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

Tyra Biosciences

Status and phase: Enrolling; Phase 1

Conditions: FGFR3 Gene Alteration; Locally Advanced Unresectable Hepatocellular Carcinoma; FGFR3 Gene Fusions; Solid Tumor, Adult; FGFR3 Gene Mutation; Metastatic Hepatocellular Carcinoma; Solid Tumors; FGFR Gene Amplification; FGFR Gene Alterations; FGF19 Gene Overexpression; FGFR4 Gene Mutation; Advanced Solid Tumors; FGFR4 Gene Fusions; FGF19 Gene Amplification

Treatments: Drug: TYRA-430

Study type: Interventional

Funder types: Industry

Identifiers

NCT06915753

TYR430-101

Details and patient eligibility

About

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.

Full 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.

Enrollment: 100 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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100 participants in 3 patient groups

Part A - Dose Escalation

Experimental group

Description:

Dose escalation of TYRA-430 as monotherapy at various dose levels.

Treatment:

Drug: TYRA-430

Part B - Cohort 1 Dose Expansion

Experimental group

Description:

Dose expansion group for TYRA-430 monotherapy in advanced HCC at a dose(s) determined in Part A.

Treatment:

Drug: TYRA-430

Part B - Cohort 2 Dose Expansion

Experimental group

Description:

Dose expansion group for TYRA-430 monotherapy in advanced solid tumors at a dose(s) determined in Part A.

Treatment:

Drug: TYRA-430