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) |
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E.1.1.1 | Medical condition in easily understood language |
patients suffering from Bladder cancer with reduced renal 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 | 18.1 |
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 | 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 median Progression Free Survival without related Severe Acute Toxicity* between arms (called SAT-PFS).
*[enlarged definition of the Severe Acute Toxicity (SAT) from the EORTC study 30986 adding vinflunine specific risks: neutropenia G4 > 7 days, neutropenic fever G3/4, neutropenic systemic sepsis G3/G4 (neutropenia G3/4), G3/G4 thrombocytopenia with bleeding, G3/4 renal toxicity, G3/4 mucositis, constipation G4 requiring surgery, and death]. |
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E.2.2 | Secondary objectives of the trial |
- To evaluate the Disease Control Rate (DCR) and the Objective Response Rate (ORR),
- To estimate the Duration of Response of Disease Control and of Stable Disease,
- To estimate the Progression-Free Survival (PFS), Time To Treatment Failure (TTF),
- To estimate the Overall Survival (OS).
- To assess the Tolerance.
- To assess the Quality of Life. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Histologically confirmed diagnosis of locally advanced or metastatic predominantly transitional cell carcinoma of the urothelium (TCC) [urinary bladder, kidney, renal pelvis, or ureter],
- Man or woman aged ³ 18 years and < 80 years,
- Signed written informed consent before completing any study-related procedure,
- Ineligibility for cisplatin-based therapy because of renal impaired function (calculated creatinine clearance by Cockroft-Gault formula < 60 mL/min),
- Presence of a “measurable” disease which has not been previously irradiated with at least one uni-dimensional lesion according to RECIST guideline (version 1.1),
- ECOG performance status of 0 or 1 and estimated life expectancy more than 12 weeks
- Patient without prior systemic anticancer therapy for TCC unless cytotoxic agents have been administered in the peri-operative setting (neoadjuvant or adjuvant chemotherapy) and if documented relapse is ³ 6 months after the last dose of chemotherapy,
- Adequate bone marrow and hepatic functions as evidenced by:
o Absolute Neutrophil Count ³ 2.0 x 109/L, Platelet count ³ 100 x 109/L, Haemoglobin ³ 10.0 g/dL
o Serum total bilirubin £ 1.5 x upper limit of normal (ULN), Transaminases £ 2.5x 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 randomization in the trial,
- 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 6 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,
- Patient access to social insurance if applicable in the local regulation. |
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E.4 | Principal exclusion criteria |
- ECOG performance status ³ 2,
- Calculated creatinine clearance < 30 mL/min (Cockcroft-Gault formula),
- Known brain metastasis or leptomeningeal involvement (computed tomography scans
not required to rule this out unless there is clinical suspicion of central nervous system
disease),
- Peripheral neuropathy Grade ≥ 2 by National Cancer Institute Common Toxicity Criteria
[NCI CTC],
- Prior radiation to ≥ 30% of the bone marrow or completed < 30 days ago or without full
recovery of toxicities,
- Other serious concomitant/uncontrolled medical condition including:
o Infection requiring systemic anti-infective therapy within 2 weeks before
randomization or suspected sepsis
o Any medical condition that might not be controlled such as unstable angina,
myocardial infarction within the previous 6 months, unstable congestive heart
failure (NYHA Stage III-IV) or uncontrolled diabetes,
- Electrocardiogram (ECG) with significant modifications suggesting a high risk of
occurrence of an acute clinical event (such as signs of angina pectoris, high risk
arrhythmia, QT/QTc prolongation),
- Prior systemic immunotherapy for advanced or metastatic urothelium carcinoma,
- Prior systemic neoadjuvant/adjuvant chemotherapy that was completed < 6 months
before documented progression,
- Patient who had received any investigational drug within 30 days before randomisation
- History of another malignancy except adequately treated basal carcinoma of the skin, insitu
cervix carcinoma, localised prostate cancer with limited risk of recurrence (pT ≤ 2b,
Gleason score ≤ 7) that did not lead to any other treatment apart from prostatectomy, or
any other tumor with a disease free interval ≥ 5 years,
- Patients who require treatment with ketoconazole, itraconazole, ritonavir, amprenavir,
indinavir, rifampicine (any potent CYP3A4 inhibitor or inducer), phenytoine or
medicinal products known to prolong QT/QTc interval,
- Known hypersensitivity to the study drugs or to drugs with similar chemical structures,
- Any previous organ allograft or any chronic system disease requiring concurrent immune
therapy,
- 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 6 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 childbearing
potential. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is to compare the median Progression Free Survival without related Severe Acute Toxicity* between arms (called SAT-PFS). |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Tumour assessment will be performed according to the RECIST guideline (version 1.1).
Assessment of measurable and non-measurable disease will be carried out at baseline and
every 6 weeks until disease progression.
Survival data and post-study treatments will be reported every 3 months after progression.
Progression and tumour 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 such as pain intensity will be assessed every 2 cycles.
|
|
E.5.2 | Secondary end point(s) |
- To evaluate the Disease Control Rate (DCR) and the Objective Response Rate (ORR),
- To estimate the Duration of Response of Disease Control and of Stable Disease,
- To estimate the Progression-Free Survival (PFS), Time To Treatment Failure (TTF),
- To estimate the Overall Survival (OS).
- To assess the Tolerance.
- To assess the Quality of Life. |
|
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) | 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 | 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 | 42 |
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 |
Czech Republic |
France |
Italy |
Poland |
Romania |
Spain |
Taiwan |
United Kingdom |
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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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The end of the study period is defined as: 20 months after the accrual of the last patient date
if at least 138 SAT-PFS events have occurred.
Survival information will be collected every 6 weeks until progression and then
approximately every 3 months until death or decision of study closure. |
|
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 | 8 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |