Phase II Clinical and Pharmacokinetic (PK) Trial of Zalypsis (Z) in Patients with Urothelial Carcinoma (UC) Progressing after a First-Line Platinum-Based Regimen

ABSTRACT Background Platinum-based chemotherapy (CT) is beneficial as first-line treatment of advanced UC. However, the majority of patients develop recurrent disease with poor long-term survival rates[1]. Attempts to improve second-line treatments have evaluated single agents and multi-drug combinations, neither of which has managed to improve survival or achieve durable responses. Z is a cytotoxic agent that induces apoptosis by acting at cell cycle level, has DNA-binding properties and inhibits transcriptional responses. Z has shown anti-tumor activity in vitro and in vivo in xenograft models[2]. Based on the activity observed in a phase I study (1PR and 2 SD) in advanced bladder cancer we have designed a phase II study to explore the efficacy of Z in this setting. Methods Patients with histologically-confirmed advanced or metastatic UC, who had failed one prior line of platinum-based CT, with proven progression or relapse before study entry, were included. Patients were treated with a Z intravenous infusion of 3 mg/m2 over 1-hour and every 3 weeks. A two-stage design was chosen; at least four (of 17) evaluable patients had to reach the primary endpoint during the first stage in order to progress into a second stage of up to 37 patients. The primary endpoint was tumor control rate (TCR): percentage of patients with objective response (OR) of any duration or patients alive and progression-free (PFS) at three months. Results Twenty patients of a median age of 71 years (r: 54–83) were enrolled after a median of one prior treatment line (r:1–2). One patient was considered non-evaluable. No ORs were observed and only one patient had PFS ≥ 3 months. The median time on treatment was 1.68 months (r: 0.76–4.21). Toxicity consisted mostly of grade 1–2 fatigue, anorexia and nausea. Five patients had isolated troponin I increases (with no ECG or LVEF findings). Hematological toxicity was mild, one patient had grade 3 neutropenia and one patient had grade 3 thrombocytopenia. Conclusion Only one patient reached the primary endpoint (TCR) during the first stage; consequently, the study was closed and no further development was considered. Disclosure All authors have declared no conflicts of interest.