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

Eligibility Criteria

• * 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.
• * 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.
• * 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.
• * 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.
• * 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.
• * Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.
• * Prior treatment with pan-FGFR inhibitors or FGFR4-selective inhibitors.
• * Histologically confirmed locally advanced/metastatic HCC.
• * Histologically confirmed urothelial cancer.