E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
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 estimate the objective response rate (as defined by the WHO criteria modified by the SWOG) in patients with TCC receiving vinflunine, who have had documented progression within 12 months after the last dose of a platinum-containing regimen and are not candidates for cystectomy. |
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E.2.2 | Secondary objectives of the trial |
1) To estimate duration of response. 2) To estimate time to response. 3) To estimate disease control rate (Complete Response + Partial Response + Stable Disease). 4) To estimate progression free survival. 5) To estimate overall survival. 6) To evaluate the safety profile of vinflunine. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Provided signed written informed consent. 2) Histologic diagnosis of predominantly locally advanced or metastastic transitional cell carcinoma (TCC) of the urothelium (urinary bladder, kidney, renal pelvis, or ureter) (NOTE: rare foci of other histologies are acceptable). 3) At the time of study entry, patient must no longer be a candidate for local/regional control of disease (surgery and/or radiotherapy, see Protocol Appendix 1 for reference). 4) Patients must have received at least two cycles of prior cisplatin at a dose of least 60 mg/m2 or prior carboplatin at a dose of at least AUC 4 (or equivalent) in any setting. (NOTE: subsequent cycles of cisplatin or carboplatin, if delivered, need not be 60 mg/m2 or AUC 4, respectively). 5) Measurable disease documented by imaging with at least one bidimensional lesion (See Protocol Section 3.3.2) 6) Documented relapse or progressive disease within 12 months (+ 2 weeks) after the last dose of a platinum containing regimen in any setting at the time of study entry. 7) Karnofsky Performance Status of 100, 90, or 80 (See Protocol Appendix 2) 8) Recovery from toxicity due to prior therapy (i.e. toxicity has resolved to baseline or is deemed irreversible). At least 2 weeks must have elapsed since last dose of chemotherapy (6 weeks for nitrosoureas, mitomycin-C, and liposomal doxorubicin), immunotherapy, or radiotherapy and the beginning of protocol therapy. 9) Men and women ≥ age 18 WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of study medication.
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E.4 | Principal exclusion criteria |
1) WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 12 weeks after the study. 2) WOCBP using a prohibited contraceptive method. 3) Diagnosis of predominantly non-transitional cell carcinoma of the urothelium (adenocarcinoma, squamous cell carcinoma, small cell, or other). 4) Diagnosis of other malignancies except adequately treated basal cell carcinoma of the skin, incidental prostate cancer (T1a or T1b, Gleason score ≤ 6, PSA < 0.5 ng/ml) or in-situ cervical carcinoma or any other tumor with a disease-free interval ≥ 5 years (4.5 years per prior BMS Medical Monitor approval). 5) Prior discontinuation of platinum for reasons of toxicity only. (Note: patients who switch platinum therapy due to toxicity are eligible if he/she does not progress between platinum agents and the two courses of therapy are considered one treatment regimen.) 6) Receipt of more than one prior chemotherapy regimen in any setting (Note: sequential regimens allowed). 7) Known brain metastases or leptomeningeal involvement. CT scans are not required to rule this out unless there is clinical suspicion of central nervous system (CNS) disease. 8) CTC (v.2.0) ≥ Grade 2 peripheral neuropathy. 9) Prior radiation to ≥ 30% of the bone marrow. (See Protocol Appendix 3) 10) A serious uncontrolled medical disorder, recent major abdominal surgery or active infection which would impair the ability of the patient to receive protocol therapy 11) Concurrent heart failure (New York Heart Association Class III - IV) or unstable angina, myocardial infarction within the prior 6 months, or poorly controlled hypertension 12) Psychological, familial, or sociological conditions that do not permit medical follow-up and/or compliance with the study protocol. 13) Inadequate hematologic function defined by an absolute neutrophil count (ANC) < 1,500 cells/mm3 or a platelet count < 100,000 cells/mm3. 14) Inadequate hepatic function defined by a total bilirubin level > 1.5 times the upper limit of normal (ULN) or transaminases (ALT, AST) level > 2.5 times the ULN (> 5 times the ULN only in case of liver metastasis). 15) Inadequate renal function defined by a serum creatinine clearance < 40 ml/min (Cockcroft-Gault formula, see Protocol Appendix 4). 16) Prior allergic reaction to any vinca alkaloid. 17) Patients who require treatment with ketoconazole, itraconazole, ritonavir, amprenavir and indinavir. 18) Any concurrent chronic systemic immune therapy (including steroids), chemotherapy, radiation therapy, hormonal therapy (except for physiologic replacement), or any other investigational agent. 19) Prisoners or patients who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious disease) illness must not be enrolled into this study. 20) Sexually active fertile men not using effective birth control during the study and up to 6 months after the study if their partners are women of child-bearing potential. 21) Women who are pregnant or breastfeeding 22) Women with a positive pregnancy test on enrollment or prior to study drug administration.
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy: The primary efficacy analysis will be based on response rate, as determined by the Independent Response Review Committee (IRRC), where tumor response rate is defined as the total number of complete and partial responders divided by the total number of treated patients.
Safety: The analysis of safety will be based on the frequency of adverse events and their severity for patients who received at least one cycle of vinflunine. Worst toxicity grades per patient will be tabulated for adverse events and laboratory measurements.
The effect of vinflunine on the QTc interval will be assessed by frequency distributions for maximum QTc and for maximum QTc changes from baseline (predose), by summary statistics for QTc and for QTc changes from baseline and linear regression of QTc changes from baseline (predose) on time-matched concentrations of vinflunine and DVFL. PR interval, QRS interval and ECG determined heart rate will be similarly assessed.
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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 | No |
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 | 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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
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) | Information not present in EudraCT |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 23 |
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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Once a patient has been taken off study, survival data will be collected every two months until death. |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |