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

Overview

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.

Interventions

• Drug TYRA-430
  Oral TYRA-430 given daily.

Primary outcome measures

• Maximum tolerated dose (MTD) [Time frame: Up to 1 year]
• Rate and severity of adverse events of TYRA-430 as monotherapy [Time frame: First dose of study drug through 28 days after the last dose of study drug]
• Recommended Phase 2 dose(s) of TYRA-430 [Time frame: Up to 2 years]

Secondary outcome measures (12)

• Cmax [Time frame: Up to 2 years]
• Tmax [Time frame: Up to 2 years]
• AUC0-last [Time frame: Up to 2 years]
• AUCTau [Time frame: Up to 2 years]
• AUC0-∞ [Time frame: Up to 2 years]
• Vd/F [Time frame: Up to 2 years]
• CL/F [Time frame: Up to 2 years]
• t1/2 [Time frame: Up to 2 years]
• Overall Response Rate (ORR) [Time frame: Up to 3.5 years]
• Duration of Response (DOR) [Time frame: Up to 3.5 years]
• Disease Control Rate (DCR) [Time frame: Up to 3.5 years]
• Time to Response (TTR) [Time frame: Up to 3.5 years]

Eligibility criteria

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.

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:

• 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, 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 9 centers

• USC Norris Comprehensive Cancer Center — Los Angeles
• UCSF Medical Center at Mount Zion — San Francisco
• Stanford Cancer Institute — Stanford
• The University of Kansas Medical Center — Westwood
• John Hopkins University — Baltimore
• Mass General Cancer Center — Boston
• Karmanos Cancer Institute — Detroit
• Columbia University Irving Medical Center — New York
• … and 1 more center

South Korea · 4 centers

• Asan Medical Center — Seoul
• Samsung Medical Center — Seoul
• Seoul National University Hospital — Seoul
• Severance Hospital, Yonsei University Health System — Seoul

Taiwan · 2 centers

• National Taiwan University Hospital — Taipei
• Taipei Veterans General Hospital — Taipei

Canada · 1 center

• University Health Network Princess Margaret Cancer Center — Toronto

Identifiers

NCT: NCT06915753 · TYR430-101

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗