E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10033130 |
E.1.2 | Term | Ovarian cancer NOS |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To demonstrate that the combination of trabectedin (Yondelis®) and pegylated liposomal doxorubicin (PLD) prolongs overall
survival (OS) over carboplatin and PLD in patients with relapsed ovarian cancer progressing within 6-12 months after end of last platinum. |
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E.2.2 | Secondary objectives of the trial |
• To evaluate the time from randomization to subsequent chemotherapy and the overall survival counted from the administration of subsequent chemotherapy.
• To evaluate serological response of CA-125 in each arm.
• To compare the quality of life (QoL) in each arm using the European Organization for Research and Treatment of Cancer
(EORTC) Quality of Life Questionnaire-C30 (QLQ-C30) and the Quality of Life Questionnaire-OV28 (QLQ-OV28).
• To compare safety profile, progression free survival (PFS), objective response rate (ORR), the type and length of remission (response rate and PFS) after subsequent therapies following each of the two combinations.
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Sub-study in selected centers: To perform pharmacokinetic (PK) analyses in both plasma and ascites in a subset of patients receiving trabectedin and PLD. |
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E.3 | Principal inclusion criteria |
1. Female, aged ≥ 18 years
2. Histologically and/or cytologically proven epithelial ovarian, epithelial fallopian tube cancer or primary peritoneal cancer
3. Progression free interval between six and twelve (6-12) months (calculated from the first day of the last cycle of the last platinumbased
chemotherapy until the date of progression confirmation through radiologic imagery). Patients may have received up to two platinum-based chemotherapy lines, of which at least one must have contained a taxane.
4. Measurable or evaluable disease confirmed by radiological imaging, such as magnetic resonance imaging (MRI), computed tomography (CT) scan, or PET/CT scan at study entry (CA-125 rise not supportedby radiological evidence of disease is not accepted as criteria for defining progression) or histological proven recurrent ovarian cancer even in the absence of postoperatively measurable or evaluable lesions.
5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2
6. Estimated life expectancy ≥ 12 weeks
7. Patients must be accessible for treatment and follow-up.
8. Adequate organ function within 14 days prior to first cycle as evidenced by:
a. Peripheral blood counts and serum chemistry values:
i. Hemoglobin ≥ 9 g/dl
ii. Absolute neutrophil count (ANC) ≥ 1,500/μl
iii. Platelet count ≥ 100,000/μl
iv. Estimated glomerular filtration rate > 60 ml/min according to the Cockroft-Gault formula
v. Creatine phosphokinase (CPK) ≤ 2.5 x ULN
b. Hepatic function variables:
i. Total bilirubin ≤ ULN
ii. Total alkaline phosphatase ≤ 2.5 ULN (consider hepatic isoenzymes 5-nucleotidase if the elevation could be osseous in origin)
iii. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) must be ≤ 2.5 x ULN
9. Patients must be able to receive dexamethasone or its equivalent, which is required if randomly assigned to treatment with trabectedin plus PLD
10. Informed consent of the patient |
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E.4 | Principal exclusion criteria |
1. Non epithelial ovarian or mixed epithelial/non epithelial tumors (e.g., Mullerian tumors)
2. Patients who did not respond to last platinum-based therapy or in whom last relapse occurred < 6 months or > 12 months from the last dose of platinum
3. Bowel obstruction, sub-occlusive disease or the presence of symptomatic brain metastases
4. Pre-existing grade > 1 motor or sensory neuropathy according to the National Cancer Institute Common Toxicity Criteria Adverse Event (NCI-CTCAE) version 4.0.
5. Myocardial infarct within six months before enrolment, New York Association (NYHA) Class II or worse heart failure (Appendix 1. The
New York Heart Association), uncontrolled angina, severe uncontrolled ventricular arrythmias, clinically significant pericardial
disease, or electrocardiographic evidence of acute ischemic or active conduction system abnormalities
6. History of liver disease.
7. Concurrent severe medical problems or any unstable medical condition unrelated to malignancy, which would significantly limit full compliance with the study or expose the patient to extreme risk or decreased life expectancy
8. Breastfeeding women and women of child bearing potential must use effective contraception during treatment and 3 months thereafter, which may include prescription contraceptives (oral, injection, or patch), intrauterine device, double-barrier method or male partner sterilization (not applicable to patients that are surgically sterile)
9. Prior exposure to trabectedin
10. Prior resistance to anthracyclines or PLD defined as a progression during anthracycline based chemotherapy or a recurrence within 6 months from its ending
11. Prior severe PLD related toxicity
12. Prior exposure to cumulative doses of doxorubicin >400mg/m2 or epirubicin >720mg/m2
13. Treatment with any investigational product within 30 days prior to inclusion in the study |
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E.5 End points |
E.5.1 | Primary end point(s) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
To be measured from the date of randomization up to the date of
death due to any cause or, for living patients, the date of last contact. |
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E.5.2 | Secondary end point(s) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
PFS: will be measured from the date of randomization to the date of documented PD or death (regardless of cause of death). |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 110 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
Denmark |
Finland |
Germany |
Greece |
Italy |
Netherlands |
Norway |
Poland |
Spain |
Sweden |
Switzerland |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Date of death or the date of last contact |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 7 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |