E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Taxane/platinum refractory/resistant patients with recurrent epithelial ovarian, primary fallopian or primary peritoneal cancer. |
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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 | 10033128 |
E.1.2 | Term | Ovarian cancer |
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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 |
Primary objective - overall survival To show superiority of patupilone in overall survival compared to pegylated liposomal doxorubicin (Doxil®/Caelyx®) in taxane/platinum refractory/resistant patients with recurrent epithelial ovarian, primary fallopian or primary peritoneal cancer |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives • To evaluate progression free survival (PFS). • To evaluate best overall response rate (CR, PR) according to RECIST criteria (Post-textsupplement 1). • To evaluate CA-125 response for patients with evaluable disease as defined by Rustincriteria (Rustin 2003). • To evaluate duration of best overall response (CR, PR). • To evaluate time to progression (TTP) • To evaluate best overall response (CR, PR, SD, PD, Unknown) • To evaluate the safety and tolerability of patupilone administered in this dose and regimenand in this patient population. • To evaluate detailed cardiac safety surveillance of a single dose of patupilone versuspegylated liposomal doxorubicin on QT interval (corrected and uncorrected), heart rate (HR) and cardiac conduction intervals (QRS, RR, and PR) in a limited number patients from selected study centers (Post-text supplement 2). |
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E.2.3 | Trial contains a sub-study | No |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Exploratory Biomarker sub-study Document type:Protocol post-text supplement Development phase:III Release date:12-Jul-2005 •To examine whether individual genetic variation in genes relating to drug metabolism, ovarian, primary fallopian, or primary peritoneal cancer, and the drug target pathway confer differential response to Patupilone. •To examine gene expression patterns, proteins, and metabolites of blood and tumor tissue that are associated with treatment response to Patupilone, or that possibly correlate with the severity or progression of ovarian, primary fallopian, or primary peritoneal cancer.
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E.3 | Principal inclusion criteria |
Inclusion criteria Each subject must meet all of the following inclusion criteria at screening in order to be enrolled in the study: 1. Histologically confirmed diagnosis of epithelial ovarian, primary fallopian or primary peritoneal cancer. Eligible histologies include: • Serous adenocarcinoma • Endometrioid adenocarcinoma • Mucinous adenocarcinoma • Undifferentiated carcinoma • Clear cell adenocarcinoma • Mixed epithelial carcinoma • Transitional cell carcinoma • Malignant Brenner's Tumor • Adenocarcinoma NOS 2. Resistant / refractory to prior intravenous or intraperitoneal platinum-based chemotherapy (up to three prior regimens) • Requirements for patients who have received one prior regimen: • Experienced disease progression during administration of, or within 6 months after completing at least 4 cycles of, either of the following first-line taxane/platinum based combination treatment regimens: • Initial dose of carboplatin at least AUC 5 – 6 administered IV, or cisplatin at least 75 mg/m2 administered IV, or cisplatin at least 100mg/m2 administered IP. OR • Initial dose of cisplatin at least 100 mg/ m2 administered IP, and subsequently switched to an IV therapy with the first dose of at least 75 mg/ m2 (cisplatin) or at least AUC 5 (carboplatin) • A third approved therapeutic agent is permitted as part of the initial first line treatment, as a triplet regimen • Requirements for patients who have received two prior regimens • First regimen as described above (see also section 3.3.1.1). • Second regimen must consist of a platinum salt as a single agent or in combination with either gemcitabine, paclitaxel, cyclophosphamide or topotecan. • Patients must have documented disease progression during or within 6 months after receiving at least 4 cycles of second line therapy, or may have experienced toxicity necessitating treatment discontinuation. • Requirements for patients who have received three prior regimens: • First regimen as described above (see also section 3.3.1.1). • Second regimen must consist of either carboplatin, cisplatin, gemcitabine, paclitaxel cyclophosphamide or topotecan, administered as a single agent or in combination therapy. • Third regimen must consist of a platinum salt as a single agent or in combination with either gemcitabine, paclitaxel, cyclophosphamide or topotecan. • Patients must have documented progression of disease during or within 6 months after the last dose of third line therapy or may have experienced toxicity necessitating treatment discontinuation. • Patients treated with one taxane platinum-based regimen as a neo-adjuvant treatment and one other taxane-platinum-based regimen as an adjuvant therapy should be considered as having received only one regimen, providing that the adjuvant chemotherapy is initiated within 4 month after the completion of the neo-adjuvant therapy. • Patients may have received consolidation therapy with an approved agent and experienced documented disease progression within 6 months after the last dose of platinum-based chemotherapy 3. Taxane/platinum refractory/resistant patients must present with either measurable or nonmeasurable progressive disease. 1. Patients with measurable disease: • Measurable disease as defined by RECIST criteria: CT scans (with 10 mm sliced cuts) or NMRI scan lesion size of ≥ 2 cm (or ≥ 1 cm via spiral CT), with documented disease progression. Disease measurement must be taken within 30 days prior to start of treatment. • Measurable disease progression is defined as the appearance of a new lesion or the 20% increase in the sum of longest diameters of pre-existing lesion(s) within 6 months after, or while receiving, prior platinum-based chemotherapy. 2. Patients with non-measurable disease must have documented disease progression based on both imaging and CA-125 evaluations, meeting the following criteria: • Non-measurable disease is defined as unidimensionally measurable lesion(s) or mass(es) with margins not clearly defined, lesion(s) with both diameters ≤ 0.5 cm, lesion(s) on scans with either diameter smaller than the distance between cuts, palpable lesion(s) with either diameter ≤ 2 cm, malignant ascites or pleural effusion occurring within 6 months after, or while receiving, prior platinumbased chemotherapy. In addition: • Disease progression is defined by an increase of CA-125 by 25% or 50% or a persistently elevated level of Ca-125 (Rustin 2003) documented within 6 months after, or while receiving, prior platinum-containing chemotherapy. See Section 3.3.2.3 for the specific definitions of CA-125 disease progression for purposes of inclusion into this study. 4. Age ≥ 18 years. 5. WHO performance status of 0, 1, or 2. 6. Left ventricular ejection fraction (LVEF) ≥ 50% by MUGA or 2-D echocardiography (examination must be recorded on videotape). |
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E.4 | Principal exclusion criteria |
Exclusion criteria Subjects with, or meeting, any one of the following criteria during screening will be excluded from entry into the study: 1. Patients with CA-125-only disease. 2. Unresolved bowel obstruction. 3. Not recovered fully from surgery for any cause. 4. Prior administration of and/or known hypersensitivity to: epothilones, anthracyclines (including doxorubicin, epirubicin, daunorubicin, mitoxantrone), and/or pegylated liposomal doxorubicin. 5. Within 3 weeks of receiving any prior chemotherapy (including consolidation taxane therapy) or who are planning to receive other chemotherapy agents while participating in the study. 6. Within 3 weeks of receiving any prior radiotherapy or who are planning to receive radiotherapy while participating in the study. (Exception: Palliative radiotherapy of metastasis in extremities is allowed, but such lesions cannot be used as target lesions.) 7. Received any investigational compound within the past 28 days or who are planning to receive other investigational drugs while participating in the study. 8. Date of first study treatment would be more than 30 days past the most recent date of confirmed disease progression 9. Any peripheral neuropathy > CTC grade 1. 10. Unresolved diarrhea of any grade within last 7 days prior to start of treatment. 11. Presenting with leptomeningeal involvement. 12. Colostomy. 13. Underlying medical disease(s) that are not controlled [e.g. uncontrolled non-insulin dependant diabetes mellitus (NIDDM)]. 14. Known HIV positive status, and/or with the presence of an active or suspected acute or chronic uncontrolled infection. 15. Severe cardiac insufficiency (NYHA III or IV), with uncontrolled and/or unstable cardiac or coronary artery disease. 16. History of another malignancy within 5 years prior to study entry, except curatively treated non-melanotic skin cancer or cervical cancer in situ. 17. Receiving hematopoietic growth factors (except erythropoietin). 18. Concomitant administration of Coumadin® or other agents containing warfarin, with the exception of low dose Coumadin® (1 mg or less daily) administered prophylactically for maintenance of in-dwelling lines or ports. 19. Concomitant administration of any drug/agent known to cause, or increase the severity of, diarrhea. Patients must cease treatment with any such agents at least 7 days prior to start of study treatment. 20. Concomitant administration of any drug/agent known to interact negatively with doxorubicin or pegylated liposomal doxorubicin. 21. Known, ongoing alcohol and/or drug abuse. 22. A history of noncompliance to medical regimens or inability or unwillingness to return to the study center for scheduled visits, including tumor assessments and blood draws. 23. Pregnant, breast-feeding, or unwilling to use an acceptable method of contraception (i.e. barrier contraception) while receiving, and for up to 3 months after cessation of, study treatment. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary end-point The primary endpoint of this study is overall survival. Overall survival time is measured from the day of randomization to the date of documented death from any cause. If a patient is not known to have died, survival will be censored at the date of last contact. |
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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 | Yes |
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 | 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) | 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 | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
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 | 11 |
E.8.5 | The trial involves multiple Member States | Yes |
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 |
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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 | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 30 |