Background: FGFR inhibition is a promising and clinically proven therapeutic approach in a number of solid tumors where genetic alterations of FGFR drive oncogenesis. PRN1371 is a highly selective oral, irreversible inhibitor of FGFR1-4 that exhibits high potency in cancer cell lines harboring FGFR alterations, including mutations and fusions.

Methods: Part A of this phase 1 open-label, multicenter clinical trial explored ascending doses of PRN1371 in adult patients with advanced solid tumors who had received at least one prior treatment for recurrent, metastatic, and/or locally advanced disease, and for whom no standard therapy options were anticipated to result in a durable remission. The primary objectives were to investigate the safety and tolerability and determine the maximum tolerated dose (MTD). Secondary objectives included determination of the pharmacokinetic (PK) profile. The trial employed a “3 + 3” design, where cohorts of three patients are studied at each dose level until additional patients need to be added to better assess safety. PRN1371 was dosed once or twice daily in continuous, 28-day cycles until disease progression. Elevated serum phosphorus, a known effect of systemic FGFR inhibition, was managed with oral phosphate-binding medications and a low phosphate diet, with dose interruptions and use of acetazolamide if certain thresholds were exceeded.

Results: In part A, PRN1371 was administered to 36 patients in cohorts at doses of 15mg, 20mg, 25mg, and 35mg QD as well as BID doses of 15mg and 25mg. The drug has been generally well tolerated. The most common side effect observed was hyperphosphatemia, which was generally managed by administration of phosphate binders, and there were no treatment-related adverse events leading to study drug discontinuation. Five of 36 patients reported treatment-related serious adverse events (SAEs). PRN1371 was well absorbed, exhibited moderate PK variability with minimal accumulation, and was approximately dose proportional between 15 and 35mg doses. Exposure of parent drug in urine exceeded the cellular IC90 at all dose levels, which may be particularly relevant for localized bladder cancer. Part B of the study has been initiated, which will enroll patients with metastatic urothelial cell carcinoma (mUC) with FGFR1, 2, 3, or 4 genetic alterations.

Citation Format: Sarina A. Piha-Paul, Cinta Hierro, Ignacio Matos, Valentina Boni, Noah Hahn, Rhonda Bitting, Todd Bauer, Aggarwal Rahul, Funda Meric-Bernstam, Steven Gourlay, Timothy D. Owens, Ken Brameld, Ann Neale, Richard Schwartz, Steve Murray, Sibel Ucpinar, Peter Foote, Eleni Venetsanakos, Josep Tabernero. A phase 1, multicenter, dose-escalation study of PRN1371, an irreversible covalent FGFR1-4 kinase inhibitor, in patients with advanced solid tumors including metastatic urothelial carcinoma (mUC) [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr A19.