Safety and Anti-Tumor Activity of TYRA-200 in Advanced Cholangiocarcinoma With Activating FGFR2 Gene Alterations

The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of TYRA-200 in cancers with FGFR2 activating gene alterations, including unresectable locally advanced/metastatic intrahepatic cholangiocarcinoma and other advanced solid tumors.

This is a single arm, multi-part, phase 1 clinical trial studying TYRA-200, a novel, potent fibroblast growth factor receptor (FGFR) 1/2/3 tyrosine kinase inhibitor, in unresectable locally advanced/metastatic intrahepatic cholangiocarcinoma and other advanced solid tumors with activating alterations in FGFR2. Part A is a dose escalation study in participants with any advanced solid tumor with FGFR/FGF pathway alterations who have exhausted approved standard therapies. Part A will evaluate the safety, tolerability, and PK of TYRA-200 to determine the optimal and maximum tolerated dose (MTD). Part B will evaluate the preliminary antitumor activity of TYRA-200 in participants with unresectable locally advanced/metastatic intrahepatic cholangiocarcinoma who have previously received an FGFR inhibitor and have FGFR2 kinase-domain mutations resistant to other FGFR inhibitors.

Eligibility Criteria:
Inclusion Criteria:

Phase 1 Part A

* Men and women 18 years of age or older.
* Eastern Cooperative Oncology Group (ECOG) performance status of ≤1.
* Any histologically confirmed advanced solid tumor with FGFR/FGF pathway alterations including FGFR gene mutations, fusions, and amplifications, as well as gene amplifications of FGFR ligands, who have exhausted or refused approved standard therapies.
* Evaluable disease according to RECIST v1.1.

Phase 1 Part B

* Men and women 18 years of age or older.
* Eastern Cooperative Oncology Group (ECOG) performance status of ≤1.
* Histologically confirmed locally advanced/metastatic intrahepatic cholangiocarcinoma with a previously identified FGFR2 gene mutation or rearrangement.
* Must have received a prior FGFR inhibitor. Participants may have received more than 1 prior FGFR inhibitor.
* Presence of an FGFR2 kinase domain mutation that confers resistance to previous/other FGFR inhibitors; resistance mutations should be identified by a US Food and Drug Administration authorized/approved companion diagnostic or a Clinical Laboratory Improvement Amendments (CLIA) validated local test performed in a certified laboratory.
* At least 1 measurable lesion by RECIST v1.1.

Exclusion Criteria:

* 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.
* Any ocular condition likely to increase the risk of eye toxicity.
* History of or current uncontrolled cardiovascular disease.
* Active, symptomatic, or untreated brain metastases.
* Gastrointestinal disorders that will affect oral administration or absorption of TYRA-200.
* Females who are pregnant, breastfeeding, or planning to become pregnant and males who plan to father a child while enrolled in this study.