized in this study, all available products are 
allowed. Carboplatin will be administered according to the directions of the prescribing 
information. Dose will be calculated according to Calvert's formula (14) to obtain an 
AUC = 5 mg/ml*min for Group A. For more details see the carboplatin Package Insert and 
http://www.drugs.com/pro/carboplatin.html. 
11.4 Gemcitabine 
Commercially available gemcitabine will be utilized in this study, all available products are 
allowed. See the gemcitabine Package Insert, for more details. 
11.5 Paclitaxel 
Commercially available paclitaxel will be utilized in this study, all available products are 
allowed. See the paclitaxel Package Insert, for more details. 
 


 
 
 
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12 Treatment schedule and schedule of assessments 
Table 4: Treatment Schedule. 
 
Screening (day) Treatment 
cycles 1-61 
End of study 
treatment 
FU-1 13 
 
- 14 to 0 
D15 
3-4 weeks after C6 D1 
or 3-4 weeks after last 
D1 (progression) 
Starting 6M after 
BL (C1 D1), every 
6 months14 
Informed consent 
X 
 
 
 
Body height 
X 
 
 
 
Concomitant diseases  
X 
 
 
 
ß-HCG-Pregnancy test (for women with 
childbearing potential) 
X 
 
 
 
Physical examination /ECOG 
X 
X 
X 
 
Charlson Score 
X 
 
X 
 
ECG11, Echocardiogram 2, 11, 6 
X 
 
X 
 
Weight 
X 
X 
X 
 
Randomization 
X 
 
 
 
Calculation of medication dose3 
 
X5 
 
 
Laboratory examinations8  
Blood count9 (before every cycle) 
X 
X12 
X 
 
Tumor evaluation (using always the same method), 
CA 12510,  
X6 
 
  TO BE PERFORMED AS STANDARD OF CARE 
 
Adverse events 
 
X 
X7 
 
Concomitant medication 
X 
X 
X 
 
Quality of Life4: 
EORTC QLQ-C30 and QLQ-OV28 
(X)15 
X15 
X 
X 
NRS 2002 
X 
 
X 
 
Documentation of Follow-up therapy, PFS and OS 
if applicable 
 
 
X 
X 
1Therapy will continue for 6 cycles or until one of the discontinuation criteria (Section 10.4.1) applies.  
2 In case of anomalies further examinations during therapy as clinically indicated.  
3 At day 1 of each therapy application 
4 Prior to first application of each therapy cycle 
5 For gemcitabine also D8 to be documented 
6 CT and Echocardiogram to be performed as standard of care and can be older than 14 days before treatment if investigator 
considers this as acceptable. 
7 AEs and SAEs to be documented until 30days after EoT or until start of new antitumor therapy, whatever occurs first 
8 Laboratory: Serum: Creatinine, ALT, AST, AP, total bilirubin, albumin, CPK 
9 Blood count: Haemoglobin, white blood cell count with differential (total neutrophil count including lymphocyte, 
monocyte, eosinophil and basophil counts), platelets 
10 Evaluation of CA 125 may not be required (Investigators decision) 
11 Findings from ECG and/or assessment of LVEF which indicate an anthracycline-related cardiotoxic process which 
contradicts administration of PLD or trabectedin in accordance with the requirements of the SmPCs is an Exclusion criteria. 
12 Trabectedin: Additional monitoring of haematological parameters bilirubin, alkaline phosphatase, aminotransferases and 
CPK should occur weekly during the first two cycles of therapy, and at least once between treatments in subsequent cycles. 
13 If EOT or other visits are planned 6 month (± 4 weeks) after Baseline, a separate visit for first FU is not necessary as long 
as all examinations and QOL assessments were performed. 


 
 
 
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14 until 5 years after Baseline or end of study 
15 Quality of Life Assessments can be obtained up to 15 days before Baseline Visit. 
 
 
 
 
  
Figure 1: Study Scheme. 
 
 
 


 
 
 
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12.1 Screening/baseline examinations and randomization 
Upon reception of patients’ informed consent the following parameters have to be performed: 
Within a maximum timeframe of 14 days before start of therapy  
(Timeframe of echocardiogram and CT/MRI can be prolonged as per investigator decision) 
 
- 
Informed consent, must be signed before any trial specific assessments take place 
- 
Medical history, body height (height can be older), concomitant diseases, preexisting 
toxicities or symptoms 
- 
Charlson score (Appendix 21.1 ) 
- 
Tumor evaluation 
- 
Mandatory: Tumor assessment/staging (CT/MRI scan of Chest and Abdomen 
including pelvic region)  
- 
Recommended: CA 125 
- 
Histological type  
- 
BRCA-mutation status 
- 
ß-HCG-Pregnancy test (for women with childbearing potential) 
- 
ECOG (see table in section 21.1) and Physical examination , in case of anomalies 
further examinations during therapy as clinically indicated 
- 
EKG (Electrocardiography) and Echocardiogram, in case of anomalies further 
examinations during therapy as clinically indicated. Findings from ECG and/or 
assessment of LVEF which indicate an anthracycline-related cardiotoxic process 
which contradicts administration of liposomal doxorubicin or trabectedin in 
accordance with the requirements of the SmPCs is an Exclusion criteria.  
- 
Weight 
- 
Calculation of medication dose, at day 1 of each therapy application 
- 
Laboratory examinations (before every cycle): Serum: Creatinine, ALT, AST, AP, 
total bilirubin, albumin, CPK 
- 
Blood count (before every cycle): Haemoglobin, white blood cell count with 
differential (absolute neutrophil count including lymphocyte, monocyte, eosinophil 
and basophil counts), platelets 
- 
Concomitant medication 
- 
Quality of Life: EORTC QLQ-C30 and QLQ-OV 28 as baseline assessments; those can 
be obtained up to 14 days before first treatment (Baseline), as this is a requirement for 
randomization  
- 
NRS 2002 (see table in section 21.3) 


 
 
 
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- 
Check of in-/exclusion criteria 
 
Important note: All examinations of CT or MRI are part of routine clinical practice. It is 
important to note that the study protocol does not limit the examinations to these mentioned 
above. The investigator shall perform all other/additional routine or center-specific examinations 
relevant for the safety of the patient or for any other planned procedures.  
Patients will be stratified according to surgery for relapse (tumor free vs. not tumor free 
resection) vs. no surgery in the same setting, and age (< 75 years vs. ≥ 75 years).  
 
12.2 Treatment in Arm A (Trabectedin/PLD) 
Patients in Arm A receive 6 3-week cycles of trabectedin/PLD as described in Chapter 8. 
12.3 Treatment in Arm B (Carboplatin/PLD, carboplatin/gemcitabine, 
carboplatin/paclitaxel) 
Patients in Arm B receive 6 cycles of carboplatin/PLD, carboplatin/gemcitabine, or 
carboplatin/paclitaxel as given in respective SmPC.  
12.4 General examinations before start of a new chemotherapy cycle (cycle 1*-6)  
- 
ECOG and Physical examination (incl. blood pressure) 
- 
Weight 
- 
Calculation of medication dose, at day 1 of each therapy application 
- 
Laboratory examinations (before every cycle): Serum: Creatinine, ALT, AST, AP, total 
bilirubin, albumin, CPK 
- 
Blood count (before every cycle): Haemoglobin, white blood cell count with differential 
(total neutrophil count including lymphocyte, monocyte, eosinophil and basophil 
counts), platelets 
For Trabectedin additional monitoring of haematological parameters bilirubin, alkaline 
phosphatase, aminotransferases and CPK should occur weekly during the first two 
cycles of therapy, and at least once between treatments in subsequent cycles. 
- 
Concomitant medication 
- 
Quality of Life: EORTC QLQ-C30 and QLQ-OV 28 
- 
Adverse Events: Assessment of toxicities and symptoms 
- 
Tumor evaluation: 
 CT /MRI as standard of care 
 Recommended: CA 125 


 
 
 
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Important note: These examinations are required by study protocol. All examinations are 
part of routine clinical practice. It is important to note that the study protocol does not limit 
the examinations to these mentioned above. The investigator shall perform all 
other/additional routine or center-specific examinations relevant for the safety of the patient 
or for any other planned procedures.  
* Assessments already performed for Screening do not have to be repeated for Cycle 1 D1 if not 
longer than 7 days ago. 
12.5 End of study treatment (EOT) 
Regular end of study treatment (EOT) is 3-4 weeks after day 1 of Cycle 6 or, in case of 
progression/relapse, 3-4 weeks after day 1 of last treatment Cycle. EOT means end of the active 
part of the trial. Follow-up for QoL and PFS/OS should continue. 
- 
Tumor evaluation: 
 CT /MRI as standard of care 
 Recommended: CA 125 
- 
ECOG and Physical examination 
- 
ECG (Electrocardiography) and Echocardiogram, in case of anomalies further 
examinations during therapy as clinically indicated 
- 
Weight 
- 
Laboratory examinations: Serum: Creatinine, ALT, AST, AP, total bilirubin, albumin, 
CPK 
- 
Blood count: Haemoglobin, white blood cell count with differential (total neutrophil count 
including lymphocyte, monocyte, eosinophil and basophil counts), platelets 
- 
Adverse Events: Assessment of toxicities and symptoms. Serious adverse events (SAE) 
reporting has to be maintained until 4 weeks after EOT! 
- 
Concomitant medication 
- 
Quality of Life: EORTC QLQ-C30 and QLQ-OV28 
- 
Charlson score (Appendix 21.1 ) 
- 
NRS 2002 (see tables in section 21.3) 
- 
Documentation of the follow-up therapy, PFS and OS if applicable 
 


 
 
 
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NOTE: Tumor assessment using CT/MRI are not a mandatory part of the EOT. The frequency 
of the CT or MRI is a recommendation of the protocol experts but sites can follow their local 
standard of care. A change from CT into MRI in the follow up period is possible at any time. 
 
12.6 Follow-up 
- 
Centers will perform follow-up starting 6 months after baseline. If EOT or other visits are 
planned 6 month (± 4 weeks) after Baseline, a separate visit for first FU is not necessary as 
long as all examinations and QOL assessments were performed. This phase ends 5 years 
after Baseline or when the study will be terminated, which is defined as the time point when 
the last patient has completed the mandatory 1 year follow-up. Follow-up will be performed 
every 6 months and includes the following parameters:  
- 
Tumor evaluation (until progression / relapse): 
 CT /MRI as standard of care 
 Recommended: CA 125 
- 
Quality of Life: EORTC QLQ-C30 and QLQ-OV28 
- 
Documentation of the follow-up therapy, PFS (until progression/relapse) and OS, if 
applicable 
- 
Adverse Events (until progression/relapse): Assessment of toxicities and symptoms. 
Serious adverse events (SAE) reporting has to be maintained until 4 weeks after EOT! 
This phase ends 5 years after Baseline or when the study will be terminated, which is defined 
as the time point when the last patient has completed 1year follow-up. 
After progression/relapse of the disease:  
Progression/Relapse should be confirmed by radiological imaging, such as magnetic resonance 
imaging (MRI), computed tomography (CT) scan; CA 125 rise not supported by radiological 
evidence of disease is not accepted as criteria for defining progression.  
After Progression/Relapse patient will enter into the follow-up phase, if she is not already in 
this phase. Further PFS documentation after this progression is not necessary. Quality of Life 
assessments, follow-up therapy and OS will be continued.  
After progression/relapse information about disease status, survival and for QoL assessments 
may be requested from the treating physician via telephone every 6 months, if the patient gives 
her consent to this procedure. This can be performed by any means possible (e.g. patient visit, 


 
 
 
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telephone contact, and mail for QoL assessments). AEs and SAEs to be documented until 30 
days after end of study treatment or until start of new antitumor therapy, whatever occurs first. 
12.7 Patient’s care after end of study 
After the end of the study, instructions of Section 10.4.3 apply. The investigators of the study 
are experienced gynecological or medical oncologists who treat patients in routine clinical 
practice. Therefore, the investigators are responsible for the further treatment of the patient after 
the end of the study for disease progression. The investigators shall support and advice the 
patient and – if required – help to organize appointments with other specialized physicians.  
13 Safety 
13.1 Definitions 
13.1.1 Adverse event (AE) 
Any untoward medical occurrence in a patient or clinical trial subject administered a medicinal 
product and which does not necessarily have a causal relationship with this treatment [Dir 
2001/20/EC Art 2(m)]. An adverse event can therefore be any unfavourable and unintended 
sign (e.g. an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal product, whether or not considered related to the medicinal product. 
The following special situations also should be considered AE, but only when they lead to an 
adverse drug reaction:  
 Drug overdose 
 Drug abuse 
 Drug misuse 
 Drug interactions 
 Drug dependency 
 Exposure in uterus 
Any event involving adverse drug reactions, illnesses with onset during the study or 
exacerbations of pre-existing illnesses should be recorded including but not limited to clinically 
significant changes in physical examination findings and abnormal objective test findings (e.g., 
CT, ECG). The criteria for determining whether an abnormal objective test finding should be 
reported as an AE are as follows: 
 The test result is associated with clinically significant symptoms, and/or 


 
 
 
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 The test result leads to a change in the study dosing or discontinuation from the clinical 
trial, significant additional concomitant drug treatment or other therapy, and/or 
 The test result leads to any of the outcomes included in the definition of a SAE, and/or 
 The test result is considered to be an AE by the investigator. 
13.1.2 Serious adverse event (SAE) 
A serious adverse event is any adverse experience occurring at any dose that suggests a 
significant hazard to the patient and includes any event that: 
 is fatal 
 is life-threatening (see clarification below)  
 requires or prolongs hospitalization 
 results in persistent or significant disability or incapacity 
 is a congenital abnormality/birth defect 
 is medically significant representing an important medical event (see clarification 
below) 
In contrast to routine safety assessments, SAE are monitored continuously. 
Life-threatening in this context refers to an adverse event in which the patient was at risk of 
death at the time of the event; it does not refer to an event that hypothetically might have caused 
death if it were more severe.  
 
Adverse events reported from clinical trials associated with hospitalization or prolongation of 
hospitalization are considered serious and must be reported as a SAE unless exempted from 
SAE reporting (see section 13.5.2). Any initial admission (even if less than 24 hours) to a 
healthcare facility meets these criteria. Admission also includes transfer within the hospital to 
an acute/intensive care unit (e.g., from the medical floor to an intensive care unit, medical floor 
to an infectious disease unit, etc). 
 
Prolongation of hospitalization is defined as any extension of an inpatient hospitalization 
beyond the stay anticipated/required for the initial admission, as determined by the Investigator 
or treating physician. 
 
Hospitalizations that do not meet criteria for SAE reporting are: 
a) Reasons described in protocol [e.g., investigational medicinal product (IMP) 
administration, protocol-required intervention/investigations, etc]. However, events 


 
 
 
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requiring hospitalizations or prolongation of hospitalization as a result of a complication 
of therapy administration or clinical trial procedures will be reported as SAEs. 
b) Hospitalization or prolonged hospitalization for technical, administrative, practical or 
social reasons, in absence of an AE. 
c) Pre-planned hospitalizations: Any pre-planned surgery or procedure must be 
documented in the source documentation. Only if the pre-planned surgery needs to be 
performed earlier due to a worsening of the condition, should this event (worsened 
condition) be reported as a SAE. 
d) An emergency visit due to an accident where the patient is treated and discharged. 
e) When the patient is held 24 hours for observation and finally is not admitted. 
f) Planned treatments at sites not associated to a hospital and generally considered as 
minor surgical procedures (i.e., laser eye surgery, arthroscopy, etc). 
 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as adverse events. However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an adverse event. For example, an 
acute appendicitis that begins during the adverse event reporting period should be reported as 
the adverse event, and the resulting appendectomy should be recorded as treatment of the 
adverse event. 
 
Disability means a substantial disruption of a person´s ability to conduct normal life´s 
functions. 
 
A medically significant event: Any adverse event may be considered serious because it may 
jeopardize the subject and may require intervention to prevent another serious condition. As 
guidance for determination of important medical events refer to the “WHO Adverse Reaction 
Terminology – Critical Terms List”. These terms either refer to or might be indicative of a 
serious disease state. In this study protocol, the definition of medically significant event 
explicitly includes the suspected transmission via a medicinal product of an infectious agent. 
Such reported events warrant special attention because of their possible association with a 
serious disease state and may lead to more decisive action than reports on other terms. 
 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious adverse events, such as important medical events that might not be 


 
 
 
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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. 
 
13.2 Relationship of an adverse event to the study drug(s) 
The causal relationship to study drug is determined by the investigators and should be used to 
assess all adverse events (AE). The causal relationship can be one of the following definitions: 
Related: There is a reasonable causal relationship between study drug administration 
and the AE. 
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE.  
The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship.  
In case of a missing causality assessment in the CRF or SAE reporting form, the event will be 
regarded as "probably related" unless further specified. 
A serious ADR (SADR) is an adverse drug reaction that meets the definition of a serious event 
(provided above). 
 
13.3 Severity of an adverse event 
The severity of an adverse event will be assessed according to the National Cancer Institute 
CTC scale (version 4.0). 
The following definitions will be used for adverse events that are not specified in the CTC scale: 
 Mild (grade 1): 
The adverse event is noticeable to the patient; it does not require discontinuation of the 
dose of the study agent but may require additional therapy. 
 Moderate (grade 2): 
The adverse event interferes with the patient's daily activities; it may require additional 
therapy or reduction of the dose of the study agent, but does not require discontinuation 
of the study agent. 
 Severe (grade 3): 
The adverse event is intolerable and necessitates additional therapy or discontinuing the 
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 Life-threatening (grade 4): 
The patient is at immediate risk of death from the adverse event. 
 Fatal (grade 5): 
The adverse event resulted in death of the patient. 
 
13.4 Unexpected adverse event / SUSAR 
An unexpected adverse event is any adverse drug event, the specificity or severity of which is 
not consistent with the current versions of the SmPCs of PLD and the standard platinum based 
therapy (see Table 5), respectively. Also, reports which add significant information on 
specificity or severity of a known, already documented adverse event constitute unexpected 
adverse events. An event more specific or more severe than described in the respective SmPC 
would be considered "unexpected". 
A suspected unexpected serious adverse reaction (SUSAR) is a serious adverse reaction, the 
nature, or severity of which is not consistent with the current SmPC. All suspected adverse 
reactions related to the IMP which occur in this trial and are both unexpected and serious 
(SUSARs) are subject to expedited reporting. 
SAEs which are "related" and "unexpected" meet the criteria for SUSAR. 
Table 5: SmPCs of reference products 
Drug 
Reference product(s*)  
PLD 
Caelyx 
Trabectedin 
Yondelis  
Carboplatin 
e.g. Carboplatin onkovis; Carboplatin Hexal; Ribocarb- L; 
Neocarbo; Carboplatin Bendalis; Carboplatin Kabi; Carboplatin –
GRY 
Gemcitabine 
e.g. Gemcitabin–GRY; Gemcitabin Kabi; Gemcitabin Oncovis; 
Gemcitabine–HAEMATO; Gemzar; Gemedac; Gemcitabin Hexal; 
Gemci Cell 
Paclitaxel 
e.g. Paclitaxel Hospira; Paclitaxel Haematom; Paclitaxel oncovis; 
Paclitaxel stragen; Paclitaxel-GRY; Celltaxel; Neotaxan; Paclitaxel 
Hexal; Ribotax; Taxomedac 
* If several generic products are available only for the underlined product the most recent 
SmPC will be made available to sites. 


 
 
 
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13.5 Reporting procedures 
13.5.1 Reporting of Adverse Events (serious and non-serious) 
All adverse events occurring during the study must be recorded in the patient's electronic case 
report form (eCRF).  
The Sponsor will collect AEs from the date of first administration of a study drug/IMP and until 
30 days after administration of the last dose of study drug/IMP or until the start of a new 
antitumor therapy, whichever occurs first. All AEs suspected to be related to study drug/IMP 
must be followed after the time of therapy discontinuation until the event or its sequelae resolve 
or until symptoms stabilization. 
All adverse events must be recorded using medical terminology. Whenever possible the 
Investigator will record the main diagnosis instead of the signs and symptoms normally 
included in the diagnoses. 
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0. If CTCAE grading does not exist for an adverse event, the 
severity of mild, moderate, severe, life-threatening, and fatal OR grades 1 – 5, will be used.  
The occurrence of adverse events should be evaluated by non-directive questioning of the 
patient at each visit during the study. Adverse events may also be identified when patients 
referencing to them during or between visits or through physical examination, laboratory test, 
or other assessments. As far as possible, each adverse event should be evaluated to determine: 
 the grade of severity according to CTCAE version 4.0 (grade 1 – 5)  
 its duration (start and end dates or if ongoing at final exam) 
 its relationship to the study drug(s) (see section 13.6) 
 the action taken (study drug dosage not changed; study drug dosage reduced; study drug 
temporarily interrupted; study drug permanently withdrawn due to this adverse event*; 
concomitant medication given*; non-drug therapy given*; hospitalization/ prolonged 
hospitalization*; not applicable*; unknown) 
 the outcome (fatal, not recovered/not resolved, recovered/resolved, recovered/resolved 
with sequelae, recovering/resolving, deteriorating, unknown) 
 whether it is a serious adverse event (SAE) (see chapter 13.1.2) 
* Will be collected for serious adverse events only. 
13.5.2 Reporting of Serious Adverse Events 
All serious adverse events (SAEs, irrespective of suspected causal relationship), including 
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the last dose of study treatment was administered, or until the start of a new antitumor therapy, 
whichever occurs first, must be reported in writing to the Institut für Klinische Krebsforschung 
IKF GmbH (IKF) for review/re-evaluation within 24 hours of Investigator and/or study center 
receiving notification of any “serious” adverse event experienced by a patient, using the study 
“Serious Adverse Event” form. The IKF will notify the sponsor / other persons involved.  
Beyond this period of time, only those SAEs suspected to be related to the IMP will be collected. 
Nonetheless, the Sponsor will evaluate any safety information related to the clinical trial that is 
spontaneously reported by an Investigator beyond the time frame specified in the protocol. 
 
All SAEs suspected to be related to the study medication/IMP must be followed until the event 
or its sequelae resolve or until symptoms stabilization. 
 
Tumor progression or appearance of new tumor lesions MUST NOT be reported as a SAE. 
Events of “disease progression” (including signs and symptoms of progression) even if they 
fulfill any seriousness criterion (i.e., fatal, requiring hospitalization, etc) are exempted from 
reporting and will only be reported in the applicable section of the CRF. 
Death, as such, is the outcome of a SAE and should not be reported as the SAE term itself. 
Instead the cause of death should be recorded as the SAE term. When available, the autopsy 
report will be provided to the Sponsor. 
 
Reports have to be sent via fax or eMail to: 
Institut für Klinische Krebsforschung IKF GmbHam Krankenhaus Nordwest Steinbacher Hohl 
2-26 
60488 Frankfurt 
Germany 
Fax: +49 69 / 7601-3655 
eMail: SAE@ikf-khnw.de 
 
The study´s medical expert will perform review and second assessment of every SAE within 
three calendar days. Serious adverse events with at least possible relation to the study drug(s) 
and assessed unexpected based on the information contained in the relevant SmPC(s) 
(Fachinformation) are reported as Suspected Unexpected Serious Adverse Reaction (SUSAR) 
to the competent authorities and relevant ethics committees in accordance with Directive 
2001/20/EC or as per national regulatory requirements. 
An annual safety report (DSUR, developmental safety update report) will be submitted by the  
 


 
 
 
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Sponsor to the competent IRB and to the competent authority (BfArM).  
Patients experiencing adverse events should be followed up carefully until the condition 
resolves, and every effort should be made to clarify the underlying cause. Follow-up 
information related to serious adverse events and reportable deaths must be submitted to the 
sponsor by telephone, fax, or e-mail as soon as relevant data become available. 
13.6 Reporting Pregnancy Cases Occurred within the Clinical Trial 
Pregnancy and suspected pregnancy (including a positive pregnancy test regardless of 
age or diseases state) of a female patient occurring while the patient is on study drug, or 
within three months from the patient´s discontinuation visit, are considered immediately 
reportable events. 
The Investigator will report the following events immediately and always within 24 hours 
from first knowledge using the study specific Pregnancy Report Form: 
 Any occurrence of a pregnancy where any kind of exposure to the study 
medication/IMP is suspected. 
 Possible exposure of a pregnant woman (this could involve a pregnant female who 
came in contact with the clinical trial study medication/IMP). 
 All reports of elevated/questionable or indeterminate beta human chorionic 
gonadotropins (β-hCGs). 
Immediately after detecting a case of suspected pregnancy in a female clinical trial 
patient, the decision on her continued participation in the clinical trial will be jointly taken 
by the trial patient, the Investigator and the Sponsor, with the patient´s best interest in 
mind. A decision to continue the pregnancy will require immediate withdrawal from the 
trial. 
Any pregnancy, suspected pregnancy, or positive pregnancy test must be reported to the 
Institut für Klinische Krebsforschung IKF GmbH (IKF) immediately by e-mail or 
facsimile using the Pregnancy Report Form.  
The Investigator will follow the pregnancy until its outcome, and should follow the 
newborn up to 2 years after the delivery, and must notify the Institut für Klinische 
Krebsforschung IKF GmbH (IKF) (of the outcome of the pregnancy and of the newborn) 
within 24 hours of first knowledge as a follow-up to the initial report. 


 
 
 
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For any event during the pregnancy which meets a seriousness criterion (including fetal 
or neonatal death or congenital anomaly) the Investigator will also follow the procedures 
for reporting SAEs. 
All neonatal deaths that occur within 30 days of birth should be reported, regardless to 
the causality, as SAEs. In addition, any infant death at any time thereafter that the 
Investigator suspects is related to the exposure to the study drug/IMP should also be 
reported to the Institut für Klinische Krebsforschung IKF GmbH (IKF) by e-mail or 
facsimile within 24 hours of the Investigators´ knowledge of the event. 
14 Quality control and quality assurance 
14.1 Quality assurance 
The Standard Operating Procedures (SOPs) of the CRO are used for the delegated processes. 
For all other processes, SOPs of the Sponsor apply. 
14.2 Standardization and randomization 
The evaluation criteria of study endpoints are identical for all participating centers. Each center 
has to file its normal ranges for hematology and blood chemistry in the investigator site file 
(ISF). The respective laboratory institutions have participated in an appropriate quality 
assurance program. All certificates for these inter-laboratory comparisons in ring trials (German 
„Ringversuchzertifikate“) have to be filed in the ISF during the duration of the trial.  
Toxicity is recorded in a standardized way according to the NCI CTC criteria version 4.0 for 
categorization and grading.  
Patients will be stratified by two parameters: Patients will be stratified by surgery for relapse 
(tumor free vs. not tumor free resection) vs. no surgery in the same setting, and age (< 75 years 
vs. ≥ 75 years) and will be randomized 1:1 into one of the study arms. The randomization plan 
will be generated by a validated SAS program and underlies strict access control. The allocation 
of the patient numbers and treatment groups will be coordinated by IWRS system integrated in 
the eCRF. 
14.3 Audits / inspections 
In case of an audit by the sponsor or an appropriate authority, the investigator will make all 
relevant documents available. If an audit visit by a regional authority is announced, the 
respective center should inform the sponsor, CRO and coordinating investigator as early as 
possible in order to allow for an appropriate preparation and support.  


 
 
 
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14.4 Monitoring 
It is understood that an outside monitor and other authorized personnel may contact and visit 
the investigator, and that they will be allowed direct access to source data/documents for trial-
related monitoring, audits, IRB review, and regulatory inspection. Direct access is defined as 
permission to examine, analyze, verify, and reproduce any records and reports that are 
important to evaluation of a clinical trial. All reasonable precautions within the constraints of 
the applicable regulatory requirement(s) to maintain the confidentiality of subjects’ identities 
and Sponsor’s proprietary information will be exercised (Guideline for Good Clinical Practice, 
ICH Harmonized Tripartite Guideline, adopted July 1996: Chapter 5.15.1 and 1.21, 
respectively). 
It is the monitor’s responsibility to inspect the case report forms at regular intervals throughout 
the trial to verify adherence to the protocol: the completeness, accuracy, and consistency of the 
data; and adherence to Good Clinical Practice guidelines. The monitor should have access to 
patient charts, laboratory reports, and other patient records needed to verify the entries on the 
case report forms. Where local rules do not allow direct access to the source data, the monitor 
will verify entries in the case report form by asking direct questions of a person or persons with 
authorized access to the source data. The Investigator agrees to cooperate with the monitor to 
ensure that any problems detected during the course of these monitoring visits are resolved. 
A monitoring plan with relevant details is issued prior to the trial.  
14.5 Plausibility check, data cleaning and coding 
Qualified members of the CRO regularly perform plausibility checks and data cleaning 
according to the data-cleaning plan. Some of the raw data of the eCRF also needs coding (e.g. 
toxicities) according to the data-coding plan. Before data base closure, data cleaning and 
manual plausibility checks have to be performed for the relevant contents (defined by the data-
cleaning plan), and all open questions have to be resolved.  
14.6 Data management 
Data collection and capture, as well as creation of queries will be performed under the 
responsibility of the CRO. Data analysis will be performed by the responsible study 
biostatistician. Good Clinical Practice (GCP)-compliant handling of the data is secured by 
adequate SOPs. Archiving of data and results electronically recorded will be at least 10 years 
after the end of this study (according to legal guidelines). 


 
 
 
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14.7 Information on study drugs to trial investigators 
Each of the drugs administered in the course of this study are market approved in Germany and 
all participating investigators will have broad experience with these medications. Therefore, 
investigators will be provided with all relevant and up-to-date clinical and pre-clinical 
information (SmPC / Fachinformation) on one example product for each component of the 
chemotherapeutic regimen. It is the responsibility of the investigator to have at hand the most 
recent information on the specific medicinal product used during local routine at the respective 
study site.  
If additional data on the study drugs with major relevance for the conduct of the study become 
evident, they will be distributed to the investigators. 
15 Regulatory and ethical obligations 
15.1 Regulatory and ethical compliance 
This clinical study was designed and shall be implemented and reported in accordance with the 
protocol, the AMG (Arzneimittelgesetz), the ICH Harmonized Tripartite Guidelines for Good 
Clinical Practice, with applicable local regulations (including European Directive 2001/20/EC), 
and with the ethical principles laid down in the Declaration of Helsinki from 1996. 
Before recruitment into the clinical trial, each patient will be informed that participation in the 
study is completely voluntary, and that she may withdraw her participation in the trial at any 
time without any declaration of reasons. This will not lead to any disadvantage for the respective 
patient. If the withdrawal is caused by an adverse drug event, the patient should inform the 
investigator about this fact. 
15.2 Registration and request for authorization of the trial 
According to GCP-V, the trial has to be submitted to and to be authorized/approved by the 
competent authority (Bundesinstitut für Arzneimittel und Medizinprodukte, BfArM) and the 
competent ethics committee responsible for the trial (“federführende Ethikkommission”). 
Additionally, all local ethics committees responsible for individual trial sites have to give their 
opinion to the competent ethics committee. The respective local authorities will be informed 
about the trial and the participation by the individual trial sites. 
The competent authority and the competent ethics committee will be informed on the course of 
the study with respect to safety aspects to be announced as well as on the termination of the 
trial and the trial results according to GCP-V. 


 
 
 
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15.3 Institutional review board / ethics committee 
Prior to start of the trial the study protocol and all additionally relevant documents will be sent 
to the competent ethics committee by the sponsor or its delegate in order to receive the 
committee’s opinion. The trial is only allowed to start after a positive vote of the ethics 
committee has been received. During the course of the study the Sponsor will inform the ethical 
committee about all amendments to the study protocol as well as on all SUSARs emerging from 
the trial according to GCP-V. In addition, the competent ethical committee will receive a DSUR 
once a year. 
All subsequent protocol amendments and amendments to the informed consent form will be 
submitted to the competent ethics committee to obtain an updated vote before implementation 
of the changes. Serious or unexpected adverse events occurring during the trial likely to affect 
the safety of the subjects or the conduct of the trial will also be reported to the ethics committee. 
In addition, the competent ethical committee will be informed on the course of the study with 
respect to the termination of the trial and the trial results.  
15.4 Informed consent 
It is the investigator’s responsibility to obtain witnessed written informed consent from the 
patient after adequate explanation of the aims, methods, anticipated benefits, and potential 
hazards of the study and before any study drug is administered. The patient should be given a 
copy of the informed consent documentation. The wet ink copy of the signed and dated 
informed consent must be retained in the institution’s records, and is subject to inspection by 
representatives of the Sponsor or representatives from regulatory agencies. 
15.5 Insurance 
A clinical trials insurance will be contracted before submission of the study to the relevant 
authorities. A copy of the confirmation and the conditions of the insurance will be handed out 
to every study participant together with the informed consent form. 
15.6 Patient confidentiality 
The investigator must ensure that the patient’s privacy is maintained. A patient should only be 
described by her year of birth and patient number on the case report forms and on other 
documents submitted to the Sponsor (pseudonymization). The investigator should keep 
documents that are not submitted to the Sponsor (e.g. signed informed consent form) in a strictly 
confidential file. 


 
 
 
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The investigator shall permit the Sponsor and authorized representatives of regulatory agencies 
to review the portion of the patient’s medical record that is directly related to the study. The 
patient must be informed that his or her records will be reviewed in this manner as a part of the 
informed consent form. 
16 Statistical design 
16.1 General considerations 
The present trial is designed as a prospective, multi-centre randomized phase IV study which 
aims at assessing the difference in QoL in patients treated with trabectedin/PLD vs. standard 
platinum-based combination therapies. QoL will be measured by TOI-QLQ-OV as an indicator 
of the overall burden of chemotherapy. In addition, several indicators of therapeutic efficacy 
will be summarized and the safety will be reviewed. 
16.2 Sample size calculation 
The primary objective of this study is to evaluate the overall burden of the therapy. Based on 
experience from our study HECTOR (NOGGO-R9, AGO Ovar 2.12 [31]) the TOI-QLQ-OV 
can be used as an indicator of the overall burden with a good reliability (Chronbach´s alpha 
>0.9). A relevant between-arm difference of the mean TOI-QLQ-OV-change per patient score 
should be at least 8 points (assuming a standard deviation of 14.2 points). 68 evaluable patients 
are needed in each treatment arm in order to be able to detect an 8 points difference in QoL 
with a two-sided significance level of 5 % and a statistical power of 90 %, based on the 
assumption that the standard deviation of the response variable is 14.2. Assuming a dropout 
rate of one third, a total of 204 patients have to be randomized. 
16.3 Study Duration 
The recruitment is planned to last 52 months (204 patients in 20 German sites), expecting 
approx. 3 patients per site and year. First patient in will be around Q3 2017. 
The treatment period per patient is 18-24 weeks with a follow-up of 1 year after last patient in 
or 5 years after BL, whichever occurs first. This will be reflected in the patient’s informed 
consent. 
 
16.4 Efficacy parameters 
QoL will be measured by the TOI-QLQ-OV. For the primary endpoint the difference of the 
changes from Baseline (assessed up to 14 days before Baseline visit) to EOT (3-4 weeks after 


 
 
 
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C6 D1 or, in case of progression/relapse, 3-4 weeks after day 1 of last treatment Cycle) will be 
used. The differences of changes from Baseline to other time points will be secondary 
outcomes. 
Other secondary outcomes are OS, which will be measured as time from randomization to death 
of any cause. PFS will be measured as time from randomization until disease progression, 
disease recurrence after surgery or death of any cause.  
Survival and survival rates for the different time points will be determined using the Kaplan-
Meier analysis of OS and PFS. Adverse events will be recorded and graded according to version 
4.0 of National Cancer Institute Common Toxicity Criteria (NCI-CTC). Peripheral sensitive 
neuropathy is graded according to a platinum-specific scale. Percentages of toxic effects, 
serious adverse events and complications will be compared between arms using the Fisher´s 
exact test. 
16.5 Analysis 
Prior to final analysis, we will perform data verification with respect to completeness and 
plausibility (data cleaning). Inconsistencies and mistakes will be clarified with the study centers 
and will be removed. The data cleaning process starts soon after first patients are enrolled and 
monitored. Major protocol violations and special cases will be listed. Finally, a conference with 
coordinating investigator, statistician, and other involved persons of the study will discuss and 
define the statistical analysis plan and the handling of special cases and major violations. In this 
conference also those violations will be defined, which will result in the exclusion of the Per 
protocol-population or even from the Efficacy population (see following section). During the 
discussion of protocol violations, the cases were blinded with respect to the therapy arm of each 
case to the members of the above-mentioned committees. 
The primary efficacy analysis will include all randomized patients with at least a QoL Score at 
baseline and EOT, with patients grouped according to the treatment assigned at randomization. 
 
 


 
 
 
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16.5.1 Study populations for the analysis 
The following data sets for analysis are defined:  
Efficacy Population (EP) 
The efficacy population (EP) includes all patients who were randomized and have evaluable 
QoL assessments at baseline and EOT. Treatment assignment is based on the randomized 
treatment (primary population). The EP is used for the primary efficacy analysis on QoL.  
 
Intent-to-treat population (ITT) 
The intent-to-treat (ITT) population includes all patients who were randomized. Treatment 
assignment is based on the randomized treatment (primary population). 
The ITT population is the primary population for the analysis of the patient’s characteristics, 
and all other efficacy endpoints such as PFS, OS and objective response. 
 
Per protocol (PP) population  
This population will include all randomized patients who fulfill major inclusion and exclusion 
criteria and receive at least one cycle of the treatment. Treatment assignment is based on the 
treatment actually received. 
 
Safety analysis set 
The safety population for chemotherapy related toxicity comprises all patients who received at 
least one cycle of any component of carboplatin or trabectedin. 
 
Several subgroup analyses including but not limited to BRCA-mutation (yes/no), surgery 
performed (yes/no), tumor rest (yes/no), age and line of chemotherapy are planned. Further 
details will be specified in the statistical analysis plan (SAP). 
 
16.5.2 Statistical methods for the analysis 
The primary endpoint will be analysed by general linear models for paired samples. 
All secondary endpoints, such as baseline and therapy-related data, will be evaluated in an 
explorative or descriptive manner, providing means, medians, ranges, standard deviations 
and/or confidence intervals. If p values are calculated (e.g. in subgroup comparisons or across 
treatment arms), they will be interpreted exploratory. Usually, no error adjustment for multiple 
testing will be performed. Thus the p values will reflect the comparison-wise error and not the 
experiment-wise error. All p values will be two-sided if not stated otherwise. The statistical 


 
 
 
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methods described in this section are suited for the data and distributions usually expected in 
this type of trials. The suitability will be checked after data entry. If necessary, the statistical 
method will be modified accordingly. 
Efficacy, toxicity and other event rates are calculated, providing confidence intervals. In case 
of comparison between patient groups, these rates will be analyzed by Fisher’s exact test or chi² 
test, respectively. 
Event related data like PFS, time to progression, duration of response and OS time will be 
estimated by the Kaplan Meier product limit method and compared using the logrank test. For 
the median values of PFS or OS the 95 % confidence interval will be calculated. Multivariate 
analyses may be performed by suitable regression models (proportional hazard regression 
model, logistic regression). 
The statistical tests, except where otherwise stated, are carried out with a two-sided significance 
level of 5 %. The analyses are carried out using current versions of IBM SPSS Statistics or R.  
Further details of the planned procedure and specific analyses will be defined in the statistical 
analysis plan, latest prior to locking the database. 
16.6 Methods against bias 
Patients will be randomly assigned to one of the treatment arms and stratified by important 
prognostic factors. Multivariate analyses will be applied whenever appropriate to evaluate the 
effect of confounding factors. The analysis will be performed according to the EP, but we will 
perform diverse additional sensitivity analyses, specified in the final SAP. 
17 Data management 
17.1 Data collection 
Designated investigator staff will enter the data required by the protocol into the electronic case 
report forms (eCRF). These persons will not be given access to the EDC (electronic data 
capture) system until they have been adequately trained. Automatic validation during data entry 
will check for data discrepancies and, by generating appropriate error messages, allow these 
data to be confirmed or corrected. The investigator must certify that the data entered into the 
eCRF are complete and accurate. After database lock, the investigator will receive a CD-ROM 
or paper copies of the patient data for archiving at the study site. 
In case of technical problems a paper CRF is available. All forms must be identified with patient 
pseudonym, date of the observation, and center number. Paper forms will be completed using 
a black ballpoint pen, and entries must be legible. Errors should be crossed by a single line but 


 
 
 
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not obliterated, the correction inserted, and the change initialed and dated by the investigator or 
an authorized member of the study staff. 
17.2 Confidentiality 
All patient-related data are recorded in a pseudonymized way. Each patient is unequivocally 
identified by a trial subject number, attributed at recruitment into the study. The investigator 
has to keep a patient identification log, including the full name and address of the subject and 
eventually additional relevant personal data.  
17.3 Investigator site file 
Each participating trial site will file relevant documents (protocol, CVs, approvals of the 
authorities etc.) and trial related correspondence in the investigator site file (ISF). 
18 Funding of the study and responsibilities 
18.1 Financing 
This study is an investigator-initiated trial (IIT). It is based on the idea and conception of the 
lead coordinating investigator (LKP). PharmaMar has provided a research grant supporting the 
conduct of the study. There will be a remuneration of the investigators for an enrolled and fully 
documented patient. The breakdown of this sum will be explained in the investigator´s contract. 
No study medication will be provided. 
18.2 Responsibilities 
The NOGGO e.V. Augustenburger Platz 1,  13353 Berlin is the Sponsor of the study according 
to German Law (AMG) and represents therefore the legal entity behind the study. Lead 
coordinating investigator (LKP according to AMG) is Prof. Sehouli. Responsible for the 
conduct of the study is the Sponsor who delegate several processes related to the study conduct 
to a Contract Research Organisation (CRO): Institut für Klinische Krebsforschung IKF GmbH 
f(IKF). The CRO is responsible for quality assurance related to the processes under its 
responsibility. For all other processes, responsibility for quality assurance remains with the 
Sponsor. The Sponsor as well as the CRO might designate experienced personnel to observe 
the GCP conformity of the study conduct. All organizational, formal, and content-related 
changes of the protocol or the logistics require consent of the Sponsor. 
Essential decisions with respect to the study conduct such as content related protocol changes 
will be communicated to the LKP, Sponsor, CRO, steering committee and or the statistician in 
charge. All these members agree that this communication can be done by phone or e-mail. For 
interim (if applicable) and final analyses safety data such as toxicity, early termination, deaths, 


 
 
 
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SUSARs etc., will be presented to the sponsor listed in tables and commented by the lead 
coordinating investigator.  
19 Administrative and legal obligations 
19.1 Protocol amendments 
Any modification to the protocol impacting on the conduct of the study, the potential benefit of 
the study, or which may affect patient safety, including changes of study objectives, study 
design, patient population, sample sizes, study procedures, or significant administrative aspects 
will require a formal amendment to the protocol.  
Any amendment to the protocol will be agreed upon by the lead coordinating investigator (LKP) 
and the Sponsor. Updated versions of the study documents will be submitted to the competent 
authority and the responsible ethical committee prior to implementation (according to §10, Abs. 
2 to 4 GCP-V). 
Administrative or technical changes of the protocol (minor corrections and/or clarifications) 
that do not affect study conduct, nor change the risk-benefit-assessment, will be agreed upon 
by the lead coordinating investigator (LKP), the Sponsor and the CRO and will be documented 
in a memorandum to the protocol. The responsible ethical committee will be informed about 
such changes at the discretion of the Sponsor/lead coordinating investigator. The Sponsor/lead 
coordinating investigator will assure that all documents related to protocol amendments have 
been included in the investigator site file at all participating study centers.  
19.2 Trial termination 
This clinical trial may be completed regularly as planned or may be prematurely discontinued 
by the Sponsor. If the trial is completed regularly, the Sponsor will notify the competent 
authority as well as the competent ethics committee in writing. If the trial is prematurely 
terminated or suspended, the Sponsor will inform the competent authority as well as the 
competent ethics committee of the termination or suspension and the reason(s) for the 
termination or suspension within 15 days in accordance with national regulations. 
19.3 Trial documentation and data storage 
The investigator must ensure that all records pertaining to the conduct of the clinical study, 
including signed (e)CRFs, informed consent forms, drug accountability records, source 
documents, and other study documentation are adequately stored for the required time period 


 
 
 
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to allow for review and reconstruction of the study. This documentation must be retained for 
10 years following completion of the study or for the length of time requested by the Sponsor. 
19.4 Publication and registration of the study 
The results of this study will be published by the lead coordinating after final analysis has been 
performed. Publication will be independent of the nature of the results obtained (whether they 
were positive or negative). The manuscript written for publication, together with the materials 
provided by the statistician can be accepted as the final study report.  
This clinical trial is registered at www.clinicaltrials.gov.  


 
 
 
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20 References 
1. 
Oskay-Özcelik, G. and J. Sehouli, Ovarialkarzinom, in Therapiealgorithmen Onkologie, S.-E. Al-
Batran and R.-D. Hofheinz, Editors. 2014, rs media GmbH: Regensburg. p. 227-234. 
2. 
Parkin, D.M., et al., Global cancer statistics, 2002. CA Cancer J Clin, 2005. 55(2): p. 74-108. 
3. 
du Bois, A., et al., 2004 consensus statements on the management of ovarian cancer: final 
document of the 3rd International Gynecologic Cancer Intergroup Ovarian Cancer Consensus 
Conference (GCIG OCCC 2004). Ann Oncol, 2005. 16 Suppl 8: p. viii7-viii12. 
4. 
Pfisterer, J. and J.A. Ledermann, Management of platinum-sensitive recurrent ovarian cancer. 
Semin Oncol, 2006. 33(2 Suppl 6): p. S12-6. 
5. 
Leitlinienprogramm Onkologie (Deutsche Krebsgesellschaft, Deutsche Krebshilfe, AWMF): S3-
Leitlinie Diagnostik, Therapie und Nachsorge maligner Ovarialtumoren, Langversion 4.01,2019, 
AWMF-Registernummer: 032/035OL,. 
6. 
du Bois, A., et al., A randomized clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel 
as first-line treatment of ovarian cancer. J Natl Cancer Inst, 2003. 95(17): p. 1320-9. 
7. 
Pfisterer, J., et al., Gemcitabine plus carboplatin compared with carboplatin in patients with 
platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC 
CTG, and the EORTC GCG. J Clin Oncol, 2006. 24(29): p. 4699-707. 
8. 
Del Campo, J.M., et al., Phase II randomized study of trabectedin given as two different every 
3 weeks dose schedules (1.5 mg/m2 24 h or 1.3 mg/m2 3 h) to patients with relapsed, platinum-
sensitive, advanced ovarian cancer. Ann Oncol, 2009. 20(11): p. 1794-802. 
9. 
National Comprehensive Cancer Network. The NCCN Clinical Practice Guidelines in Oncology 
Ovarian Cancer (version 1.2009). Available from: http://www.nccn.org. 
10. 
Pujade-Lauraine, E., et al., Pegylated liposomal Doxorubicin and Carboplatin compared with 
Paclitaxel and Carboplatin for patients with platinum-sensitive ovarian cancer in late relapse. 
J Clin Oncol, 2010. 28(20): p. 3323-9. 
11. 
Monk, B.J., et al., Trabectedin plus pegylated liposomal Doxorubicin in recurrent ovarian 
cancer. J Clin Oncol, 2010. 28(19): p. 3107-14. 
12. 
Deutsche Krebsgesellschaft, Deutsche Krebshilfe, and AWMF, Leitlinienprogramm Onkologie: 
S3-Leitlinie Diagnostik. Therapie und Nachsorge maligner Ovarialtumoren, Langversion 
Version 1.0 - Juni 2013, AWMF-Registernummer: 032/035OL, 2013. 
13. 
Armstrong, D.K., Relapsed ovarian cancer: challenges and management strategies for a chronic 
disease. Oncologist, 2002. 7 Suppl 5: p. 20-8. 
14. 
Parmar, M.K., et al., Paclitaxel plus platinum-based chemotherapy versus conventional 
platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-
2.2 trial. Lancet, 2003. 361(9375): p. 2099-106. 
15. 
Ozols, R.F., et al., Phase III trial of carboplatin and paclitaxel compared with cisplatin and 
paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology 
Group study. J Clin Oncol, 2003. 21(17): p. 3194-200. 
16. 
Dranitsaris, G., J. Elia-Pacitti, and W. Cottrell, Measuring treatment preferences and willingness 
to pay for docetaxel in advanced ovarian cancer. Pharmacoeconomics, 2004. 22(6): p. 375-87. 
17. 
Roila, F. and E. Cortesi, Quality of life as a primary end point in oncology. Ann Oncol, 2001. 12 
Suppl 3: p. S3-6. 
18. 
Jodrell, D.I., et al., Relationships between carboplatin exposure and tumor response and 
toxicity in patients with ovarian cancer. J Clin Oncol, 1992. 10(4): p. 520-8. 
19. 
Wagstaff, A.J., et al., Carboplatin. A preliminary review of its pharmacodynamic and 
pharmacokinetic properties and therapeutic efficacy in the treatment of cancer. Drugs, 1989. 
37(2): p. 162-90. 
20. 
Markman, M., et al., Clinical features of hypersensitivity reactions to carboplatin. J Clin Oncol, 
1999. 17(4): p. 1141. 
21. 
Dizon, D.S., et al., Analysis of patients with epithelial ovarian cancer or fallopian tube 
carcinoma retreated with cisplatin after the development of a carboplatin allergy. Gynecol 
Oncol, 2002. 84(3): p. 378-82. 


 
 
 
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22. 
Carter, N.J. and S.J. Keam, Trabectedin : a review of its use in the management of soft tissue 
sarcoma and ovarian cancer. Drugs, 2007. 67(15): p. 2257-76. 
23. 
Kong, B., et al. Influence of tumor control on tumor-related events (TRE) in relapsed ovarian 
cancer (ROC): Results from OVA-301, a randomized phase III study of trabectedin (Tr) with 
pegylated liposomal doxorubicin (PLD) versus PLD alone. in ASCO Annual Meeting Proceedings. 
2010. 
24. 
Monk, B.J., et al., Trabectedin plus pegylated liposomal doxorubicin (PLD) versus PLD in 
recurrent ovarian cancer: overall survival analysis. Eur J Cancer, 2012. 48(15): p. 2361-8. 
25. 
Sessa, C., et al., Trabectedin for women with ovarian carcinoma after treatment with platinum 
and taxanes fails. J Clin Oncol, 2005. 23(9): p. 1867-74. 
26. 
Krasner, C.N., et al., A Phase II study of trabectedin single agent in patients with recurrent 
ovarian cancer previously treated with platinum-based regimens. Br J Cancer, 2007. 97(12): p. 
1618-24. 
27. 
Romero, I., et al. Tolerability of long-term use of trabectedin (Tr) in combination with pegylated 
liposomal doxorubicin (PLD) in patients (pts) with relapsed ovarian cancer (ROC). in ASCO 
Annual Meeting Proceedings. 2010. 
28. 
Aaronson, N.K., et al., The European Organization for Research and Treatment of Cancer QLQ-
C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer 
Inst, 1993. 85(5): p. 365-76. 
29. 
Ware, J.E., et al., Conceptualization and measurement of health for adults in the Health 
Insurance Study. 1980. 
30. 
Greimel, E., et al., An international field study of the reliability and validity of a disease-specific 
questionnaire module (the QLQ-OV28) in assessing the quality of life of patients with ovarian 
cancer. Eur J Cancer, 2003. 39(10): p. 1402-8. 
31. 
Sehouli, J., et al. Topotecan plus carboplatin versus standard therapy with paclitaxel plus 
carboplatin (PC) or gemcitabin plus carboplatin (GC) or carboplatin plus pegylated doxorubicin 
(PLDC): A randomized phase III trial of the NOGGO-AGO-Germany-AGO Austria and GEICO-
GCIG intergroup study (HECTOR). in ASCO Annual Meeting Proceedings. 2012. 
32. 
Webster, K., D. Cella, and K. Yost, The Functional Assessment of Chronic Illness Therapy (FACIT) 
Measurement System: properties, applications, and interpretation. Health Qual Life Outcomes, 
2003. 1: p. 79. 
33. 
Gordon, A.N., et al., Recurrent epithelial ovarian carcinoma: a randomized phase III study of 
pegylated liposomal doxorubicin versus topotecan. J Clin Oncol, 2001. 19(14): p. 3312-22. 
34. 
Ferrero, J.M., et al., Second-line chemotherapy with pegylated liposomal doxorubicin and 
carboplatin is highly effective in patients with advanced ovarian cancer in late relapse: a 
GINECO phase II trial. Ann Oncol, 2007. 18(2): p. 263-8. 
35. 
Pujade-Lauraine, E., et al. A randomized, phase III study of carboplatin and pegylated liposomal 
doxorubicin versus carboplatin and paclitaxel in relapsed platinum-sensitive ovarian cancer 
(OC): CALYPSO study of the Gynecologic Cancer Intergroup (GCIG). in ASCO Annual Meeting 
Proceedings. 2009. 
36. 
Wagner, U., et al., Final overall survival results of phase III GCIG CALYPSO trial of pegylated 
liposomal doxorubicin and carboplatin vs paclitaxel and carboplatin in platinum-sensitive 
ovarian cancer patients. Br J Cancer, 2012. 107(4): p. 588-91. 
37. 
Charlson, M.E., et al., A new method of classifying prognostic comorbidity in longitudinal 
studies: development and validation. J Chronic Dis, 1987. 40(5): p. 373-83. 
38. 
Charlson, M., et al., Validation of a combined comorbidity index. J Clin Epidemiol, 1994. 47(11): 
p. 1245-51. 
 
 


 
 
 
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21 Appendices 
 
21.1 Charlson Score 
 
Table 6: Charlson Score with age points [37, 38]    
 Assigned weights 
for diseases 
 Conditions 
1 
Myocardial infarct  
Congestive heart failure  
Peripheral vascular disease  
Cerebrovascular disease  
Dementia  
Chronic pulmonary disease  
Connective tissue disease  
Ulcer disease  
Mild liver disease  
Diabetes 
2 
Hemiplegia  
Moderate or severe renal disease  
Diabetes with end organ damage  
Any tumor Leukemia  
Lymphoma  
3 
Moderate or severe liver disease  
6 
Metastatic solid tumor  
AIDS 
Assigned weights for each condition that a patient has. The total equals the score.  
Example: chronic pulmonary (1) and lymphoma (2) = total score (3). 
 
Additionally, each decade of age ≥50 years is equivalent to a 1-point increase in 
comorbidity (ie, 50–59 years=1 point; 60–69 years=2 points). 
 
 
 


 
 
 
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21.2 ECOG-Classification  
 
Table 7: ECOG Performance Status as developed by the Eastern Cooperative Oncology Group. 
 
Grade ECOG Performance Status 
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 selfcare but unable to carry out any work 
activities; up and about more than 50% of waking hours 
3 
Capable of only limited selfcare; confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled; cannot carry on any selfcare; totally confined to bed or 
chair 
5 
Dead 
 
 


 
 
 
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21.3 NRS 
 


Nutritional Risk Screening (NRS 2002)   ­ English Version 
 
 
 
If the answer to any question is YES, Final Screening is performed.  
If the answer is NO to all questions, the patient is re-screened at weekly intervals. If, for example, the patient is 
scheduled for a major operation, a preventative nutritional care plan is considered to avoid the associated risk status.  
 
1. Is BMI < 20.5? 
2. Has the patient lost weight within the last 3 months? 
3. Has the patient had a reduced dietary intake in the last week? 
4. Is the patient severely ill (e.g. in intensive therapy)? 
 
 
Final Screening 
Impaired nutritional status 
Severity of disease ( = increase in requirements) 
Absent 
Score 0 
Normal nutritional requirements 
Absent 
Score 0 
Normal nutritional requirements 
Mild  
Score 1 
Wt loss > 5% in 3 months, or food 
intake below 50-75% of normal 
requirement in preceding week 
Mild  
Score 1 
Hip fracture, chronic patients, in par
ticular, with acute complications: 
cirrhosis, COPD, chronic 
hemodialysis, diabetes, oncology 
Moderate 
Score 2 
Wt loss > 5% in 2 months, or BMI 
18.5-20.5 + impaired general 
condition, or food intake of 20-60% 
of normal requirement in preceding 
week 
Moderate 
Score 2 
Major abdominal surgery, stroke,   s
evere pneumonia, hematologic 
malignancy 
Severe  
Score 3 
Wt loss > 5% in 1 month ( > 15% in 
3 months), or BMI < 18.5 + impaired 
general condition, or food intake of 
0-25% of normal requirement in 
preceding week 
Severe  
Score 3 
Head injury,  bone marrow 
transplantation,  intensive care 
patients (APACHE  > 10)  
Score:                     +                                                    Score:                = Total score:  
Age                        if ≥ 70 years: add 1 to total score above                    = Age-adjusted total score  
Score ≥ 3: the patient is nutritionally at risk, and a nutritional care plan is initiated. 
Score < 3: Weekly rescreening of the patient. If the patient, for example, is scheduled for a major operation, a 
preventative nutritional care plan is considered to avoid the associated risk status. 
 
 
 
 


Prototypes for Severity of Disease 
Score=1: a patient with chronic disease, admitted to hospital due to complications. The patient is weak, but out of 
bed regularly. Protein requirement is increased, but can be covered by oral diet or supplements in most cases. 
 
 
Score=2: a patient confined to bed due to illness, e.g. following major abdominal surgery. Protein requirement is 
substantially increased, but can be covered, although artificial feeding is required in many cases. 
 
Score=3: a patient in intensive care with assisted ventilation etc. Protein requirement is increased, and cannot be 
covered, even by artificial feeding. Protein breakdown and nitrogen loss can be significantly attenuated. 
 


 
 
 
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21.4 EORTC QLQ-C30 version 3.0 (German Version) 
 
 


 
 
 
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ENGLISH 
 
 
EORTC QLQ-C30 (version 3)  
 
We are interested in some things about you and your health. Please answer all of the questions yourself by circling the 
number that best applies to you. There are no "right" or "wrong" answers. The information that you provide will 
remain strictly confidential. 
 
Please fill in your initials: 
 
Your birthdate (Day, Month, Year): 
 
Today's date (Day, Month, Year):  
31  
__________________________________________________________________________________________ 
 
 
Not at 
A 
Quite 
Very 
 
 
All 
Little 
a Bit 
Much 
1. 
Do you have any trouble doing strenuous activities,  
 
like carrying a heavy shopping bag or a suitcase? 
1 
2 
3 
4 
 
2. 
Do you have any trouble taking a long walk? 
1 
2 
3 
4 
 
3. 
Do you have any trouble taking a short walk outside of the house? 
1 
2 
3 
4 
 
4. 
Do you need to stay in bed or a chair during the day? 
1 
2 
3 
4  
 
5. 
Do you need help with eating, dressing, washing  
 
yourself or using the toilet? 
1 
2 
3 
4 
 
 
During the past week:  
Not at 
A 
Quite 
Very 
 
 
All 
Little 
a Bit 
Much 
 
6. 
Were you limited in doing either your work or other daily activities? 
1 
2 
3 
4 
 
7. 
Were you limited in pursuing your hobbies or other 
 
leisure time activities? 
1 
2 
3 
4 
 
8. 
Were you short of breath? 
1 
2 
3 
4 
 
9. 
Have you had pain? 
1 
2 
3 
4 
 
10. Did you need to rest? 
1 
2 
3 
4 
 
11. Have you had trouble sleeping? 
1 
2 
3 
4 
 
12. Have you felt weak? 
1 
2 
3 
4 
 
13. Have you lacked appetite? 
1 
2 
3 
4 
 
14. Have you felt nauseated? 
1 
2 
3 
4 
 
15. Have you vomited? 
1 
2 
3 
4 
 
16. Have you been constipated? 
1 
2 
3 
4 
 
 
Please go on to the next page 
 


ENGLISH 
 
© Copyright 1995 EORTC Quality of Life Group. All rights reserved. Version 3.0 
 
 
 
During the past week:  
Not at 
A 
Quite 
Very 
 
 
All 
Little 
a Bit 
Much 
 
17. Have you had diarrhea? 
1 
2 
3 
4 
 
18. Were you tired? 
1 
2 
3 
4 
 
19. Did pain interfere with your daily activities? 
1 
2 
3 
4 
 
20. Have you had difficulty in concentrating on things, 
 
like reading a newspaper or watching television? 
1 
2 
3 
4 
 
21. Did you feel tense? 
1 
2 
3 
4 
 
22. Did you worry? 
1 
2 
3 
4 
 
23. Did you feel irritable? 
1 
2 
3 
4 
 
24. Did you feel depressed? 
1 
2 
3 
4 
 
25. Have you had difficulty remembering things? 
1 
2 
3 
4 
 
26. Has your physical condition or medical treatment 
 
interfered with your family life? 
1 
2 
3 
4 
 
27. Has your physical condition or medical treatment 
 
interfered with your social activities? 
1 
2 
3 
4 
 
28. Has your physical condition or medical treatment 
 
caused you financial difficulties? 
1 
2 
3 
4 
 
 
For the following questions please circle the number between 1 and 7 that  
best applies to you 
 
29. How would you rate your overall health during the past week? 
 
 
 1 
2 
3 
4 
5 
6 
7 
 
 Very poor 
 
 
 
 
 
Excellent 
 
 
30. How would you rate your overall quality of life during the past week? 
 
 
 1 
2 
3 
4 
5 
6 
7 
 
 Very poor 
 
 
 
 
 
Excellent 
 
 


 
 
 
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21.5 EORTC QLQ-OV28 (German Version) 
 
 


 
 
 
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ENGLISH 
 
 
EORTC QLQ - OV28 
 
 
Patients sometimes report that they have the following symptoms or problems.  Please indicate the 
extent to which you have experienced these symptoms or problems during the past week. 
 
 
During the past week: 
Not at 
A 
Quite 
Very  
 
 
All 
Little 
a Bit 
Much 
 
31. Did you have abdominal pain? 
1 
2 
3 
4 
 
32. Did you have a bloated feeling in your abdomen / stomach? 
1 
2 
3 
4 
 
33. Did you have problems with your clothes feeling too tight?  
1 
2 
3 
4 
 
34. Did you experience any change in bowel habit as a result of  
your disease or treatment?  
1 
2 
3 
4 
 
35. Were you troubled by passing wind / gas / flatulence?  
1 
2 
3 
4 
 
36. Have you felt full too quickly after beginning to eat?  
1 
2 
3 
4 
 
37. Have you had indigestion or heartburn?  
1 
2 
3 
4 
 
38. Have you lost any hair?  
1 
2 
3 
4 
 
39. Answer this question only if you had any hair loss: 
 
Were you upset by the loss of your hair?  
1 
2 
3 
4 
 
40. Did food and drink taste different from usual?  
1 
2 
3 
4 
 
41. Have you had tingling hands or feet?  
1 
2 
3 
4 
 
42. Have you had numbness in your fingers or toes?  
1 
2 
3 
4 
 
43. Have you felt weak in your arms or legs?  
1 
2 
3 
4 
 
44. Did you have aches or pains in your muscles or joints?  
1 
2 
3 
4 
 
45. Did you have problems with hearing?  
1 
2 
3 
4 
 
46. Did you urinate frequently?  
1 
2 
3 
4 
 
47. Have you had skin problems (e.g. itchy, dry)?  
1 
2 
3 
4 
 
48. Did you have hot flushes?  
1 
2 
3 
4 
 
49. Did you have night sweats?  
1 
2 
3 
4 
 
 
Please go on to next page 


ENGLISH 
 Copyright 1997 EORTC Quality of Life Group.  All rights reserved. 
 
 
 
During the past week: 
Not at 
A 
Quite 
Very  
 
 
All 
Little 
a Bit 
Much 
 
50. Have you felt physically less attractive as a result  
 
of your disease or treatment?  
1 
2 
3 
4 
 
51. Have you been dissatisfied with your body?  
1 
2 
3 
4 
 
52. How much has your disease been a burden to you?  
1 
2 
3 
4 
 
53. How much has your treatment been a burden to you?  
1 
2 
3 
4 
 
54. Were you worried about your future health?  
1 
2 
3 
4 
 
 
During the past 4 weeks:  
Not at 
A 
Quite 
Very  
 
 
All 
Little 
a Bit 
Much 
 
55. To what extent were you interested in sex? 
1 
2 
3 
4 
 
56. To what extent were you sexually active? 
1 
2 
3 
4 
 
 
Answer the following two questions only if you were sexually active: 
 
57. To what extent was sex enjoyable for you?  
1 
2 
3 
4 
 
58. Did you have a dry vagina during sexual activity?  
1 
2 
3 
4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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