| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced relapsed ovarian cancer |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10033130 |
| E.1.2 | Term | Ovarian cancer NOS |
|
| 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 |
| The primary objective of the study is to demonstrate that the combination of YONDELIS + DOXIL improves progression-free survival (PFS) compared with DOXIL alone in the management of ovarian cancer in second-line therapy. |
|
| E.2.2 | Secondary objectives of the trial |
| Secondary objectives are to compare overall survival (OS), demonstrate an increase of overall response rate (ORR), and to compare the safety profiles of the combination therapy and monotherapy with DOXIL alone. The pharmacokinetics of DOXIL and YONDELIS in each treatment arm will be characterized. |
|
| 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 |
Pharmacogenomics
Exploratory evaluation of subject pharmacogenomic profiles and hypothesis-generating evaluation of the relationship between circulating tumor cells (CTCs), response to therapy, disease progression, and OS. This will include evaluation of genotypes and gene expression markers that may be related to the metabolism of, the response to or the susceptibility to toxicity of YONDELIS. A subset of the available pharmacogenomic data (training and confirmation sets of subject data) will be used to identify candidate targets. The remaining subset of the data will be used for confirming the impact of the target. These evaluations will be done at selected sites that are able to do the testing in subjects willing and consenting to participate. The exploratory and hypothesisgenerating data will be analyzed and reported separately from the clinical study. |
|
| E.3 | Principal inclusion criteria |
• Female, age 18 or older
• Histologically proven epithelial ovarian cancer, epithelial fallopian tube cancer, or primary peritoneal cancer
• Prior treatment with only 1 chemotherapy regimen, including adjuvant therapy, which must be platinum-based and may include sequential maintenance therapy or second look debulking surgery (no gaps in administration of initial therapy may occur other than a delay no longer than 2 months for treatment toxicity).
• Eastern Cooperative Oncology Group performance status is equal to or less than 2
• Estimated life expectancy of at least 3 months
• Recurrence or progression after 6 full cycles of a complete 6 cycle initial treatment regimen or 6 months after the beginning (first dose) of the initial treatment line of platinum-based chemotherapy for ovarian cancer to include
− Subjects with platinum-resistant disease (platinum-free interval from the end of first-line treatment less than 6 months)
− Subjects with platinum-sensitive disease (platinum-free interval from the end of first-line treatment equal to or more than 6 months) who are not expected to benefit from or who are ineligible for or who are not willing to receive retreatment with platinum-based chemotherapy
• Measurable disease that can be evaluated by RECIST guidelines for response or progression or both and documented by radiographic methods such as magnetic resonance imaging (MRI) or computed tomography (CT) scan. Date of radiological evidence is the documented date of progression
• Must be able to receive dexamethasone or its equivalent
• Adequate organ function as evidenced by the following peripheral blood
counts or serum chemistry values within 7 days before randomization:
hemoglobin ≥9 g/dL; absolute neutrophil count (ANC) ≥1,500/µL; and platelet count ≥100,000/µL serum creatinine ≤1.5 mg/dL (≤132.6 µmol/L) or creatinine clearance ≥60 mL/min; creatine phosphokinase (CPK) ≤upper limit of normal (ULN)
• Hepatic function variables
Total bilirubin ≤1.5 ULN, direct bilirubin ≤ULN
Total alkaline phosphatase (ALP) ≤1.5 ULN, or if >1.5 ULN, then ALP
liver fraction or 5’ nucleotidase must be ≤ULN
AST and ALT must be ≤2.5 × ULN
• Left ventricular ejection fraction (LVEF) by baseline multigated acquisition (MUGA) scan or 2-d echocardiogram must be within normal limits for the institution (see Section 6.2.2)
• Adequately recovered from the acute toxicity from any prior treatment
• Subjects (or their legally acceptable representatives) must have signed an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study.
• At investigative sites that are participating in the optional CellSearch,
pharmacogenomic, or protein testing portion of this protocol, the subject
(or their legally acceptable representative) must sign the informed consent
forms for CellSearch enumeration alone, or for additional pharmacogenomic testing, utilizing CellSearch, additional blood or paraffin samples or serum for DNA, mRNA, and protein expression analysis. These informed consent documents will indicate whether or not the subject wishes to participate in these parts of the study. Participation in the pharmacogenomics and CellSearch aspects of this study is not
mandatory. |
|
| E.4 | Principal exclusion criteria |
• Subjects treated with more than 1 prior chemotherapy regimen (including adjuvant therapy)
• Refractory disease, defined as disease progression within 6 months of the
beginning (first dose) of the initial line of platinum-based chemotherapy for ovarian cancer
• Isolated rise in CA-125 without documented radiological evidence of disease progression
• Prior exposure to anthracyclines for ovarian cancer or to YONDELIS or hypersensitivity to the pharmacologically active substance or to any of the excipients
• Subjects unwilling or unable to have a central venous catheter, which is required if randomly assigned to treatment with YONDELIS + DOXIL
• Subjects of child bearing potential not employing adequate contraception, which may include prescription contraceptives (oral, injection, or patch), intrauterine device, double-barrier method or male partner sterilization (not applicable to subjects that are surgically sterile) or subjects who are lactating.
• Less than 4 weeks from radiation or experimental therapy, less than 2 weeks from last dose of hormonal therapy, or less than 3 weeks from prior chemotherapy or biological therapy.
• History of another neoplastic disease (except basal cell carcinoma or cervical carcinoma in situ adequately treated) unless in remission for 5 years or more
• Known hypersensitivity to doxorubicin or to excipients in the formulations of either DOXIL or YONDELIS.
• Known clinically relevant central nervous system metastasis
• Active viral hepatitis or history of liver disease
• Myocardial infarct within 6 months before enrollment, New York Heart Association (NYHA) Class II or greater heart failure (Attachment 1), uncontrolled angina, severe uncontrolled ventricular arrhythmias, clinically significant pericardial disease, or electrocardiographic evidence of acute ischemic or active conduction system abnormalities.
• Any other unstable medical conditions, such as:
− Uncontrolled diabetes
− Psychiatric disorder (including dementias) that prevents compliance with protocol
− Uncontrolled seizures
− Acute deep vein thrombosis requiring intravenous or subcutaneous therapeutic anticoagulant therapy (chronic coumadin or prophylactic subcutaneous heparin allowed)
− Active infection. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint, PFS, is defined as the time between the date of randomization and the date of disease progression or death. This analysis will utilize the determination of progression date documented by central review (Section 11.4.5). Subjects who complete the study without disease progression will continue to have tumor assessments every 8 weeks and will be censored at the last tumor assessment before the end of the study. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Information not present in EudraCT |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Quality of life relationship between circulating tumor cells (CTCs) and efficacy |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Information not present in EudraCT |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Information not present in EudraCT |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
| 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 | Information not present in EudraCT |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| Combination of Yondelis with comparator (Caelyx) against comparator alone |
|
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| 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 | Information not present in EudraCT |
| 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 |
|
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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