Phase I Study With Sorafenib in Addition to Vinflunine in Metastatic Transitional Cell Carcinoma of the Urothelial Tract

Study Overview
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Brief Summary
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This study aims to analyse the tolerability (side effects and safety) with standard treatment (Javlor®) with the addition of a second anti-tumour drug: sorafenib (Nexavar®). This is the first time this treatment combination is studied in humans. Samples of blood, urine and tumour tissues will be analysed for molecular biomarkers. These biomarkers may potentially help us in the future in predicting whether a patient will benefit or not from the cancer treatment. The study also aims to investigate if a newer imaging method, called PET-CT (positron emission tomography-computed tomography), at an earlier stage (than a normal CT scan) can identify patients who will benefit from the given treatment.

Detailed Description
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Objectives To explore the safety of sorafenib in combination with vinflunine in patients with transitional cell carcinoma of the urothelial tract and to define a recommended phase II dose for this treatment combination To correlate early tracer 18F-FDG-PET/CT functional imaging readouts with standard RECIST (version 1.1) evaluations with the intention to explore new endpoints for targeted therapy To find predictive tumour tissue biomarkers for sorafenib/vinflunine treatment To evaluate serum and urine markers of apoptosis as potential markers of sorafenib/vinflunine treatment Rationale/Goal To evaluate the tolerability and activity of sorafenib combined with vinflunine in patients with advanced or metastatic urothelial cancer. Tumour biopsies will be collected before and after one cycle of therapy. The translational part of this study aims to explore the predictive value of a number of biomarkers related to the targeted properties of sorafenib and presumptive markers for vinflunine treatment. In addition, the predictive value of an early functional imaging tracer 18F-FDG-PET/CT will be evaluated.

Official Title
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An Exploratory Phase I Study With Sorafenib in Addition to Vinflunine in Progressive Locally Advanced or Metastatic Transitional Cell Carcinoma of the Urothelial Tract

Conditions
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Urothelial Carcinoma, Bladder Cancer, Renal Pelvis Cancer, Ureter Cancer, Urethra Cancer

Intervention / Treatment
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* Drug: Vinflunine
* Drug: Sorafenib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: signed informed consent; histologically confirmed transitional cell (pure or mixed histology including transitional cell carcinoma are allowed) carcinoma of the urothelial tract; patients who have received neoadjuvant or adjuvant platinum-containing chemotherapy and who are diagnosed with locoregional recurrent or metastatic disease prior to or at the 6-months visit , are eligible or patients who have received palliative platinum-containing chemotherapy and who are diagnosed with progression prior to or at the 6-months visit, are eligible or patients who have contraindication to platinum-containing chemotherapy; previous systemic chemotherapy must have been stopped 14 days before the inclusion with recovery (G1 or less) from any treatment related toxicity; measurable and/or non-measurable disease using RECIST and defined as: Measurable disease: lesions that can be measured in at least one dimension and which have not been previously irradiated. Longest diameter 20 mm with conventional techniques or 10 mm with spiral CT scan or MRI. Non-measurable disease: lesions which have not been previously irradiated, or longest diameter <20 mm with conventional techniques or <10 mm with spiral CT scan or MRI, or truly non measurable lesions including bone lesions, ascites, pleural/pericardial effusion, and lymphangitis cutis/pulmonitis; age 18 up to 80 years; ECOG / WHO Performance Status (PS) ≤1; haematological function: haemoglobin ≥100 g/L absolute neutrophil count 1.0 x LL (lower limit of normal value) platelets 100 x 109/L; hepatic function: bilirubin <1.5 x ULN*, transaminases <2.5 x ULN* *ULN = upper limit of normal value renal function: creatinine clearance 40 ml/min (measured by either iohexol clearance or Cr-EDTA technique); Clinically normal cardiac function based on ejection fraction (LVEF assessed by MUGA or ECHO, LVEF ≥50%); able to swallow and retain oral medication; previous treatment related toxicity must be grade ≤1 at time of inclusion and no presence of asthenia, hand-foot skin reaction or rash grade >1 (NCI CTCAE v4.0) at enrolment; no known or suspected allergy to the investigational agent or any agents given in association with this trial; Exclusion Criteria: non-transitional cell carcinoma of the urothelial tract (e.g. pure adenocarcinoma or squamous cell carcinoma); prior treatment with vinflunine; diagnosed brain metastases or leptomeningeal involvement. Brain CT-scans or MRI are not required unless there is clinical suspicion of central nervous system involvement. peripheral neuropathy G3 (NCI CTCAE v4.0); history of serious or concurrent illness or uncontrolled medical disorder; any medical condition that might be aggravated by treatment or which could not be controlled: active infection requiring antibiotics within 2 weeks before the study inclusion, unstable diabetes mellitus, uncontrolled hypercalcaemia >2.9 mmol/L (or >G2 NCI CTCAE v4.0), concurrent congestive heart failure NYHA (class III-IV) or any type of angina pectoris and/or a diagnosis of myocardial infarction during the previous 6 months and/or poorly controlled hypertension will be excluded, QTc >450 ms at baseline, additional risk factors for Torsade de Pointes (heart failure and hypokalemia (≥G1, i.e. P-K <LLN-2.5 mM) or family history of long QT-syndrome), cardiac arrhythmias requiring anti-arrhythmics (excluding beta-blockers or digoxin for chronic atrial fibrillation); patients having received more than one previous systemic chemotherapy for advanced or metastatic disease; patients who have received any other investigational or anti-cancer therapy 14 days before the inclusion; other malignancies, except adequately treated basal 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; pregnant or lactating women; men or women of childbearing potential not employing adequate contraception; any psychological, familial, sociological, or geographical condition which does not permit protocol compliance and medical follow-up. poorly controlled hypertension. At baseline, blood pressure >150/90 is defined as poorly controlled. renal dysfunction: creatinine clearance <40 ml/min measured by either iohexol clearance or Cr-EDTA technique. ECOG / WHO Performance Status ≥2 presence of hand-foot skin reaction or rash >G1 at enrolment; known or suspected allergy to the investigational agent or any agents given in association with this trial; current medical treatment with any compound that prolongs QTc

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: vinflunine + sorafenib<br>Single arm study. | Drug: Vinflunine<br>* Vinflunine (Javlor®, Pierre Fabre Pharma): 320 mg/m2 I.V., day 1, repeated every 21 days for patients with PS 0, adequate renal (creatinine clearance >60 ml/min) and hepatic function (as described in the inclusion criteria). PLEASE NOTE THAT THE 320 mg/m2 ARM IS CLOSED FOR RECRUITMENT. For patients with PS 1, or age 75 to 80 years, or exposed to radiation of the lower pelvis region, or with impaired renal function (creatinine clearance 40-60 ml/min) but adequate hepatic function (as described in the inclusion criteria), the dose of vinflunine is 280 mg/m2 I.V. day 1, repeated every 21 days.<br>* Other names: Javlor;Drug: Sorafenib<br>* Sorafenib (Nexavar®, Bayer HealthCare) daily dosage from day 2 through day 21 (repeated every 21 days): Step 1: 400 mg P.O. (i.e. one (1) tablet 200 mg morning and evening, 1+0+1) Step 2: 600 P.O. (i.e. one (1) tablet 200 mg morning and two tablets evening, 1+0+2) Step 3: 800 mg P.O. (i.e. two (2) tablets 200 mg morning and evening, 2+0+2) Doses of sorafenib higher than 400 mg P.O. b.i.d. are not allowed.<br>* Other names: Nexavar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with adverse events | Primary endpoint: Define the recommended phase II dose (RPTD) by the number of dose limiting toxicity events (recorded during treatment cycle 1 and 2) | 6 weeks |