E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
The trial concerns patients suffering from advanced or metastatic Transitional Cell Carcinoma of the Urothelium (TCCU) who are unfit for Cisplatin-containing first-line treatment due to reduced renal function (GFR 30-60 mL/min) or due to reduced cardiac function (NYHA II-III) |
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E.1.1.1 | Medical condition in easily understood language |
patients suffering from Bladder cancer with reduced renal function or cardiac function |
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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 | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10046722 |
E.1.2 | Term | Urothelial carcinoma bladder stage IV |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 determine the disease control rate as defined by RECIST assessment criteria [Complete Response (CR) + Partial Response (PR) + Stable Disease (SD) rates] for both Vinflunine-Gemcitabine and Vinflunine-Carboplatin combinations |
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E.2.2 | Secondary objectives of the trial |
To assess the safety profile of the treatment.
To evaluate other efficacy parameters: Objective Response Rate (CR + PR rates), duration of response and duration of disease control, Time to treatment failure (TTF), Progression free survival (PFS) and Overall survival (OS).
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Man or woman aged ≥ 18 years and < 80 years
• Signed written informed consent
• Histologically confirmed diagnosis of locally advanced or metastatic predominantly transitional cell carcinoma of the urothelium (TCCU) [urinary bladder, kidney, renal pelvis, or ureter]
• With the following disease conditions:
Ineligibility for cisplatin-based therapy because of at least one of the following two medical conditions:
- Calculated creatinine clearance (Cockroft-Gault formula) < 60 mL/min
- New York Heart Association Classification Stage II-III Congestive Heart Failure (documented by medical history)
• “Measurable” disease with at least one uni-dimensional lesion according to RECIST guideline (version 1.1)
• ECOG performance status of 0 or 1
• Estimated life expectancy of at least 12 weeks
• Patient without prior systemic anticancer therapy unless if it had been administered as neoadjuvant or adjuvant CT for TCCU and if the patient has documented relapse ≥ 6 months after the last dose of CT (prior intravesical CT allowed)
• Adequate bone marrow and hepatic functions as evidenced by:
- Absolute Neutrophil Count ≥ 2,000/mm3 (≥ 2.0 x 10^9/L)
- Haemoglobin ≥ 10 g/dL
- Platelet count ≥ 100,000/mm3
- Serum total bilirubin ≤ 1.5 x upper limit of normal (ULN)
- Transaminases ≤ 2.5 x ULN [≤ 5 x ULN only in case of liver metastasis]
• Absence of psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; these conditions should be assessed with the patient before registration in the trial
• Patient access to social insurance if applicable in the local regulations
• Women of childbearing potential must be using a medically accepted method of contraception to avoid pregnancy during the 2 months preceding the start of study treatment, throughout the study period and for up to 3 months after the last dose of study treatment; women of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to the start of study treatment
• Fertile men must be using an effective method of birth control during the study and up to 6 months after the last dose of study treatment if their partners are women of childbearing potential
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E.4 | Principal exclusion criteria |
• ECOG performance status ≥ 2
• Woman if pregnant or lactating or with positive pregnancy test at inclusion; woman of child-bearing potential who did not use or is unwilling or unable to use an acceptable method to avoid pregnancy during the 2 months preceding the start of study treatment, for the entire study period and for up to 3 months after the last dose of study treatment; sexually active fertile man not using effective birth control during the study and up to 6 months after the last dose of study treatment if his partner is a woman of child-bearing potential
• Known brain metastasis or leptomeningeal involvement. (Computed Tomography (CT)-scans are not required to rule this out unless there is clinical suspicion of central nervous system (CNS) disease)
• Peripheral neuropathy Grade ≥ 2 by NCI CTC [National Cancer Institute Common Terminology Criteria]
• Prior radiation to ≥ 30% of the bone marrow or completed < 30 days ago or without full recovery of toxicities
• Other serious illness or medical condition including:
- Infection requiring systemic anti-infective therapy
- Any medical condition that might not be controlled, for instance patients with unstable angina, patients with myocardial infarction within 6 months or uncontrolled diabetes
• Prior systemic chemotherapy for advanced or metastatic disease or neoadjuvant/adjuvant chemotherapy that was completed < 6 months before documented progression
• Patient who had received any other investigational drug or anti-cancer therapy within 30 days before randomisation
• Other malignancies except adequately treated basal carcinoma of the skin, in-situ cervix carcinoma, localised prostate cancer with limited risk of recurrence (pT < or = 2b, Gleason score < or =7) that was incidentally discovered and did not lead to any other treatment apart from prostatectomy, or any other tumor with a disease free interval ≥ 5 years
• Inadequate renal function defined by a serum creatinine clearance < 30 mL/min (Cockcroft-Gault formula)
• Known hypersensitivity to the study drugs or to drugs with similar chemical structures
• Patients who require treatment with ketoconazole, itraconazole, ritonavir, amprenavir, indinavir, rifampicine (any potent CYP3A4 inhibitor or inducer) or phenytoine
• Any concurrent chronic system immune therapy or previous organ allograft
• Electrocardiogram (ECG) with significant modifications suggesting a high risk of occurrence of an acute clinical event (such as signs of angina pectoris or high risk arrhythmia…)
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is to determine the disease control rate as defined by RECIST assessment criteria [Complete Response (CR) + Partial Response (PR) + Stable Disease (SD) rates] for both Vinflunine-Gemcitabine and Vinflunine-Carboplatin combinations |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Will be determined by using RECIST criteria (version 1.1). as follows:
- assessment of lesions (measurable and non-measurable) at baseline and every 2 cycles.
- Progression and tumor response will be evaluated for all randomized patients by the investigators.
- Duration of disease control and response will be evaluated for all patients with disease control and responding patients, respectively.
- Moreover, clinical parameters as pain intensity will be performed every 2 cycles. |
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E.5.2 | Secondary end point(s) |
To assess the safety profile of the treatment.
To evaluate other efficacy parameters: Objective Response Rate (CR + PR rates), duration of response and duration of disease control, Time to treatment failure (TTF), Progression free survival (PFS) and Overall survival (OS) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
as timepoints for primary endpoint evaluation |
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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 | No |
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) | 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 | 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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 27 |
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 |
Austria |
Belgium |
France |
Germany |
Italy |
Poland |
Spain |
Taiwan |
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E.8.7 | Trial has a data monitoring committee | No |
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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The end of the study is defined as the time from 30 days after the last treatment administration of the last patient under treatment in the study. |
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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 | 2 |
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 | 2 |
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 |