Safety and Preliminary Anti-Tumor Activity of TYRA-430 in Advanced Hepatocellular Carcinoma and Other Solid Tumors With Activating FGF/FGFR Pathway Aberrations
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.
Eligibility
Sex
ALL
Min age
18 Years
Max age
—
Healthy volunteers
No
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, 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.
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
* 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 outcome measure(s)
Maximum tolerated dose (MTD) — Up to 1 year MTD determination: dose limiting toxicity (DLT) rate in the first 28-day cycle
Rate and severity of adverse events of TYRA-430 as monotherapy — First dose of study drug through 28 days after the last dose of study drug Number of participants with TEAEs as assessed by CTCAE, v5.0
Recommended Phase 2 dose(s) of TYRA-430 — Up to 2 years To determine recommended Phase 2 dose(s) of TYRA-430
Trial sites (16)
Facility
City
Region
Status
USC Norris Comprehensive Cancer Center
Los Angeles
California
Recruiting
UCSF Medical Center at Mount Zion
San Francisco
California
Recruiting
Stanford Cancer Institute
Stanford
California
Recruiting
The University of Kansas Medical Center
Westwood
Kansas
Recruiting
John Hopkins University
Baltimore
Maryland
Recruiting
Mass General Cancer Center
Boston
Massachusetts
Recruiting
Karmanos Cancer Institute
Detroit
Michigan
Recruiting
Columbia University Irving Medical Center
New York
New York
Recruiting
Sarah Cannon Research Institute Oncology Partners
Nashville
Tennessee
Withdrawn
University Health Network Princess Margaret Cancer Center
Toronto
Ontario
Recruiting
Asan Medical Center
Seoul
South Korea
Recruiting
Samsung Medical Center
Seoul
South Korea
Recruiting
Seoul National University Hospital
Seoul
South Korea
Recruiting
Severance Hospital, Yonsei University Health System
This page summarises publicly available registry data for informational purposes — not medical advice. Eligibility is determined by each study team; patients should discuss participation with their clinician.
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