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 | 20.0 |
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 | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To compare the OS after treatment with trabectedin+DOXIL combination therapy to that observed after treatment with DOXIL monotherapy for subjects with platinum-sensitive advanced-relapsed epithelial ovarian, primary peritoneal, or fallopian tube cancer who have received 2 previous lines of platinum-based chemotherapy. |
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E.2.2 | Secondary objectives of the trial |
- To evaluate PFS. - To evaluate the objective response rate (ORR). - To characterize the plasma pharmacokinetics of trabectedin using a sparse sampling scheme in the trabectedin+DOXIL treatment group. - To evaluate the safety of the trabectedin+DOXIL combination therapy and DOXIL monotherapy |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Histologically proven advanced-relapsed epithelial ovarian, primary peritoneal, or fallopian tube cancer - Eastern Cooperative Oncology Group (ECOG) performance status grade of 0 or 1 - Received first-line treatment with a platinum-based regimen and had no evidence of disease progression for 6 months after the last dose - Received second-line treatment with a platinum-based regimen, with progression of disease after attaining a complete response (CR) or partial response (PR) -progression of disease based on imaging after the second-line platinum-based regimen (individuals treated with a DOXIL-containing regimen as a second-line therapy are eligible if subsequent disease progression occurs >=9 months from the first dose) - Evidence of measurable disease at screening as evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) (Version 1.1) -Criterion modified per amendment: per Amendment 6, subjects no longer need to be able to receive intravenous (IV) dexamethasone or an equivalent IV corticosteroid - Have a known BRCA 1/2 mutation status (for participants who do not have a known BRCA 1/2 status at screening, a blood sample will be collected to determine the status with the results available prior to randomization - Laboratory values within protocol -defined parameters - Have left ventricular ejection fraction by multigated acquisition scan (MUGA) scan or 2D-ECHO within normal limits for the institution - Have side effects (except alopecia) of prior treatment resolved to at least Grade 1 according to the National Cancer Institute – Common Terminology Criteria of Adverse Events (NCI-CTCAE) (Version 4.0) - Have a negative urine or serum pregnancy test at screening - Agrees to protocol-defined use of effective contraception
Please refer to protocol for full inclusion criteria
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E.4 | Principal exclusion criteria |
- Diagnosis of ovarian carcinoma with mucinous histology - Had more than 2 prior lines of chemotherapy - Criterion modified per amendment: per Amendment 6, subjects who had a Prior exposure to trabectedin or hypersensitivity to any of the excipients will not be excluded from receiving single-agent DOXIL - Prior treatment with doxorubicin or other anthracycline at cumulative doses greater than 300 mg/m2 (calculated using doxorubicin equivalent doses: 1 mg doxorubicin = 1 mg Doxil= 1.8 mg epirubicin = 0.3 mg mitoxantrone = 0.25 mg idarubicin) - Criterion modified per amendment: per Amendment 6, subjects unwilling or unable to have a central venous catheter placed will not be excluded from receiving single-agent DOXIL - Pregnant or breast-feeding - Less than 3 weeks from radiation therapy, experimental therapy, hormonal therapy, prior chemotherapy, or biological therapy - History of another neoplastic disease (except non-metastatic basal cell carcinoma or squamous cell carcinoma of the skin or cervical carcinoma in situ adequately treated) unless in remission for 5 years - Known allergies, hypersensitivity, or intolerance to Doxil, dexamethasone, or their excipients - Known history of central nervous system metastasis - Known significant chronic liver disease, such as cirrhosis or active hepatitis (potential participants who test positive for hepatitis B surface antigen or hepatitis C antibodies are allowed provided they do not have active disease requiring antiviral therapy) - Had a myocardial infarct within 6 months before enrollment, New York Heart Association (NYHA) Class II or greater heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, clinically significant pericardial disease, or electrocardiographic evidence of acute ischemic or active conduction system abnormalities - Has any of the following medical conditions: uncontrolled diabetes, psychiatric disorder (including dementia) that prevents compliance with protocol, uncontrolled seizures, newly diagnosed deep vein thrombosis, active systemic infection that is likely to interfere with study procedure or results - Has any condition that, in the opinion of the investigator, would compromise the well-being of the participant or the study or prevent the participant from meeting or performing study requirements
Please refer to protocol for full exclusion criteria |
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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 |
up to 2 months after the last participant has received the last dose of study medication or when 514 deaths have been observed, whichever is later Following Amendment 6, study data collection including laboratory tests, cardiovascular monitoring, physical examinations, tumour assessments, PROs, and ECOG status will cease when all subjects on study treatment have completed the treatment termination visit assessments as specified in the Time and Events Schedule for Amendment 6 or by 18 January 2018, whichever occurs first. For subjects continuing treatment with single-agent DOXIL, as per the local standard of care, only serious adverse events should be reported to JR&D as outlined in Section 12.3.2.
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E.5.2 | Secondary end point(s) |
•Progression free survival rate Time frame: up to the date of disease progression or death measured up to 2 months after the last participant has received the last dose of study medication or when 514 deaths have been observed, whichever is later
•Objective response rate Time frame: up to 2 months after the last participant has received the last dose of study medication or when 514 deaths have been observed, whichever is later
•Area under the concentration curve of trabectedin as derived from sparse population pharmacokinetics Time frame = predose Day 1, 1 hour after start of study dose infusion, 10 minutes before the end of study dose infusion, and 0.5, 24, and 168 hours after the end of study dose infusion on Cycle 1 only
•Minimum observed plasma concentration of trabectedin as derived from sparse population pharmacokinetics Time frame = Time frame = predose Day 1, 1 hour after start of study dose infusion, 10 minutes before the end of study dose infusion, and 0.5, 24, and 168 hours after the end of study dose infusion on Cycle 1 only
•Maximum observed plasma concentration of trabectedin as derived from sparse population pharmacokinetics Time frame = Time frame = predose Day 1, 1 hour after start of study dose infusion, 10 minutes before the end of study dose infusion, and 0.5, 24, and 168 hours after the end of study dose infusion on Cycle 1 only
•Number of participants affected by an adverse event Time frame = up to 30 days after the last participant has received the last dose of study medication
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Following Amendment 6, study data collection including laboratory tests, cardiovascular monitoring, physical examinations, tumour assessments, PROs, and ECOG status will cease when all subjects on study treatment have completed the treatment termination visit assessments as specified in the Time and Events Schedule for Amendment 6 or by 18 January 2018, whichever occurs first. For subjects continuing treatment with single-agent DOXIL, as per the local standard of care, only serious adverse events should be reported to JR&D as outlined in Section 12.3.2. |
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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 | Yes |
E.6.11 | Pharmacogenomic | Yes |
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 | 1 |
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 | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 16 |
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 |
Australia |
China |
Israel |
New Zealand |
Poland |
Russian Federation |
South Africa |
Switzerland |
United Kingdom |
United States |
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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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 13 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 7 |
E.8.9.2 | In all countries concerned by the trial days | 19 |