PROOF 302: A randomized, double-blind, placebo-controlled, phase III trial of infigratinib as adjuvant therapy in patients with invasive urothelial carcinoma harboring FGFR3 alterations.

Abstract

TPS600 Background: Radical surgery ± cisplatin‐based (neo)adjuvant therapy (NAT) is the mainstay of treatment for invasive urothelial carcinoma of the upper urinary tract (UTUC) or bladder (UBC), but recurrence rates are high. Furthermore, many patients (pts) are unable to receive NAT because of cisplatin ineligibility. Fibroblast growth factor receptor 3 (FGFR3) genetic alterations occur in up to 70% of UTUC and up to 20% of UBC, and may constitute a potential candidate for targeted therapy. Infigratinib (BGJ398), a selective FGFR1–3 inhibitor, has shown promising clinical activity and tolerability in pts with advanced urothelial carcinoma having FGFR3 alterations [Pal et al. Cancer Discov 2018]. PROOF 302 has been designed to investigate the efficacy and safety of infigratinib versus placebo as adjuvant therapy in pts with high-risk invasive urothelial carcinoma and FGFR3 alterations. Methods: PROOF 302 is a randomized, double-blind, placebo-controlled, phase III study of approx. 218 pts. Adults with high-risk invasive UTUC or UBC with FGFR3 genetic alterations (i.e. mutations, gene fusions or translocations) who are ≤120 days following surgical resection and ineligible for cisplatin-based adjuvant chemotherapy or with residual disease after cisplatin- based NAT are eligible. Those who received non cisplatin-based NAT are eligible if they have residual disease and are ineligible for adjuvant cisplatin. Pts receive oral infigratinib 125 mg or placebo (1:1 ratio) once daily on days 1–21 every 28 days for up to 52 weeks or until disease recurrence, unacceptable toxicity or death. Primary endpoint: centrally reviewed disease-free survival (DFS). Secondary endpoints: DFS including intraluminal low-risk recurrence; metastasis-free survival; overall survival; DFS (per investigator); safety and tolerability. Exploratory endpoints include: quality of life; pharmacokinetics; cell-free DNA (cfDNA) and/or RNA for resistance mechanisms. The study will involve approximately 120 centers worldwide. Enrollment is expected to begin in January 2020. Trial registration: EudraCT 2019-003248-63. Clinical trial information: EudraCT 2019-003248-63.