Background: FGFR1-4 gene alterations are infrequent across solid tumors though preclinical and clinical evidence indicate activating alterations drive oncogenesis and tumor growth. Pharmacological inhibition of FGFR1-4 leads to tumor shrinkage and disease control. Reversible FGFRi are approved for the treatment of pts with locally advanced or metastatic CCA harboring FGFR2 gene fusions or rearrangements (pemigatinib and infigratinib) or metastatic urothelial carcinoma (UC) with susceptible FGFR2 or FGFR3 genetic alterations (erdafitinib). A critical limitation of current clinical-stage FGFRi is the emergence of secondary, on-target resistance mutations (mutn) that reduce duration of response, and indeed, about 70% of CCA patients treated with either reversible or irreversible FGFRi exhibit secondary FGFR2 kinase domain resistance mutn at the time of relapse. KIN-3248 is a next-generation, selective, irreversible, small molecule pan-FGFRi, structurally designed to inhibit primary FGFR oncogenic alterations as well as secondary kinase domain mutn associated with disease progression. Preclinically, KIN-3248 has favorable pharmaceutical properties, is well-tolerated with continuous, daily oral administration in GLP toxicology studies and is efficacious against primary FGFR2 and FGFR3 oncogenic driver alterations as well as secondary FGFR2 resistance mutn (e.g., gatekeeper and molecular brake) in human cancer cell and PDX models. Methods: This is a FIH, multicenter, non-randomized Ph1 study of KIN-3248 in adult pts with advanced and metastatic solid tumors (AMST) harboring FGFR2 and/or FGFR3 gene alterations. KIN-3248 is given PO QD continuously in 28-day cycles until drug intolerance or disease progression. Part A is a dose-escalation assessing single agent KIN-3248 via a BOIN design to determine the MTD/RP2D; Part B will evaluate a selected dose of KIN-3248 in 3 cohorts of pts (CCA, UC, or other AMST), each driven by specified FGFR alterations—FGFRi-naïve and -pretreated pts are eligible in both parts. Enrollment criteria include ECOG PS 0-1, intact organ function, prior receipt of standard treatment or medical judgment that such is not appropriate. Pts may have measurable or evaluable disease. Key exclusion criteria include known active brain metastases and active/uncontrolled HBV/HCV. Planned sample size is ~120 pts. Primary endpoints are safety/tolerability (Part A), and preliminary antitumor activity: objective response rate, disease control rate, duration of response, and duration of stable disease (Part B). Secondary objectives include pharmacokinetic and pharmacodynamic assessments including measures of FGFR pathway modulation. The study is actively enrolling patients in the US and globally. Clinical trial information: NCT05242822.