Pazopanib and Vinflunine in Urothelial Cancer of the Bladder

Inclusion criteria

• Written informed consent
• Age ≥ 18 years
• Histologically confirmed Transitional Cell Carcinoma of the Urothelium (TCCU) with lymphatic (N-stage 2-3) and/or distant metastases (M-stage 1) not amenable to definitive regional/local therapy
• Progression of tumor disease after platinum containing systemic chemotherapy for advanced or metastatic disease
• Eastern Cooperative Oncology Group (ECOG) performance status of 1
• estimated minimal life expectancy of 3 months at screening
• At least one measurable tumor lesion according to RECIST 1.1 criteria
• Adequate organ system function at screening
• Adequate contraception

Exclusion criteria

• More than 1 prior chemotherapy, biologic therapy or hormonal therapy within 14 days prior to the first dose of study medication
• Prior malignancy within 5 years prior to inclusion (exception: successfully treated basal cell carcinoma or in situ carcinoma)
• History or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis
• Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding within 28 days prior to beginning study treatment, e.g

• Active peptic ulcer disease
• Known intraluminal metastatic lesion/s with risk of bleeding
• Inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease), or other gastrointestinal conditions with increased risk of perforation
• History of abdominal fistula, gastrointestinal perforation, or intraabdominal abscess
• Clinically significant gastrointestinal abnormalities that may affect absorption of investigational product, e.g.

• Malabsorption syndrome
• Major resection of the stomach or small bowel
• Active infection requiring antibiotics within 14 days before registration
• Corrected QT interval (QTc) > 480 msecs using Bazett's formula at screening
• Screening-electrocardiogram (ECG) with any significant modifi¬cations suggesting a high risk of occurrence of an acute clinical event (such as signs of angina pectoris, high risk arrhythmia etc.)
• History of one or more of the following cardiac / cardiovascular conditions within the past 6 months before registration:

• Cardiac angioplasty or stenting
• Myocardial infarction
• Unstable angina
• Coronary artery bypass graft surgery
• Symptomatic peripheral vascular disease
• NYHA Class II, III or IV congestive heart failure
• Uncontrolled cardiac arrhythmia
• Poorly controlled hypertension, defined as systolic blood pressure (SBP) of ≥140 mmHg or diastolic blood pressure (DBP) of ≥ 90 mmHg
• History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months before registration
• Peripheral neuropathy grade ≥ 2 (NCI CTC v3.0)
• Unstable diabetes mellitus
• Uncontrolled hypercalcaemia > 2.9 mmol/L
• Prior major surgery or trauma within 28 days prior to registration and/or presence of any non-healing wound, fracture, or ulcer (procedures such as catheter placement not considered to be major)
• Evidence of active bleeding e.g. GI bleeding or bleeding diathesis at screening.
• Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels
• Hemoptysis with bleeding of > 2.5 mL within 8 weeks before registration
• Any serious and/or unstable pre-existing medical, psychiatric/psychological, familial, sociological, geographical or other condition that could interfere with subject's safety, provision of informed consent, or compliance to study procedures
• prior to the first dose of study drug and for the duration of the study
• Radiation, surgery or tumor embolization or any investigational treatment within 14 days prior to the first dose of study medication
• Any ongoing toxicity from prior anti-cancer therapy that is > Grade 1 and/or progressing in severity, except nausea, vomiting, alopecia
• ASA 4
• Pre-treatment with Pazopanib or Vinflunine
• Pregnancy or lactation