Clinical trial NCT06915753: Safety and Preliminary Anti-Tumor Activity of TYRA-430 in Advanced Hepatocellular Carcinoma and Other Solid Tumors With Activating FGF/FGFR Pathway Aberrations
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Metastatic Hepatocellular Carcinoma
Solid Tumors
Solid Tumor, Adult
FGFR Gene Amplification
FGFR Gene Alterations
FGFR3 Gene Alteration
FGFR3 Gene Mutation
Advanced Solid Tumors
FGFR4 Gene Mutation
FGFR4 Gene Fusions
FGF19 Gene Amplification
FGF19 Gene Overexpression
FGFR3 Gene Fusions
Locally Advanced Unresectable Hepatocellular Carcinoma
Keywords: Hepatocellular Carcinoma
metastatic cancer
solid tumors
FGF19 gene amplifications
FGFR4 gene alterations
FGFR3 gene alterations
FGF19 gene alterations
FGFR4 gene mutations
FGFR4 gene fusions
FGFR3 gene mutations
FGFR3 gene fusions
FGF19 gene overexpression
locally advanced unresectable cancer
Lead sponsor: Tyra Biosciences, Inc
Sponsor class: INDUSTRY
First posted: 2025-04-08
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Maximum tolerated dose (MTD)
timeFrame: Up to 1 year
measure: Rate and severity of adverse events of TYRA-430 as monotherapy
timeFrame: First dose of study drug through 28 days after the last dose of study drug
measure: Recommended Phase 2 dose(s) of TYRA-430
timeFrame: Up to 2 years
Secondary outcomes:
measure: Cmax
timeFrame: Up to 2 years
measure: Tmax
timeFrame: Up to 2 years
measure: AUC0-last
timeFrame: Up to 2 years
measure: AUCTau
timeFrame: Up to 2 years
measure: AUC0-∞
timeFrame: Up to 2 years
measure: Vd/F
timeFrame: Up to 2 years
measure: CL/F
timeFrame: Up to 2 years
measure: t1/2
timeFrame: Up to 2 years
measure: Overall Response Rate (ORR)
timeFrame: Up to 3.5 years
measure: Duration of Response (DOR)
timeFrame: Up to 3.5 years
measure: Disease Control Rate (DCR)
timeFrame: Up to 3.5 years
measure: Time to Response (TTR)
timeFrame: Up to 3.5 years
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: USC Norris Comprehensive Cancer Center
state: California
city: Stanford
country: United States
facility: Stanford Cancer Institute
state: California
city: Baltimore
country: United States
facility: John Hopkins University
state: Maryland
city: Boston
country: United States
facility: Mass General Cancer Center
state: Massachusetts
city: Toronto
country: Canada
facility: University Health Network Princess Margaret Cancer Center
state: Ontario
Study officials:
affiliation: Tyra Biosciences, Inc
name: Doug Warner, MD
role: STUDY_CHAIR
References: