130TiP - Phase I study evaluating KIN-3248, a next-generation, irreversible pan-FGFR inhibitor, in patients with advanced cholangiocarcinoma, urothelial carcinoma and other solid tumors harboring FGFR2 and/or FGFR3 gene alterations

Background

Preclinical and clinical evidence indicates that activating FGFR1-4 gene alterations drives oncogenesis and tumor growth. Pharmacological inhibition of FGFR1-4 leads to tumor shrinkage and disease control, supporting development of FGFR inhibitors. A critical limitation of currently approved, clinical-stage FGFRi is the emergence of secondary, on-target resistance mutations (mutn) that reduce duration of response. About 70% of cholangiocarcinoma (CCA) patients treated with 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, 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 (eg, gatekeeper and molecular brake) in human cancer cells and PDX models.

Trial design

KN-4802 (NCT05242822) is a first in human, multicenter, Ph1 study of KIN-3248 in pts with advanced and metastatic solid tumors (AMST) harboring FGFR2 and/or FGFR3 gene alterations. KIN-3248 is given continuously in 28-day cycles until drug intolerance or disease progression. The study is conducted in 2 parts: Part A is a dose escalation of KIN-3248 to MTD/RP2D. Part B evaluates a selected dose of KIN-3248 in previously treated intrahepatic cholangiocarcinoma (ICC) or urothelial carcinoma (UC), treatment naïve ICC or UC, or other AMST. Enrollment criteria include ECOG PS 0-1 and prior standard treatment with clinical benefit, if appropriate. Primary endpoints are safety and preliminary antitumor activity. Secondary objectives include pharmacokinetic and pharmacodynamic assessments including measures of FGFR pathway modulation. Planned sample size is 140 pts and the study is enrolling patients in the US, EU and globally.

Clinical trial identification

NCT05242822.

Editorial acknowledgement

Legal entity responsible for the study

Kinnate Biopharma Inc.

Funding

Kinnate Biopharma Inc.

Disclosure

B. Garmezy: Financial Interests, Institutional, Research Grant: AbbVie, AstraZeneca, CRISPR Therapeutics, Exelixis, Genetech, Janssen, Loxo Oncology, Arcus Biosciences, Xencor, Aveo Oncology, Zenshire, Accutar Biotechnology, Kinnate Biopharma, Jubilant Therapeutics, Janux Therapeutics, Mink Therapeutics, Nuvation Bio, Profound Bio, Kineta; Financial Interests, Institutional, Other, Consulting: Amgen, Arvin's, Aveo, Bayer, Exelixis, Janssen, Merck, Sanofi-Aventis. M. Borad: Financial Interests, Institutional, Research Funding: Kinnate Biopharma. C. Lin: Financial Interests, Personal, Other, Travel support: BeiGene, Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Blueprint Medicines, Bristol Myers Squibb, Daiichi Sankyo, Novartis, AbbVie, PharmaEngine, Merck KGaA, Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: Eli Lilly, Novartis, Roche; Financial Interests, Personal, Other, Travel Support: IMPACT Therapeutics. L. Chen: Financial Interests, Personal, Invited Speaker: PharmaEngine (TW), ONO, BMS, Eli Lilly, Ipsen, Novartis, TTY (TW), C-Stone (TW); Financial Interests, Personal, Other, Medical Monitoring for clinical trial.: Taivex (TW); Financial Interests, Personal, Other, DSMC member for clinical trials: OBI (TW); Financial Interests, Personal, Advisory Board: MSD, AstraZeneca, SynCore (TW); Financial Interests, Personal, Advisory Board, Scientific Advisory Committee: ScinoPharm Taiwan, Onward; Financial Interests, Personal, Full or part-time Employment, Co-affiliated, Distinguished Investigator and Senior Physician Staff: National Institute of Cancer Research, National Health Research Institutes, Taiwan; Financial Interests, Personal, Full or part-time Employment, Professor of Internal Medicine: Kaohsiung Medical Univrsity Hopsital, Kaohsiung Medical University, Kaohsiung, Taiwan; Financial Interests, Personal, Member of Board of Directors, Independent Director: ScinoPharm Taiwan, Ltd.; Financial Interests, Personal, Advisory Board, Alpha-enolase specific antibodies: HuniLife Biotechnology, Inc., Taiwan; Financial Interests, Personal, Steering Committee Member, TOPAZ-1, phase III trial: AstraZeneca; Financial Interests, Personal, Steering Committee Member, ATTRACTIONs trials, ATT-2 (3L), ATT-4 (1L), ATT-5 (Adjuvant) and ATT-6 (1L).: ONO; Financial Interests, Personal, Trial Chair, SynCore CT4006, phase 3 trial: Syncore BioPharma, Taiwan; Financial Interests, Institutional, Trial Chair, Research funding and study medication for TCOG IIT.: Celgene; Financial Interests, Institutional, Trial Chair, Industry-sponsored, phase 2 bridging trial in TCOG.: TTY, Taiwan; Financial Interests, Institutional, Steering Committee Member, C3651003 (Cancer cachexia), Operations steering Committee, country lead: Pfizer; Non-Financial Interests, Principal Investigator, Investigator-initiated trials: Taiwan Cooperative Oncology Group, National Institute of Cancer Research, Taiwan; Non-Financial Interests, Institutional, Product Samples, Medication support for TCOG trial.: Syncore BioPharma, Taiwan; Non-Financial Interests, Member of Board of Directors, Managing Director: Taiwan Oncology Society, Taiwan; Non-Financial Interests, Leadership Role, President (2021.09 ∼): Taiwan NeuroEndocrine Tumor Society (TNETS); Non-Financial Interests, Member of Board of Directors: Taiwan Pancreas Society, Taiwan; Non-Financial Interests, Institutional, Product Samples, Medication for TCOG trials: TTY; Non-Financial Interests, Institutional, Product Samples, Targeted Cancer Panel NGS testing.: ACTgenomics (TW); Non-Financial Interests, Other, International Staring Committee Member (ISCM), Academic Planning Committee, JSMO: Japanese Society of Medical Oncology (JSMO); Non-Financial Interests, Leadership Role, Council Member: Asian Oncology Society (AOS). C.A. Perez: Financial Interests, Institutional, Local PI: Accutar Biotech, Kinnate Biopharma, Relay Therapeutics, Seagen Inc, Kura Oncology, Hyamab Inc, Xilio Therapeutics, Elucida Oncology, Tallac Therapeutics, Ribbon Therapeutics, Mirati Therpeutics, Elpiscience Biopharmaceuticals, Dracen Pharmaceuticals, Zhuhai Yufan Biotechnologies Co., Genentech, Inc., Jazz Pharmaceuticals, Artios Pharma. S. Kato: Financial Interests, Personal, Other, Consultant: Medpace, Foundation Medicine, Neogenomics, CureMatch; Financial Interests, Personal, Invited Speaker: Chugai, Roche/Genentech, Bayer; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Research Funding: ACT Genomics, Sysmex, Konica Minolta, OmniSeq, Personalis, Function Oncology. B. Tam: Financial Interests, Personal, Full or part-time Employment: Kinnate Biopharma; Financial Interests, Personal, Stocks/Shares: Kinnate Biopharma, Samumed. P. Severson: Financial Interests, Personal, Full or part-time Employment: Kinnate Biopharma; Financial Interests, Personal, Stocks/Shares: Kinnate Biopharma. C.S. Quah: Financial Interests, Personal, Full or part-time Employment: Kinnate Biopharma Inc; Financial Interests, Personal, Stocks/Shares: Kinnate Biopharma Inc. J.J. Harding: Financial Interests, Personal, Advisory Board: Adaptiimune, Bristol Myer Squib, CytoMx, Eisai, Exelexis, Elevar, Hepion, Eli Lilly, AstraZeneca, Medivir, QED, Sevier, Merck.