Retrospective Multicenter Study of Elderly Patients With Ovarian Cancer Treated With Trabectedin and PLD According to SmPC
Conditions: Ovarian Cancer
Sponsor: Grupo Español de Investigación en Cáncer de Ovario

GEICO 105-O: Final Study Report  
V1 of 14 December 2022 
Page 1 of 89 
 
 
 
 
 
 
 
 
 
 
 
 
 
FINAL STUDY REPORT 
 
Title: 
Retrospective multicenter study of elderly patients with ovarian cancer treated 
with trabectedin and PLD according to SmPC 
 
Study Number: GEICO 105-O 
 
Retrospective, non-interventional (observational) study 
 
Report Version: V1 of 14 December 2022 
 
Sponsor: Grupo Español de Investigación en Cáncer de Ovario (GEICO) 
 
 
 
 
 
Clinical Coordinating Investigator:  
Dr. María Jesús Rubio – Hospital Universitario Reina Sofía (Córdoba)  
 
 
Funding entity:  
PharmaMar 
 
 
The information contained in this document is confidential and cannot be revealed to other persons without the written authorization of 
the Sponsor. 

GEICO 105-O: Final Study Report  
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Study Information 
Title 
Retrospective multicenter study of elderly patients with ovarian cancer 
treated with trabectedin and PLD according to SmPC 
 
Sponsor 
Grupo Español de Investigación en Cáncer de Ovario (GEICO) 
 
Version identifier of the 
final study report 
V1 of 14 December 2022 
Date of last version of 
the final study report 
14 December 2022 
Active substance(s) 
Two drugs under observation: 
• Trabectedin 
• Doxorubicin hydrochloride 
 
Medicinal product(s) 
Two drugs under observation: 
• Trabectedin 
• Pegylated liposomal doxorubicin 
 
Marketing authorization 
holder 
• PharmaMar (Trabectedin) 
• Pegylated liposomal doxorubicin (various manufacturers) 
 
Research question and 
objectives 
Trabectedin in combination with pegylated liposomal doxorubicin (PLD) 
is indicated for platinum-sensitive relapsed ovarian cancer and is an 
option for those patients in whom platinum is not the best option. There 
are some studies with trabectedin in combination with PLD in which 
some patients with this profile have been included, although not 
exclusively. Therefore, it is of interest to study the safety and efficacy 
profile of this treatment in elderly patients.  
 
The general objective of the study is to describe the real-life use of 
trabectedin + PLD in elderly patients diagnosed with platinum-sensitive 
relapsed ovarian cancer treated according to the Summary of Product 
Characteristics (SmPC).  
 
The specific objective is to evaluate real-world data about:  
 
• Safety profile  
• Progression-free survival (PFS)  
• Overall response rate (ORR) (CR+PR) according to RECIST 1.1 
criteria  
• Disease control rate (DCR) (CR+PR+SD)  
• Overall survival (OS)  
• Trabectedin + PLD treatment information  
• Previous and subsequent treatments to trabectedin + PLD  
• Patient characteristics and medical history  
 
Country of study 
Spain 
 

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Author 
Patricio Ledesma 
Head of Clinical Operations 
Sofpromed Investigación Clínica, SL  
CRO appointed by the Sponsor (GEICO) 
 
 
 
 

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TABLE OF CONTENTS 
1. 
Abstract ......................................................................................................................................... 6 
2. 
List of abbreviations ................................................................................................................... 10 
3. 
Investigators ................................................................................................................................ 11 
4. 
Other responsible parties ........................................................................................................... 12 
5. 
Milestones .................................................................................................................................... 13 
6. 
Rationale and background ......................................................................................................... 14 
7. 
Research questions and objectives ............................................................................................ 16 
8. 
Amendments and updates .......................................................................................................... 17 
9. 
Research methods ....................................................................................................................... 18 
9.1 
Study design and setting ........................................................................................................ 18 
9.2 
Subjects ................................................................................................................................. 18 
9.3 
Variables................................................................................................................................ 18 
9.4 
Data sources and measurement ............................................................................................. 19 
9.5 
Bias ........................................................................................................................................ 19 
9.6 
Study size .............................................................................................................................. 19 
9.7 
Data transformation ............................................................................................................... 19 
9.8 
Statistical methods................................................................................................................. 21 
9.8.1 
Main summary measures ............................................................................................... 21 
9.8.2 
Main statistical methods ................................................................................................ 21 
9.8.3 
Missing values ............................................................................................................... 21 
9.8.4 
Sensitivity analyses ........................................................................................................ 21 
9.8.5 
Amendments to the statistical analysis plan .................................................................. 21 
9.9 
Quality control....................................................................................................................... 21 
10. 
Results ...................................................................................................................................... 23 
10.1 Participants ............................................................................................................................ 23 
10.2 Descriptive data ..................................................................................................................... 23 
10.3 Outcome data......................................................................................................................... 68 
10.4 Main results ........................................................................................................................... 76 
10.5 Other analyses ....................................................................................................................... 76 
10.6 Adverse events/adverse reactions.......................................................................................... 76 
11. 
Discussion................................................................................................................................. 85 
11.1 Key results ............................................................................................................................. 85 

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11.2 Limitations ............................................................................................................................ 85 
11.3 Interpretation ......................................................................................................................... 85 
11.4 Generalisability ..................................................................................................................... 85 
12. 
Other information ................................................................................................................... 86 
13. 
Conclusion ............................................................................................................................... 87 
14. 
References ................................................................................................................................ 88 
 
 
 
 
 

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1. Abstract 
 
Title 
 
Retrospective multicenter study of elderly patients with ovarian cancer treated with trabectedin and 
PLD according to SmPC 
 
Keywords 
 
Trabectedin, pegylated liposomal doxorubicin, ovarian cancer 
 
Rationale and background 
 
The median age at which ovarian cancer is diagnosed is 63 years (50-75). This is still a significant 
adverse factor for survival results. Seventy years can be considered the lower limit for the elderly 
term, since most of age-related changes occur later. Because of this, this group of patients is often 
not included in clinical trials and sometimes they do not receive adequate treatment. Little 
information is available on chemotherapy treatments in elderly patients. Data on the use of first-line 
chemotherapy in this population (EWOC-1) have recently been published [4].  
 
Trabectedin in combination with PLD is indicated for platinum-sensitive relapsed ovarian cancer and 
is an option for those patients in whom platinum is not the best option. There are some studies with 
trabectedin in combination with PLD in which some patients with this profile have been included, 
although not exclusively. Therefore, it is of interest to study the safety and efficacy profile of this 
treatment in elderly patients. With this information we will be able to know its real use in routine 
clinical practice at the national level in Spain in this population for which not much information is 
available.  
 
Safety and efficacy data (e.g., PFS, ORR, OS) will be collected retrospectively in order to draw 
conclusions about the combination of trabectedin + PLD, as a treatment option in this patient profile. 
 
Research question and objectives 
 
Trabectedin in combination with pegylated liposomal doxorubicin (PLD) is indicated for platinum-
sensitive relapsed ovarian cancer and is an option for those patients in whom platinum is not the best 
option. There are some studies with trabectedin in combination with PLD in which some patients 
with this profile have been included, although not exclusively. Therefore, it is of interest to study the 
safety and efficacy profile of this treatment in elderly patients.  
 
The general objective of the study is to describe the real-life use of trabectedin + PLD in elderly 
patients diagnosed with platinum-sensitive relapsed ovarian cancer treated according to the Summary 
of Product Characteristics (SmPC).  
 
The specific objective is to evaluate real-world data about:  
 
• Safety profile  
• Progression-free survival (PFS)  
• Overall response rate (ORR) (CR+PR) according to RECIST 1.1 criteria  
• Disease control rate (DCR) (CR+PR+SD)  
• Overall survival (OS)  

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• Trabectedin + PLD treatment information  
• Previous and subsequent treatments to trabectedin + PLD  
• Patient characteristics and medical history 
 
Study design and setting 
 
The study consists of a retrospective observational, multicenter study in which the fundamental 
exposure factor being investigated is a drug (trabectedin and PLD). The study was developed at 
national level with 15 sites in Spain, during a data collection period of 5 months, including patients 
treated with trabectedin and PLD according to the SmPC. 
 
The main treatment observed in this study was trabectedin in combination with PLD in elderly 
patients with platinum-sensitive relapsed ovarian cancer according to the SmPC. The recommended 
dose of trabectedin plus PLD is administered every three weeks by infusion over 3 hours at a dose of 
1.1 mg/m2 immediately after 30 mg/m2 of PLD. 
 
Subjects, study size, and inclusion/exclusion criteria 
 
The sample size was determined by all patients diagnosed with platinum-sensitive relapsed ovarian 
cancer treated with trabectedin and PLD between January 1st 2015 and December 31st 2019.  
 
This retrospective clinical study was planned to include approximately 45-50 patients with the 
referred characteristics (no formal sample size was calculated due to the observational nature of the 
study).  
 
Given that the study was a multicenter study at national level in Spain, considering a percentage of 
failures in the collection or analysis of the samples (missing or unevaluable data) of around 10%, a 
sample size of 40-45 patients with evaluable data was estimated. 
 
The study recruited women according to the following criteria:  
 
Inclusion criteria:  
 
1. Written informed consent must be signed by all patients participating in the study who can be 
interviewed in the hospital (accessible, alive patients) or absence of consent sheet must be 
signed by the investigator. Informed consent may not be required from inaccessible patients 
(dead, lost, etc.) according to ethics committee permissions and applicable law for 
retrospective studies in Spain. 
2. Adult women (≥70 years at the time of treatment initiation with trabectedin and PLD).  
3. Histological diagnosis of platinum-sensitive relapsed ovarian cancer (PFI ≥ 6 months).  
4. Treatment started with trabectedin and PLD (at least one cycle) as standard of care between 
January 1st 2015 and December 31st 2019.  
5. Patients must have received at least one cycle of trabectedin + PLD.  
 
Exclusion criteria:  
 
1. Patients without medical record available (lost, empty or unretrievable clinical information). 
2. Patients who explicitly refuse to participate in the study.  
 

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Variables and data sources 
 
• Safety profile: All trabectedin + PLD-related hematological and non-hematological, serious 
and non-serious adverse events (grade, start date, end date, action taken with trabectedin 
and/or PLD, outcome) will be collected. In addition, adverse event treatments will be 
registered in the study database.  
• Progression-free survival (PFS): Defined as the time in months since first trabectedin + PLD 
dose date until radiological progression (or death due to any cause) according to RECIST 1.1 
criteria.  
• Overall response rate (ORR): Defined as the number of patients having a best overall 
response (BOR) of complete response (CR) or partial response (PR), divided by the total 
number of response-evaluable patients (according to RECIST 1.1 criteria).  
• Disease control rate (DCR): Defined as the percentage of patients having a complete response 
(CR), partial response (PR), or stable disease (SD) according to RECIST 1.1 criteria.  
• Overall survival (OS): Defined as the number of months since first trabectedin + PLD dose 
date until death due to any cause. OS will be censored at the last date the patient was known 
to be alive.  
• Trabectedin + PLD treatment information (for both drugs): Line number in which trabectedin 
+ PLD was given, starting dose, relative dose intensity (RDI), total dose, dose management 
(reductions, delays, omissions, interruptions, and their reasons), number of treatment 
discontinuations, reasons for discontinuations, duration of treatment, treatment status (ended 
or ongoing), and number of cycles.  
• Previous and subsequent treatments to trabectedin + PLD: Number of previous/subsequent 
treatments, type, date, previous antiangiogenic agents, and clinical results of treatments 
before and after trabectedin + PLD.  
• Patient characteristics and medical history: Sex, age, ECOG, platinum sensitivity, platinum-
free interval (PFI), progression free survival (PFS), mutational status (BRCA1, BRCA2, and in 
other HRR genes [germline/somatic] and variant classification [pathogenic, probably 
pathogenic, or VOUS]), histology, tumor grade and number of previous relapses.  
 
These data were obtained from the participating hospitals per local practice (clinical records, local 
reports). 
 
Results 
 
Between November 2021 and June 2022, 43 patients were recruited with median age 74 years (70-
86). At initial diagnosis, most common FIGO stages were IIIC (51.2%), IVB (11.6%), and IIIB 
(7.0%). Before trabectedin+PLD (baseline), patients had ECOG performance status 0, 1, or 2 
(34.1%, 41.5%, and 9.8%) and 81.4% had measurable disease. The median number of previous lines 
was 2 (1-6). The initial dose of trabectedin was 1.1 mg/m2 in 76.7% of patients (16.3% with <1.1 and 
4.7% with >1.1 mg/m2) while 76.7% of patients had PLD at 30 mg (18.6% with <30 mg and 2.3% 
with >30 mg). The median of trabectedin+PLD cycles was 5 (1-21) and 53.5% of patients had at 
least one cycle delayed. All patients ended treatment for the following reasons: patient’s decision 
(7.0%), doctor’s decision (23.3%), disease progression (39.5%), toxicity (23.83%) and 7.0% due to 
other factors. Median PFS for the trabectedin+PLD combination was 7.7 months (95% CI 4.4-9.4) 
with best overall response rates of 4 CR (9.3%), 14 PR (32.6%), 13 SD (30.2%), and 5 PD (11.6%). 
Median overall survival (OS) was 19.5 months (95% CI 12.8-27.2). Overall, the most common G3-4 
hematological events were neutropenia (23.3%), thrombocytopenia (7.0%), and anemia (2.3%), 

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being asthenia (11.6%), mucositis (4.7%), and transaminitis (4.7%) the most frequent G3 non-
hematological toxicities. 
 
Discussion 
 
The safety profile of the trabectedin+PLD combination for elderly women in real-life setting is 
manageable and efficacy results are comparable to those of previous clinical trials. 
 
Marketing Authorization Holder 
 
PharmaMar 
 
Names and affiliations of principal investigators 
 
1. María Jesús Rubio – Hospital Universitario Reina Sofía de Córdoba (Coordinating 
Investigator) 
2. Blanca Hernando Fernández – Hospital Universitario de Burgos 
3. Eva Guerra – Hospital Universitario Ramón y Cajal 
4. Anna Carbó – Instituto Català d’Oncologia (ICO) 
5. Luis Miguel de Sande – Hospital Universitario de León 
6. Arancha Manzano – Hospital Clínico San Carlos  
7. Alba González-Haba – Hospital Universitario de Badajoz 
8. Alfonso Yubero-Esteban - Hospital Clínico Universitario Lozano Blesa 
9. María del Mar Gordon – Hospital Universitario de Jerez de la Frontera 
10. Diego Soto de Prado – Hospital Clínico de Valladolid 
11. Ignacio Romero – Fundación Instituto Valenciano de Oncología 
12. Purificación Estévez - Hospital Universitario Virgen del Rocío  
13. Carlos E. Robles – Hospital Virgen de Valme 
14. Jerónimo Martínez – Hospital Clínico Universitario Virgen de la Arrixaca 
15. Miguel Corbellas – Hospital Universitario Dr. Peset 
 
 

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2. List of abbreviations 
 
• AE: Adverse Event 
• CM: Concomitant Medication 
• CR: Complete Response 
• CRO: Clinical Research Organization 
• ECOG:  Eastern Cooperative Oncology Group 
• E-CRF: Electronic Case Report Form 
• GEICO: Grupo Español de Investigación en Cáncer de Ovario 
• ICF: Informed Consent Form 
• KM: Kaplan-Meier 
• MH: Medical History 
• ORR: Overall Response Rate 
• PFS: Progression-Free Survival 
• PIS: Patient Information Sheet 
• PR: Partial Response 
• RECIST: Response Evaluation Criteria in Solid Tumors 
• SD: Stable Disease 
 
 

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3. Investigators 
 
1. María Jesús Rubio – Hospital Universitario Reina Sofía de Córdoba (Coordinating 
Investigator) 
2. Blanca Hernando Fernández – Hospital Universitario de Burgos 
3. Eva Guerra – Hospital Universitario Ramón y Cajal 
4. Anna Carbó – Instituto Català d’Oncologia (ICO) 
5. Luis Miguel de Sande – Hospital Universitario de León 
6. Arancha Manzano – Hospital Clínico San Carlos  
7. Alba González-Haba – Hospital Universitario de Badajoz 
8. Alfonso Yubero-Esteban - Hospital Clínico Universitario Lozano Blesa 
9. María del Mar Gordon – Hospital Universitario de Jerez de la Frontera 
10. Diego Soto de Prado – Hospital Clínico de Valladolid 
11. Ignacio Romero – Fundación Instituto Valenciano de Oncología 
12. Purificación Estévez - Hospital Universitario Virgen del Rocío  
13. Carlos E. Robles – Hospital Virgen de Valme 
14. Jerónimo Martínez – Hospital Clínico Universitario Virgen de la Arrixaca 
15. Miguel Corbellas – Hospital Universitario Dr. Peset 
 
 
 

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4. Other responsible parties 
 
The Sponsor of this study was the Grupo Español de Investigación en Cancer de Ovario (GEICO). 

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5. Milestones 
 
Milestone 
Planned date 
Actual date 
Comments 
Start of data 
collection 
1 November 2021 
29 November 2021 
 
End of data 
collection 
31 March 2022 
10 June 2022 
Includes data 
cleaning period. 
Delay caused by the 
need of issuing 
additional queries. 
Final report of 
study results 
30 June 2022 
14 December 2022 
Delay caused by the 
need of issuing 
additional queries. 
 
 

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6. Rationale and background 
 
Ovarian cancer is a devastating disease, being the fourth leading cause of cancer death in women. Its 
incidence increases at menopause, the mean age at diagnosis is 63 years. This is still a significant 
adverse factor for survival results, therefore better treatments are needed for older patients [1].  
 
Aging is the progressive reduction of the functional reserve of multiple organ systems, as the result 
of spontaneous depletion and environmental influences. Seventy years of age can be considered the 
lower limit of senescence because most age-related changes occur after senescence.  
 
Sabatier, Renaud, et al published a study “Prognostic factors for epithelial ovarian epithelial cancer 
in the elderly: a case-control study” in which they conclude that the prognosis of ovarian cancer is 
worse for older women, due to the fact that they are more frequently suboptimally tretated. In this 
study, no correlation could be observed between geriatric factors and the achievement of surgery or 
chemotherapy. Therefore, the treatment decision should be based on an objective geriatric evaluation 
to improve the outcome in this population [2].  
 
GOG conducted an observational study (GOG 273) of chemotherapy toxicity in elderly patients with 
ovarian, primary peritoneal, or fallopian tube carcinoma. 290 patients were enrolled between August 
2011 and Dec 2019. Patients receive chemotherapy comprising carboplatin, paclitaxel, and colony 
stimulating factors (regimen 1) or carboplatin alone (regimen 2) every 21 days for 4 cycles as chosen 
by their physicians and / or patients. Patients may undergo additional surgery and / or chemotherapy 
at the discretion of the treating physician. Baseline blood tests are drawn at 1, 6, and 24 hours of each 
cycle for pharmacokinetic studies. The quality of life of the patients is assessed using the FACT-O, 
FACT-Ntx, IADL questionnaires and the ability to complete the social activity questionnaires at the 
beginning of the study, before cycles 1 and 3, and after 3 to 6 weeks after completing treatment. 
Nutritional status, such as body mass index and weight loss, and comorbidity and hearing 
impairment are also assessed. They conclude that patients with a higher baseline IADL (instrumental 
activities of daily living) score (more independent) were more likely to complete 4 cycles of 
chemotherapy and less likely to experience grade 3 or higher toxicity [3].  
 
The results of the EWOC-1 study, a randomized study to evaluate 3 regimens of 1st-line 
chemotherapy in vulnerable elderly patients diagnosed with ovarian cancer (A GCIG-ENGOT-
GINECO study) have recently been published, concluding after comparing 3 chemotherapy regimens 
(two combinations of carboplatin + paclitaxel and the third with carboplatin alone), that monotherapy 
is less active and vulnerable patients have less survival than with combination regimens. Therefore, 
even elderly patients should be offered a carboplatin + paclitaxel regimen [4].  
 
Currently, there are few studies that collect data on ovarian cancer in this population exclusively and 
in second or later lines.  
 
In clinical trials, a part of the population affected by the disease (elderly) is not usually included. 
This patient profile is more common in daily clinical practice: older patients, with ECOG or PS 1-2, 
with comorbidities, polymedicated, etc. Around 23% of ovarian cancer patients are 70 years or older 
[5] and their prognosis so far tends to be worse overall, probably due to the misperception of the 
possibilities of optimal surgery and adequate systemic treatment.  
 
Trabectedin in combination with pegylated liposomal doxorubicin (PLD) is indicated for the 
treatment of patients with recurrent platinum-sensitive ovarian cancer following the results of study 
OVA-301 [6]. When choosing a therapy in recurrent disease, we must not only take into account the 

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platinum free interval, but also the morbidities, toxicities, number of previous platinum lines, 
response to the last line, BRCA mutational status, etc. [7]. The results of the real-life European 
NIMES-ROC study consistently support that trabectedin + PLD is active in patients with platinum-
sensitive recurrent ovarian cancer with an acceptable and manageable safety profile. The overall 
findings appear to be consistent with those previously observed in a randomized controlled clinical 
phase III trial and further support the use of trabectedin + PLD for heavily pre-treated patients with 
platinum-sensitive recurrent ovarian cancer [8].  
 
In the OVA-301 study [9] and the real-life study, NIMES ROC [8], some patients with these 
characteristics (62-86 years) were included, so it is considered that it would be of interest to collect 
retrospective data from safety and efficacy at the national level to have information on the use of 
trabectedin in combination with PLD in daily clinical practice in elderly patients, since this is not 
currently available in this population.  
 
Currently the data that are available in the population of elderly women with recurrent ovarian 
cancer are through non-pre-planned sub-analyzes, that is, there is no study that specifically collects 
the data of this profile of patients.  
 
Oza et al. (ROSiA study) explored the efficacy and safety of bevacizumab in patients older than 70 
years compared to a young population with newly diagnosed ovarian cancer. 12% of the patients 
included were 70 years or older, had greater comorbidities than the young population (hypertension, 
stage IV, ECOG greater than 1). Older patients experienced a higher incidence of adverse effects of 
all grades compared to the younger profile. Regarding progression-free survival at two years, the 
results obtained are similar between the two populations despite having a worse prognosis [10].  
In the platinum-resistant elderly population, there are data from the AURELIA study subanalysis, 
where 37% were 65 years or older. The median PFS and response rate were similar between those 
<65 and ≥65 years. Grade 2 and 3 hypertension were more common in the older than 65 age group 
[11].  
 
Olaparib has been studied in this population after an analysis of 8 prospective studies. Data were 
collected from 398 patients (78 of them aged 65 years or older), the majority had received ≥ 5 prior 
lines of chemotherapy. Tolerability and toxicity of olaparib was similar between women ≥ 65 years 
and < 65 years of age treated for advanced recurrent ovarian cancer [12].  
 
Regarding trabectedin, the data available are from the patients included in the phase III OVA-301 
trial and in the real-life study NIMES ROC [8]. Although this population is not exclusively analyzed, 
patients older than 65 years and polytreated have been included [8,9]. Vergote et al., analyzed the 
safety profile in the population older than 65 years included in the OVA-301. There were no marked 
differences by age in the safety profile/tolerability of trabectedin + PLD, except for more fatigue in 
the older subset (≥ 65 years) compared with younger patients (< 65 years) [13]. Therefore, it would 
be of interest to collect data on the safety and efficacy of trabectedin in combination with PLD in 
elderly patients with advanced relapsed ovarian cancer to obtain information on daily clinical 
practice at the national level in this subgroup of patients. 
 
 
 

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7. Research questions and objectives 
 
Trabectedin in combination with pegylated liposomal doxorubicin (PLD) is indicated for platinum-
sensitive relapsed ovarian cancer and is an option for those patients in whom platinum is not the best 
option. There are some studies with trabectedin in combination with PLD in which some patients 
with this profile have been included, although not exclusively. Therefore, it is of interest to study the 
safety and efficacy profile of this treatment in elderly patients.  
 
The general objective of the study was to describe the real-life use of trabectedin + PLD in elderly 
patients diagnosed with platinum-sensitive relapsed ovarian cancer treated according to the Summary 
of Product Characteristics (SmPC).  
 
The specific objective was to evaluate real-world data about:  
 
• Safety profile  
• Progression-free survival (PFS)  
• Overall response rate (ORR) (CR+PR) according to RECIST 1.1 criteria  
• Disease control rate (DCR) (CR+PR+SD)  
• Overall survival (OS)  
• Trabectedin + PLD treatment information  
• Previous and subsequent treatments to trabectedin + PLD  
• Patient characteristics and medical history 
 
 

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8. Amendments and updates 
 
One amendment was performed to generate protocol version 2.0 of 27 October 2021, which included 
the following changes: 
 
5.3 Population.  
 
- Inclusion criteria 2: ≥70 years at the time of treatment initiation with trabectedin and PLD (not the 
time of initial diagnosis).  
- Inclusion criteria 3 has been clarified in terms of platinum sensitivity, specifying that PFI must be ≥ 
6 months.  
- Exclusion criteria 3: Life expectancy < 3 months has been deleted as it is not applicable for a 
retrospective observational study.  
 
PFI was clarified to "Platinum Free-Interval", and PFS as “Progression Free-Survival” in all 
corresponding sections.  
 
 
 

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9. Research methods 
 
9.1 Study design and setting 
 
The study consisted of a retrospective observational, multicenter study in which the fundamental 
exposure factor being investigated was a drug (trabectedin and PLD). The study was developed at 
national level with 15 sites in Spain, during a data collection period of 5 months, including patients 
treated with trabectedin and PLD according to the SmPC. 
 
The main treatment observed in this study was trabectedin in combination with PLD in elderly 
patients with platinum-sensitive relapsed ovarian cancer according to the SmPC. The recommended 
dose of trabectedin plus PLD was administered every three weeks by infusion over 3 hours at a dose 
of 1.1 mg/m2 immediately after 30 mg/m2 of PLD. 
 
9.2 Subjects 
 
The study recruited women according to the following criteria:  
 
Inclusion criteria:  
 
1. Written informed consent must be signed by all patients participating in the study who can be 
interviewed in the hospital (accessible, alive patients) or absence of consent sheet must be 
signed by the investigator. Informed consent may not be required from inaccessible patients 
(dead, lost, etc.) according to ethics committee permissions and applicable law for 
retrospective studies in Spain. 
2. Adult women (≥70 years at the time of treatment initiation with trabectedin and PLD). 
3. Histological diagnosis of platinum-sensitive relapsed ovarian cancer (PFI ≥ 6 months).  
4. Treatment started with trabectedin and PLD (at least one cycle) as standard of care between 
January 1st 2015 and December 31st 2019.  
5. Patients must have received at least one cycle of trabectedin + PLD.  
 
Exclusion criteria:  
 
1. Patients without medical record available (lost, empty or unretrievable clinical information). 
2. Patients who explicitly refuse to participate in the study.  
 
9.3 Variables 
 
• Safety profile: All trabectedin + PLD-related hematological and non-hematological, serious 
and non-serious adverse events (grade, start date, end date, action taken with trabectedin 
and/or PLD, outcome) will be collected. In addition, adverse event treatments will be 
registered in the study database.  
• Progression-free survival (PFS): Defined as the time in months since first trabectedin + PLD 
dose date until radiological progression (or death due to any cause) according to RECIST 1.1 
criteria.  
• Overall response rate (ORR): Defined as the number of patients having a best overall 
response (BOR) of complete response (CR) or partial response (PR), divided by the total 
number of response-evaluable patients (according to RECIST 1.1 criteria).  

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• Disease control rate (DCR): Defined as the percentage of patients having a complete response 
(CR), partial response (PR), or stable disease (SD) according to RECIST 1.1 criteria.  
• Overall survival (OS): Defined as the number of months since first trabectedin + PLD dose 
date until death due to any cause. OS will be censored at the last date the patient was known 
to be alive.  
• Trabectedin + PLD treatment information (for both drugs): Line number in which trabectedin 
+ PLD was given, starting dose, relative dose intensity (RDI), total dose, dose management 
(reductions, delays, omissions, interruptions, and their reasons), number of treatment 
discontinuations, reasons for discontinuations, duration of treatment, treatment status (ended 
or ongoing), and number of cycles.  
• Previous and subsequent treatments to trabectedin + PLD: Number of previous/subsequent 
treatments, type, date, previous antiangiogenic agents, and clinical results of treatments 
before and after trabectedin + PLD.  
• Patient characteristics and medical history: Sex, age, ECOG, platinum sensitivity, platinum-
free interval (PFI), progression free survival (PFS), mutational status (BRCA1, BRCA2, and in 
other HRR genes [germline/somatic] and variant classification [pathogenic, probably 
pathogenic, or VOUS]), histology, tumor grade and number of previous relapses.  
 
9.4 Data sources and measurement 
 
The data collected in this study included family history characteristics, clinical-pathological features of 
the tumor, treatment approaches (including therapies before and after the main treatment under study), 
safety and efficacy information, and long-term outcomes. These data were obtained from the 
participating hospitals per local practice (clinical records, local reports).  
 
9.5 Bias 
 
Since this was a retrospective observational study, no sources of bias were identified. 
 
9.6 Study size 
 
The sample size was determined by all patients diagnosed with platinum-sensitive relapsed ovarian 
cancer treated with trabectedin and PLD between January 1st 2015 and December 31st 2019.  
 
This retrospective clinical study was planned to include approximately 45-50 patients with the 
referred characteristics (no formal sample size was calculated due to the observational nature of the 
study).  
 
Given that the study was a multicenter study at national level in Spain, considering a percentage of 
failures in the collection or analysis of the samples (missing or unevaluable data) of around 10%, a 
sample size of 40-45 patients with evaluable data was estimated. 
 
9.7 Data transformation 
 
Stratification Factors 
 
No particular stratification factors were used. 
 
Patients Characteristics  

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The information of patients such as age, sex, race and other baseline characteristics were 
summarized.  
 
Exposure  
 
All data collected that was not free text was reported: mean starting dose, number of dose reductions, 
reasons for reductions, number of treatment discontinuations, reasons for discontinuations, and 
duration of treatment. 
 
Concomitant Medications (CMs) and Medical History (MH)  
 
The CMs were presented in the summary using frequency counts and percentages. When 
summarizing the number and percentage of subjects with some concomitant medications, subjects 
with multiple occurrences of the same CM were counted only once.  
 
In MH all data collected that was not free text was reported: number of previous relapses, number of 
previous chemotherapy regimens, types of treatments received (chemotherapy, targeted therapies), 
prior maintenance or with maintenance, treatment-free interval (platinum-based chemotherapy, non-
platinum-based chemotherapy, targeted therapy).  
 
Initial Ovarian Cancer Diagnosis  
 
The information of initial diagnosis such as age, tumor histology, and FIGO stage was summarized.  
 
Ovarian Cancer Treatments (Previous Surgeries)  
 
All the data collected was summarized as the number of previous surgeries (categorically and 
numerically).  
 
Ovarian Cancer Treatments (Previous Systemic Treatments)  
 
All data collected other than free text was reported: total number of previous lines, total number of 
each type of treatment received per patient. 
 
Progression-Free Survival (PFS)  
 
PFS: Measured in months from the date of the first dose to the date of the first progression (PD) 
(whether radiological, clinical or biological) or to the date of death from any cause, whichever occurs 
first.  
 
Objective Response Rate (ORR)  
 
ORR: Confirmed best overall tumor response of CR or PR according to RECIST v1.1. 
 
Adverse Events (AEs) 
 
The AEs were presented in the summary using counts and frequency percentages. They were 
stratified by grade and event. The number of events and the number of patients and percentage who 
had that event was indicated.  

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Clinical Laboratory Evaluations  
 
Laboratory raw variables collected in the baseline visit were summarized. 
 
9.8 Statistical methods 
 
9.8.1 Main summary measures 
 
All variables will be summarized separately. Depending on the type of the variable, the following 
statistics were reported:  
 
• Continuous variables: number of subjects (n), number of missings, mean, standard deviation 
(STD), median, standard error (SE, if needed), 25th and 75th percentiles, minimum, and 
maximum.  
• Categorical variables: frequencies and percentages (calculated over the number of non-
missing values).  
 
In general, minimum and maximum were reported using the same number of decimal places as 
collected in the raw data. Mean, STD, median, 25th and 75th percentiles will be reported with one 
additional decimal place.  
 
9.8.2 Main statistical methods 
 
Time to event data was listed and summarized at every specified timepoint using the number patients 
at risk, number of patients censored, number of patients with the event, Kaplan Meier estimate (%), 
and the 95% confidence interval. In addition, 25th, 50% and 75th percentiles from Kaplan-Meier 
(KM) curves will be used.  
 
9.8.3 Missing values 
 
No imputation of missing data was performed.  
 
9.8.4 Sensitivity analyses 
 
Not applicable. 
 
9.8.5 Amendments to the statistical analysis plan 
 
No amendments were made to the initial statistical analysis plan. 
 
9.9 Quality control 
 
Each study site was subject to remote clinical monitoring and review by the ethics committees. 
 
The study data was reviewed and cleaned by periodic inspection of the e-CRFs. Remote reviews 
were performed with enough frequency to ascertain the following:  
 
• Integrity and accuracy of data:  
- 
Informed consent (version, signature and date)  

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- 
Eligibility criteria  
• e-CRF completion.  
• Protocol deviations according GCPs and the applicable regulatory local requirements. Taking 
appropriate action to prevent recurrence to the detected deviations.  
• Compliance with approved protocol and all approved amendments, if any.  
• That the investigator receives all documents needed to conduct the study properly and to 
comply with the applicable regulations.  
• That the investigator and local staff are adequately informed about the study through 
telephone initiation visits.  
 
The study appointed CRO reviewed the e-CRFs for compliance with the protocol, and for 
inconsistent or missing data. When any missing data or data anomalies were found, queries were sent 
to the relevant center for resolution. Following the required reviews, the e-CRF data items were 
exported into the clinical study database for statistical analysis.  
 

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10. Results 
 
10.1 
Participants 
 
The study recruited a total of 43 eligible participants. 
 
10.2 
Descriptive data 
 
 

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10.3 
Outcome data 
 
PFS for trabectedin+PLD treatment (43 patients): 
 
 
 
 
PFS for platin-containing regimens when given right after trabectedin+PLD (27 patients): 
 
 
 
 
 

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PFS listings for trabectedin+PLD treatment: 
 
 
 

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Overall survival for trabectedin+PLD treatment: 
 
 
 
 

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10.4 
Main results 
 
Between November 2021 and June 2022, 43 patients were recruited with median age 74 years (70-
86). At initial diagnosis, most common FIGO stages were IIIC (51.2%), IVB (11.6%), and IIIB 
(7.0%). Before trabectedin+PLD (baseline), patients had ECOG performance status 0, 1, or 2 
(34.1%, 41.5%, and 9.8%) and 81.4% had measurable disease. The median number of previous lines 
was 2 (1-6). The initial dose of trabectedin was 1.1 mg/m2 in 76.7% of patients (16.3% with <1.1 and 
4.7% with >1.1 mg/m2) while 76.7% of patients had PLD at 30 mg (18.6% with <30 mg and 2.3% 
with >30 mg). The median of trabectedin+PLD cycles was 5 (1-21) and 53.5% of patients had at 
least one cycle delayed. All patients ended treatment for the following reasons: patient’s decision 
(7.0%), doctor’s decision (23.3%), disease progression (39.5%), toxicity (23.83%) and 7.0% due to 
other factors. Median PFS for the trabectedin+PLD combination was 7.7 months (95% CI 4.4-9.4) 
with best overall response rates of 4 CR (9.3%), 14 PR (32.6%), 13 SD (30.2%), and 5 PD (11.6%). 
Median overall survival (OS) was 19.5 months (95% CI 12.8-27.2). Overall, the most common G3-4 
hematological events were neutropenia (23.3%), thrombocytopenia (7.0%), and anemia (2.3%), 
being asthenia (11.6%), mucositis (4.7%), and transaminitis (4.7%) the most frequent G3 non-
hematological toxicities. 
 
10.5 
Other analyses 
 
No other analyses were performed. 
 
10.6 
Adverse events/adverse reactions 
 
 

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11. Discussion 
 
11.1 
Key results 
 
• Between November 2021 and June 2022, 43 patients were recruited with median age 74 years 
(70-86).  
• At initial diagnosis, most common FIGO stages were IIIC (51.2%), IVB (11.6%), and IIIB 
(7.0%).  
• Before trabectedin+PLD (baseline): 
- 
Patients had ECOG performance status 0, 1, or 2 (34.1%, 41.5%, and 9.8%) and 81.4% had 
measurable disease.  
- 
The median number of previous lines was 2 (1-6).  
• The initial dose of trabectedin was 1.1 mg/m2 in 76.7% of patients (16.3% with <1.1 and 
4.7% with >1.1 mg/m2) while 76.7% of patients had PLD at 30 mg (18.6% with <30 mg and 
2.3% with >30 mg).  
• The median of trabectedin+PLD cycles was 5 (1-21) and 53.5% of patients had at least one 
cycle delayed.  
• All patients ended treatment for the following reasons: patient’s decision (7.0%), doctor’s 
decision (23.3%), disease progression (39.5%), toxicity (23.83%) and 7.0% due to other 
factors.  
• Median PFS for the trabectedin+PLD combination was 7.7 months (95% CI 4.4-9.4) with 
best overall response rates of 4 CR (9.3%), 14 PR (32.6%), 13 SD (30.2%), and 5 PD 
(11.6%).  
• Median overall survival (OS) was 19.5 months (95% CI 12.8-27.2). 
• Overall, the most common G3-4 hematological events were neutropenia (23.3%), 
thrombocytopenia (7.0%), and anemia (2.3%), being asthenia (11.6%), mucositis (4.7%), and 
transaminitis (4.7%) the most frequent G3 non-hematological toxicities. 
 
11.2 
Limitations 
 
Potential study limitations included:  
 
• Heterogeneous population in terms of baseline characteristics (retrospective study)  
• Limited follow-up and missing data  
 
11.3 
Interpretation 
 
This study demonstrated that the safety profile of the trabectedin+PLD combination for elderly 
patients in real-life setting is manageable and efficacy results are comparable to those of previous 
clinical trials.  
 
11.4 
Generalisability 
 
The safety and efficacy results of this study are comparable to those of previous clinical trials with 
trabectedin and PLD. 
 

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12. Other information 
 
All patients participating in the study (accessible, alive patients who could be interviewed in the 
hospital) received a Patient Information Sheet (PIS) describing, in simple language, the goals, scope, 
procedures and relevant implications of the study.  
 
The PIS integrated an Informed Consent Form (ICF) to be signed by the patient, which was 
indispensable for study participation (for accessible patients).  
 
Written informed consent had to be given by each accessible/reachable patient before study initiation 
(prior to registration of the patient in the e-CRF). The PIS/ICF included the consent of patients for 
the collection and analysis of their clinical data.  
 
Data of inaccessible/unreachable patients (dead, lost, etc.) could still be used according to the 
permissions of ethics committees and Spanish law, regarding the use of data in retrospective studies.  
 
 
 

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13. Conclusion 
 
The safety profile of the trabectedin+PLD combination for elderly women in real-life setting is 
manageable and efficacy results are comparable to those of previous clinical trials. The results of this 
study are aligned with those reported in the literature for the general population. 
 
 
 

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14. References 
 
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country and age: results of EUROCARE--5-a population-based study. Lancet Oncol. 2014 
Jan;15(1):23-34. doi: 10.1016/S1470-2045(13)70546-1.  
 
[2] Sabatier R, et al. Prognostic factors for ovarian epithelial cancer in the elderly: a case-control 
study. Int J Gynecol Cancer. 2015 Jun;25(5):815-22. doi: 10.1097  
 
[3] Von Gruenigen VE, et al. Chemotherapy completion in elderly women with ovarian, primary 
peritoneal or fallopian tube cancer - An NRG oncology/Gynecologic Oncology Group study. 
Gynecol Oncol. 2017;144(3):459‐467. doi:10.1016/j.ygyno.2016.11.033  
 
[4] Falandri C, et al. EWOC-1: A randomized trial to evaluate the feasibility of three different first-
line chemotherapy regimens for vulnerable elderly women with ovarian cancer (OC): A GCIG-
ENGOT-GINECO study. J Clin Oncol 37, 2019, no. 15_suppl, 5508-5508.  
 
[5] Ovarian Cancer Incidence by International Agency for Research Cancer and WHO website: 
https://gco.iarc.fr/today/online-analysis-
table?v=2018&mode=cancer&mode_population=continents&population=900&populations=900&ke
y=asr&sex=2&cancer=39&type=0&statistic=5&prevalence=0&population_group=0&ages_group%
5B%5D=0&ages_group%5B%5D=17&group_cancer=1&include_nmsc=1&include_nmsc_other=1  
 
[6] Trabectedin (Yondelis®): Summary of Product Characteristics. 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Scientific_Discussion/human/000773/WC500045836.pdf  
 
[7] Colombo N, et al. ESMO-ESGO consensus conference recommendations on ovarian cancer: 
pathology and molecular biology, early and advanced stages, borderline tumours and recurrent 
disease. Annals of Oncology. 2019. 30:672-705.  
 
[8] Pignata S, et al. A European, observational, prospective trial of trabectedin plus pegylated 
liposomal doxorubicin in patients with platinum-sensitive ovarian cancer. Oncologist. 2020 Dec 8. 
doi: 10.1002/onco.13630. Online ahead of print.  
 
[9] Monk BJ, et al. Trabectedin plus pegylated liposomal Doxorubicin in recurrent ovarian cancer. J 
Clin Oncol. 2010 Jul 1;28(19):3107-14. doi: 10.1200/JCO.2009.25.4037.  
 
[10] Oza AM, et al. Efficacy and Safety of Bevacizumab-Containing Therapy in Newly Diagnosed 
Ovarian Cancer: ROSiA Single-Arm Phase 3B Study. Int J Gynecol Cancer. 2017 Jan;27(1):50-58. 
doi: 10.1097  
 
[11] Sorio R, et al. Safety and efficacy of single-agent bevacizumab-containing therapy in elderly 
patients with platinum-resistant recurrent ovarian cancer: Subgroup analysis of the randomised phase 
III AURELIA trial. Gynecol Oncol. 2017;144(1):65‐71. doi:10.1016  
 
[12] Dockery LE, et al. Tolerance and toxicity of the PARP inhibitor olaparib in older women with 
epithelial ovarian cancer. Gynecol Oncol. 2017;147(3):509‐513. doi:10.1016  
 

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[13] Vergote I, et al. Safety analysis of trabectedin in combination with pegylated liposomal 
doxorubicin (PLD) vs PLD alone in ovarian cancer patients 65 years of age and older. vol 7 Supl (2) 
pages 458 (Abs. Nº P8028) ECCO 15-34th ESMO European Society for Medical Oncology, 
september 20-24, 2009. Berlin. Eur J Cancer