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

Prior treatment

• 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:
  • Any immunotherapy or other antibody therapy within 28 days prior to the first dose of the study drug.
  • A TKI \< 5 days or 5X the terminal Phase elimination half-lives, whichever is longer, prior to the first dose of TYRA-430.
  • 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
• Prior treatment with pan-FGFR inhibitors or FGFR4-selective inhibitors.
  • Part B, Cohort 2:

Other illness

• Have disease that is suitable for local therapy administered with curative intent.
• History of or current uncontrolled cardiovascular disease.
• Have a diagnosis of primary CNS malignancies.
• Gastrointestinal disorders that will affect oral administration or absorption of TYRA-430.
• Histologically confirmed urothelial cancer.

Lab values

• Has a serum phosphorus level \> upper limit of normal (ULN) during screening that remains \>ULN despite medical management.

Other

• All Patients:
• Active, symptomatic, or untreated brain metastases.
• 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.
• Histologically confirmed locally advanced/metastatic HCC.

• 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, 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 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 FGFR4 gene, or focal amplifications of FGF19
• Archival tumor tissue biopsy specimen , if available. If a tissue biopsy specimen is not available, a biopsy is not required.
• At least 1 measurable lesion by RECIST v1.1.