FUZE clinical trial: a phase 2 study of Debio 1347 in FGFR fusion-positive advanced solid tumors irrespectively of tumor histology.

Abstract

TPS3157 Background: Dysregulation of fibroblast growth factor receptor (FGFR) signaling by FGFR fusions is implicated in many cancers. Debio 1347 is a selective oral inhibitor of FGFR 1-3 tyrosine kinases. It exhibited high antitumor activity in in vitro and in vivo tumor models with FGFR1-3 gene fusions. Preliminary data from an ongoing phase 1 trial show efficacy and tolerability in patients (pts) harboring FGFR 1-3 fusion irrespectively of tumor type. We present the design for a multicenter, basket, 2-stage, adaptive single arm Phase 2 trial investigating Debio 1347 in pts with solid tumors harboring FGFR1-3 fusion/rearrangement. Methods: Adults with locally advanced/unresectable or metastatic tumors with documented FGFR1-3 gene fusion/rearrangement who require systemic therapy and have progression after ≥1 prior standard treatment or have no satisfactory alternative treatment option are eligible. Three cohorts are included: biliary tract cancer (cohort 1), urothelial cancer (cohort 2) and all other solid tumors (cohort 3). Primary brain tumors are excluded. Other key exclusion criteria include prior treatment with FGFR1-3 selective inhibitor; clinically significant corneal/retinal disorder; history of calcium/phosphate homeostasis disorder or systemic mineral imbalance with ectopic soft tissue calcification, and symptomatic/unstable brain metastases < 1 month before enrollment. Genomic screening of tumor tissue is done at local or central laboratory with post-hoc central confirmation by RNA sequencing. Eligible pts will receive Debio 1347, 80 mg PO once daily in 28-day cycles until occurrence of progression or unacceptable toxicity. Primary Endpoint is objective response rate (ORR) based on independent central review using RECIST v.1.1. The targeted sample size (N=125) will provide approximately 90% power to reject H0: ORR ≤ 15% at an overall 5% significance level based on an expected ORR of 30% in at least one of the cohorts. Secondary endpoints are: duration of response, disease control rate, progression-free survival, overall survival, safety, tolerability, and quality of life. An interim analysis for futility and homogeneity will be performed after 27 evaluable pts. PK sparse sampling is performed to assess exposure-response relationships with efficacy and safety. Biomarkers of response and resistance will be explored. Accrual is opened in US, EU, Asia and Australia. Clinical trial information: NCT03834220.