Salvage chemotherapy for advanced urothelial cancer (UC) yields suboptimal response rates of 15-40%, a median progression-free survival of 2-4 months and a median overall survival of 6 months. A rationale for targeting angiogenesis in UC is supported by preclinical evidences and early signals of clinical activity of anti-VEGF TKI as demonstrated by our group with the use of pazopanib.

Despite this activity, progression inevitably occurs and mechanisms determining resistance to conventional anti-angiogenic agents are under investigation.

PF-03446962 (Pfizer Inc) is a novel fully human monoclonal antibody (mAb) against ALK1 with dose-dependent antiangiogenic activity as demonstrated in nonclinical studies in a chimera mouse model bearing human tumor xenograft. The investigators suggest that PF-03446962 may increase current results for patients with advanced urothelial cancer failing upfront chemotherapy due to its mechanisms of action. Due to the lack of reliable and reproducible predictors of response as well as of imaging tools to assess tumor response, the trial will provide incorporation of 18FDG-PET/CT and contrast-enhanced ultrasound to stage and evaluate response of urothelial cancers, together with standard imaging modalities (RECIST criteria). Blood and tissue samples will be collected for translational purposes.

This is an open-label, single arm, non randomised, phase II proof-of-concept study of the monoclonal antibody against TGF-beta receptor ALK1 (PF03446962) for patients with urothelial cancer relapsing/progressing after first line chemotherapy.

The study is planned according to Simon's Optimal two-stage design. The primary endpoint is the proportion of patients who are progression-free at 2-months. A 2-month PFS rate of 50% is not promising, while a 70% rate will be promising. In stage 1, 21 evaluable patients will be accrued. If 12 patients at least will be progression-free at 2 months, enrollment will be extended to the 2nd stage for further 24 patients. If, out of the total of 45 patients, 27 at least will be progression-free at 2 months, treatment will be declared worthy for further investigations.

Maximum overall accrual is 45 patients. Type I and type II error rates will be set both at the 10% level.

Inclusion Criteria:

• Age > 18 years.
• ECOG Performance status of 0 or 1.
• Life expectancy of at least 12 weeks.
• Measurable disease criteria (RECIST v1.1).
• Histological diagnosis of urothelial cancer.
• Locally advanced or metastatic disease.
• Failure of at least 1 prior chemotherapy regimen for metastatic disease.
• Neoadjuvant/adjuvant therapy considered if relapse occurred within 6 months of the last cycle of chemotherapy.
• Adequate bone marrow, liver and renal function requirements, to be conducted within 7 days prior to screening.

Exclusion Criteria:

• Cardiovascular or CNS disease.
• Previously untreated CNS metastases.
• Active Hepatitis B, C, HIV infection.
• Pregnant or breast-feeding patients.
• GI abnormalities and any other clinical condition at high risk of bleeding.
• Substance abuse and any other condition which may interfere with patient's participation in the study or evaluation of study results.