Safety and Preliminary Anti-Tumor Activity of TYRA-430 in Advanced Hepatocellular Carcinoma and Other Solid Tumors With Activating FGF/FGFR Pathway Aberrations (SURF431)

A Multicenter, Open-label, First-in-Human Study of TYRA-430 in Advanced Hepatocellular Carcinoma and Other Solid Tumors With Activating FGF/FGFR Pathway Aberrations

A Phase 1 study to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamic (PD), and preliminary antitumor activity of TYRA-430 in cancers with FGF/FGFR pathway aberrations, including locally advanced/metastatic hepatocellular carcinoma and other advanced solid tumors.

Study Overview

• Status: Recruiting
• Conditions: Advanced Solid Tumors; Solid Tumors; Solid Tumor, Adult; FGFR Gene Amplification; FGFR3 Gene Mutation; Metastatic Hepatocellular Carcinoma; FGFR3 Gene Alteration; FGFR Gene Alterations; FGFR4 Gene Mutation; FGFR4 Gene Fusions; FGF19 Gene Amplification; FGF19 Gene Overexpression; FGFR3 Gene Fusions; Locally Advanced Unresectable Hepatocellular Carcinoma
• Intervention / Treatment: Drug: TYRA-430

Detailed Description

This is an open-label, multi-center, first-in-human, Phase 1 global study of TYRA-430, a first-in-class, selective, reversible fibroblast growth factor receptor (FGFR) 4 and 3 inhibitor, in locally advanced/metastatic hepatocellular carcinoma and other advanced solid tumors that contain FGF/FGFR pathway aberrations.

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Grace Indyk; Phone Number: 858-356-2323; Email: TyraClinicalTrials@tyra.bio

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2C4
      • Recruiting
      • University Health Network Princess Margaret Cancer Center
      • Contact: Arndt Vogel, MD; Email: arndt.vogel@uhn.ca
• South Korea
  • Seoul, South Korea
    • Recruiting
    • Samsung Medical Center
  • Seoul, South Korea
    • Recruiting
    • Seoul National University Hospital
  • Seoul, South Korea
    • Recruiting
    • Asan Medical Center
  • Seoul, South Korea
    • Recruiting
    • Severance Hospital, Yonsei University Health System
• Taiwan
  • Taipei, Taiwan
    • Recruiting
    • Taipei Veterans General Hospital
  • Taipei, Taiwan
    • Recruiting
    • National Taiwan University Hospital
• United States
  • California
    • Los Angeles, California, United States, 90033
      • Recruiting
      • Usc Norris Comprehensive Cancer Center
      • Contact: Negeen Izadian; Email: Negeen.Izadian@med.usc.edu
      • Contact: Lorraine Martinez Seng; Email: Lorraine.Martinez@med.usc.edu
    • San Francisco, California, United States, 94158
      • Recruiting
      • UCSF Medical Center at Mount Zion
    • Stanford, California, United States, 94305
      • Recruiting
      • Stanford Cancer Institute
      • Contact: Swetha Vadde; Email: svadde@stanford.edu
  • Kansas
    • Westwood, Kansas, United States, 66205
      • Recruiting
      • The University of Kansas Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Recruiting
      • John Hopkins University
      • Contact: Email: phase1trials@jh.edu
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Recruiting
      • Mass General Cancer Center
      • Contact: Ilyas Sahin, MD; Phone Number: 617-724-4000; Email: isahin@mgh.harvard.edu
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Recruiting
      • Karmanos Cancer Institute
  • New York
    • New York, New York, United States, 10043
      • Recruiting
      • Columbia University Irving Medical Center
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Recruiting
      • Sarah Cannon Research Institute Oncology Partners

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

All Patients:

• Age ≥ 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤1.
• Adequate end organ function.
• Ability to swallow oral formulations.
• Ability to understand and willingness to sign the ICF.

Part A:

• Histologically confirmed locally advanced unresectable/metastatic HCC or histologically confirmed advanced solid tumor with documented FGF/FGFR pathway alterations

• For participants with histologically confirmed locally advanced or metastatic HCC:

  • Barcelona Clinic Liver Cancer (BCLC) stage B that is not eligible for locoregional therapy, or stage C.
  • Child-Pugh Score class A
• Must have previously received SOC appropriate for their tumor type. Any number of prior therapies, including FGFR inhibitors, are permitted.
• Agree to provide archival tumor tissue no older than 2 years from the time of enrollment, if available. If an archived specimen is not available, a biopsy is not required.

Part B, Cohort 1:

• Histologically confirmed locally advanced/metastatic HCC who have previously received standard of care.
• Barcelona Clinic Liver Cancer (BCLC) stage B that is not eligible for locoregional therapy, or stage C.
• Child-Pugh Score class A
• Availability of an archival formalin-fixed paraffin-embedded (FFPE) tumor tissue specimen obtained ≤2 years prior to screening for submission to sponsor-designated central laboratory for FGF19 IHC testing.
• At least 1 measurable lesion by RECIST v1.1.

Part B, Cohort 2:

• Histologically confirmed advanced solid tumor except FGFR3-altered urothelial carcinoma and primary central nervous system tumors who have previously received standard of care. Note: Participants with confirmed diagnosis of locally advanced or metastatic HCC are not eligible for Cohort 2.
• Must have an eligible activating gain-of-function alteration in the FGFR3 or FGFR4 gene, or focal amplifications of FGF19
• Archival tumor tissue biopsy specimen no older than 2 years from the time of enrollment, if available. If a tissue biopsy specimen is not available, a biopsy is not required.
• At least 1 measurable lesion by RECIST v1.1.

Key Exclusion Criteria:

All Patients:

• Have disease that is suitable for local therapy administered with curative intent.
• Have not recovered from reversible toxicity of prior anticancer therapy to < Grade 1 or baseline (except toxicities that are not clinically significant or not expected to resolve, including but not limited to, alopecia, fatigue, skin discoloration, or Grade 1 neuropathy).

• Have received the following anticancer therapy:

  1. Any immunotherapy or other antibody therapy within 28 days prior to the first dose of the study drug.
  2. A TKI < 5 days or 5X the terminal Phase elimination half-lives, whichever is longer, prior to the first dose of TYRA-430.
  3. Other systemic therapy not listed above < 14 days prior to the first dose of the study drug.
• Participant discontinued a prior anti-FGFR therapy due to significant toxicity, defined as hepatotoxicity ≥ Grade 3 or any Grade 4 toxicity according to CTCAE v5.0.
• Has a serum phosphorus level > upper limit of normal (ULN) during screening that remains >ULN despite medical management.
• History of or current uncontrolled cardiovascular disease.
• Active, symptomatic, or untreated brain metastases.
• Have a diagnosis of primary CNS malignancies.
• Gastrointestinal disorders that will affect oral administration or absorption of TYRA-430.
• Females who are pregnant, breastfeeding, or planning to become pregnant and males who plan to father a child while enrolled in this study.
• Any reason that, in the view of investigator, would substantially impair the ability of the participant to comply with study procedures and increase the risk to the participant.

Part B, Cohort 1:

• Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.
• Prior treatment with pan-FGFR inhibitors or FGFR4-selective inhibitors.

Part B, Cohort 2:

• Histologically confirmed locally advanced/metastatic HCC.
• Histologically confirmed urothelial cancer.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A - Dose Escalation; Dose escalation of TYRA-430 as monotherapy at various dose levels.	Drug: TYRA-430; Oral TYRA-430 given daily.
Experimental: Part B - Cohort 1 Dose Expansion; Dose expansion group for TYRA-430 monotherapy in advanced HCC at a dose(s) determined in Part A.	Drug: TYRA-430; Oral TYRA-430 given daily.
Experimental: Part B - Cohort 2 Dose Expansion; Dose expansion group for TYRA-430 monotherapy in advanced solid tumors at a dose(s) determined in Part A.	Drug: TYRA-430; Oral TYRA-430 given daily.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum tolerated dose (MTD)	MTD determination: dose limiting toxicity (DLT) rate in the first 28-day cycle	Up to 1 year
Rate and severity of adverse events of TYRA-430 as monotherapy	Number of participants with TEAEs as assessed by CTCAE, v5.0	First dose of study drug through 28 days after the last dose of study drug
Recommended Phase 2 dose(s) of TYRA-430	To determine recommended Phase 2 dose(s) of TYRA-430	Up to 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cmax		Up to 2 years
Tmax		Up to 2 years
AUC0-last		Up to 2 years
AUCTau		Up to 2 years
AUC0-∞		Up to 2 years
Vd/F		Up to 2 years
CL/F		Up to 2 years
t1/2		Up to 2 years
Overall Response Rate (ORR)	The proportion of patients who experience a best response of confirmed CR or PR per RECIST 1.1	Up to 3.5 years
Duration of Response (DOR)	Time from first investigator-assessed response to radiographic disease progression or death.	Up to 3.5 years
Disease Control Rate (DCR)	Best response of CR, PR, or SD per RECIST v1.1 > 12 months.	Up to 3.5 years
Time to Response (TTR)	The median time from the start of therapy to first response in confirmed responders.	Up to 3.5 years

Collaborators and Investigators

• Sponsor: Tyra Biosciences, Inc
• Investigators: Study Chair: Doug Warner, MD, Tyra Biosciences, Inc

Study record dates

Study Major Dates

• Study Start (Actual): April 24, 2025
• Primary Completion (Estimated): January 1, 2028
• Study Completion (Estimated): September 1, 2028

Study Registration Dates

• First Submitted: March 31, 2025
• First Submitted That Met QC Criteria: March 31, 2025
• First Posted (Actual): April 8, 2025

Study Record Updates

• Last Update Posted (Actual): November 20, 2025
• Last Update Submitted That Met QC Criteria: November 18, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: Hepatocellular Carcinoma; metastatic cancer; solid tumors; FGFR3 gene alterations; FGF19 gene amplifications; FGFR4 gene alterations; FGF19 gene alterations; FGFR4 gene mutations; FGFR4 gene fusions; FGFR3 gene mutations; FGFR3 gene fusions; FGF19 gene overexpression; locally advanced unresectable cancer
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Digestive System Neoplasms; Digestive System Diseases; Liver Diseases; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Liver Neoplasms; Neoplastic Processes; Carcinoma; Pathological Conditions, Signs and Symptoms; Carcinoma, Hepatocellular; Neoplasm Metastasis
• Other Study ID Numbers: TYR430-101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No