E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Locally advanced or Metastatic urothelial carcinoma |
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E.1.1.1 | Medical condition in easily understood language |
Advanced tumor and metastastic disease originating from the urothelial tract |
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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 | 10046721 |
E.1.2 | Term | Urothelial carcinoma bladder stage III |
E.1.2 | System Organ Class | 100000004864 |
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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 | 10046723 |
E.1.2 | Term | Urothelial carcinoma ureter |
E.1.2 | System Organ Class | 100000004864 |
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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 | 10046714 |
E.1.2 | Term | Urothelial carcinoma bladder |
E.1.2 | System Organ Class | 100000004864 |
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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.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10046725 |
E.1.2 | Term | Urothelial carcinoma ureter metastatic |
E.1.2 | System Organ Class | 100000004864 |
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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 | 10046730 |
E.1.2 | Term | Urothelial carcinoma urethra metastatic |
E.1.2 | System Organ Class | 100000004864 |
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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 | 10046728 |
E.1.2 | Term | Urothelial carcinoma urethra |
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 progression free survival (FPS) of vinflunine/gemcitabine versus carboplatin/gemcitabine in patients with locally advanced or metastatic transitional cell carcinoma of the urothelial tract unfit for cisplatin based chemotherapy due to impaired renal function. |
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E.2.2 | Secondary objectives of the trial |
To evaluate the tumour response (ORR), overall survival (OS) and disease control rate (DCR) of vinflunine/gemcitabine versus carboplatin/gemcitabine in patients with locally advanced or metastatic transitional cell carcinoma of the urothelial tract unfit for cisplatin based chemotherapy due to impaired renal function.
To assess the safety and toxicity of vinflunine/gemcitabine versus carboplatin/gemcitabine.
To investigate and compare Quality of life during treatment with vinflunine/gemcitabine and carboplatin/gemcitabine respectively.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
•Signed informed consent.
•Histological or cytological confirmed transitional cell carcinoma of the urothelial tract (mixed histology including transitional cell carcinoma are allowed).
•Non-curable unresectable (T4b), locally advanced (lymph node positive (N+)) or metastatic (M1) urothelial carcinoma (including renal pelvic tumours, ureteral tumours, urinary bladder tumours and urethral primary tumours).
•No prior antineoplastic chemotherapy or other anti-cancer drugs. Patients who have received neoadjuvant or adjuvant platinum containing chemotherapy and who are diagnosed with loco regional recurrent or metastatic disease after 6 months are eligible.
•Creatinine clearance 30 – 60 ml/min (measured by Iohexol or Cr-EDTA technique)
•ECOG/WHO Performance Status (PS) 0-1.
•≥ 4 weeks since prior major surgery, ≥ 2 weeks since prior minor surgery (i.e. TUR-B) and ≥ 1 week since prior radiation therapy.
•Measurable and/or non-measurable disease using the RECIST v 1:1 criteria defined as:
-Measurable disease: lesions that can be measured in at least one dimension and which have not been previously irradiated. Longest diameter 10 mm or lymph nodes ≥15 mm in short axis with CT scan or MRI
-Non-measurable disease: lesions which have not been previously irradiated, longest diameter <10 mm or lymph nodes 10-14 mm in short axis with CT scan or MRI, or truly non measurable lesions including bone lesions, ascites, pleural/pericardial effusion, and lymphangitis cutis/pulmonitis.
•CNS metastases and/or leptomeningeal metastases are allowed provided these have been adequately treated with radiotherapy, are stable and not generating any related neurological symptoms.
•Spinal cord compression due to metastatic lesions is allowed provided adequate surgery and/or radiotherapy has been delivered, the metastases are stable and not generating any related neurological symptoms.
•No known or suspected allergy to the investigational agents or any agents given in association with this trial.
•18 years of age or older.
•Fertile men and women of childbearing potential must use secure contraception (women - intrauterine devices, hormonal contraceptives (contraceptive pills, implants, transdermal patches, hormonal vaginal devices or injections with prolonged release), men – condom and for a female partner as described above) from before 2 months entering the study until 6 months after end of chemotherapy.
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E.4 | Principal exclusion criteria |
•Not fulfilling inclusion criteria as described above
•Pure non-transitional cell carcinoma of the urothelial.
•Pronounced heamaturia in need of repeated blood transfusions, palliative radiotherapy to the bladder or palliative resection (TUR-B).
•Impaired bone marrow function defined as WBC < 3.0 x 109/L, neutrophils < 1.5 x 109/L, platelets < 125 x 109/L, haemoglobin < 100 g/L.
•Impaired liver function defined as serum bilirubin > 1.5 x upper limit of normal (ULN) and/or ASAT/ALAT > 2.5 x ULN (> 5 x ULN if known liver metastasis).
•Electrocardiogram (ECG) with significant modifications suggesting a high risk of occurrence of angina pectoris or high risk of arrhythmia.
•Other malignancies, except adequately treated basal carcinoma or squamos cell carcinoma of the skin or in-situ cervix carcinoma or incidental prostate cancer (T1a, Gleason score ≤ 6, PSA < 0.5 ng/ml), or any other tumour with a disease free survival of ≥ 5 years.
•History of serious or concurrent illness or uncontrolled medical disorder; any medical condition that might be aggravated by chemotherapy treatment or which could not be controlled; including, but not restricted to:
-Active infection requiring antibiotics within 2 weeks before the study inclusion,
-Unstable diabetes mellitus,
-Hypercalcaemia >2.9 mmol/L (= grade 2 according to CTCAE v 4.0),
-Concurrent congestive heart failure NYHA (class III-IV),
-Unstable angina pectoris, or myocardial infarction within 6 months and/or poorly controlled hypertension,
-QTc > 450 ms at baseline,
-Inflammatory bowel disease,
-Peripheral neuropathy grade 2 according to CTCAE v 4.0,
•Patients who require treatment with ketoconazole, flukonazole, itraconazole, ritonavir, amprenavir, indinavir, rifampicine (any potent CYP3A4 inhibitor or inducer) or phenytoine.
•Pregnant or lactating women.
•Any psychological, familial, sociological, or geographical condition which does not permit protocol compliance and medical follow-up.
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression free survival (PFS), (CR + PR + SD) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Continously evaluation every second cycle (e.g. every sixth week) until progression. |
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E.5.2 | Secondary end point(s) |
Overall response rate (ORR) (ORR = CR + PR)
Overall survival (OS)
Disease control rate (DCR), (DCR = CR + PR + Stable Disease (SD)), according to RECIST, every 2nd cycle
Data on safety (Serious Adverse Events, Adverse Events leading to premature withdrawal)
Data on Quality of Life (Quality of Life Questionnaire C30 (QLQ-C30) Version 3.0)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
The comparator is standard treatment Carboplatin/ Gemcitabine |
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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 | 13 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 13 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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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30 +/-2 days after radiological verified progressive disease during treatment with the study drugs |
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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 years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |