Chemotherapy (ChT) exerts moderate activity in advanced and metastatic PSCC, and efficacy outcomes are poor. Neoadjuvant treatment is a reliable setting to address activity of new drug approach (Necchi A et al. ASCO-GU 2017). The vascular endothelial growth factor (VEGF) receptor is overexpressed in approximately 50% of PSCC. Cabozantinib (Cabo) is a multiple receptor tyrosine kinase inhibitor (TKI) primarily targeting MET and VEGFR2.
In an open-label, single-arm, single-center, phase 2 trial, patients (pts) with clinical stage N2-3 (TNM 2009, locally-advanced [LA]) or M1 PSCC will receive Cabo, orally, at a dose of 60 mg/day continuously until surgery, evidence of disease progression or onset of unacceptable toxicity. Prior ChT administration is not allowed. Response will be evaluated by RECIST criteria v.1.1, matched with 18FDG-PET/CT assessment, every 2 months. At each time of disease restaging, responding pts with LA PSCC who will be considered eligible to radical lymphadenectomy will undergo surgery. After surgery, pts will be managed according to standard guidelines. The primary endpoint (EP) is the objective response-rate (ORR=CR+PR according to RECIST v1.1). Secondary EP are safety, progression-free survival (PFS) and overall survival (OS), and pathologic response. The study is planned according to Simon’s Optimal two-stage design, with H1=20% and H0= 5%, and type I and type II error rates set at the 10% level. In stage 1, 12 evaluable pts will be accrued. If 1 pt at least will be responding, enrolment will be extended to the 2nd stage for further 25 pts. If, out of the total of 37 pts, 4 at least will be responding, treatment will be declared worthy for further investigations. Stopping rules based on the Bayesian posterior probability (PP) to demonstrate that the ORR exceeded 20% are set. Translational analyses on pre- and post-Cabo tumor samples and matched blood samples will include in-situ hybridization for HPV and next generation sequencing (Ion Torrent Personal Genome Machine). These profiles will be associated with response to treatment and PFS/OS (EudraCT number 2017-001963-19).
Clinical trial identification
EudraCT number 2017-001963-19
Legal entity responsible for the study
Fondazione IRCCS Istituto Nazionale dei Tumori
All authors have declared no conflicts of interest.