Background: FGFR1-4 gene alterations are observed in approximately 7% of all human cancers. There are currently 3 FDA-approved, reversible FGFRi for treatment of patients w/previously treated, locally advanced or metastatic (met) cholangiocarcinoma (CCA) harboring FGFR2 gene fusions/rearrangements (pemigatinib and infigratinib) or met urothelial carcinoma (UC) w/susceptible FGFR2 or FGFR3 genetic alterations (erdafitinib). A major limitation of approved and clinical-stage FGFRi is emergence of secondary, on-target resistance mutations (mutn) that reduce duration of response. Up to 67% of CCA patients treated with either reversible or irrev FGFRi exhibit secondary FGFR2 kinase domain resistance mutn at the time of relapse. KIN-3248 is a next-generation, selective, irrev, small molecule pan-FGFRi, structurally designed to inhibit primary FGFR oncogenic alterations as well as secondary kinase domain mutn associated w/disease progression. Preclinically, KIN-3248 has favorable pharmaceutical properties, is well-tolerated with continuous, daily oral administration in 28d GLP toxicology studies in rats and beagle dogs 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 in vitro and in vivo. Methods: This is a FIH, multicenter, non-randomized Ph1 study of KIN-3248 in adult pts with advanced & 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. Planned sample size is approx. 120 pts: Part A is a dose-escalation to MTD for pts w/AMST having either FGFR2 and/or FGFR3 alterations. Part A assesses single agent KIN-3248; Part B will evaluate a selected dose of KIN-3248 in 3 cohorts of pts (ICC, UC, or other AMST), each driven by specified FGFR alterations. Standard Ph1 enrollment criteria are required (ECOG PS 0-1, normal 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. FGFRi-naïve & -pretreated patients are both eligible. Primary endpoints are safety/tolerability (Part A), and preliminary antitumor activity: objective response rate, disease control rate, duration of response, & duration of stable disease (Part B). Secondary objectives include pharmacokinetic and pharmacodynamic assessments including measures of FGFR pathway modulation. Enrollment is expected to commence in April 2022. Clinical trial information: NCT05242822.