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

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.

• Phase 1 Part A - dose escalation TYRA-200 taken once daily by mouth in 28-day cycles (Drug): TYRA-200 is an oral, novel potent FGFR 1/2/3 tyrosine kinase inhibitor that targets tumors that contain activating gene alterations of FGFR2.
• Phase 1 Part B - dose expansion TYRA-200 taken once daily by mouth in 28-day cycles (Drug): TYRA-200 is an oral, novel potent FGFR 1/2/3 tyrosine kinase inhibitor that targets tumors that contain activating gene alterations of FGFR2.

Primary outcomes

• Phase 1 Part A: To determine the maximum tolerated dose (MTD) of TYRA-200. [Initiation of study treatment through 28 Days]
• Phase 1 Part B: To determine the optimal dose of TYRA-200. [Initiation of study treatment through 28 days (up to approximately 18 months]

Secondary outcomes

• Number of participants with adverse events (AEs) and serious adverse events (SAEs) as a measure of safety and tolerability. [From day 1 treatment through 28-days post treatment (up to 2 years)]
• Frequency in changes in laboratory parameters and physical signs of toxicity. [From day 1 treatment through 28-days post treatment (up to 2 years)]
• Pharmacokinetics: maximum plasma concentration (Cmax). [From Day 1 through Cycle 3 Day 1 (each cycle is 28 days)]
• Pharmacokinetics: time to reach maximum plasma concentration (Tmax). [From Day 1 through Cycle 3 Day 1 (each cycle is 28 days)]
• Pharmacokinetics: area under the plasma concentration-time curve (AUC). [From Day 1 through Cycle 3 Day 1 (each cycle is 28 days)]
• Pharmacokinetics: half-life of Tyra-200 (t1/2). [From Day 1 through Cycle 3 Day 1 (each cycle is 28 days)]
• Overall response rate (ORR) defined as the proportion of participants with complete response (CR) or partial response (PR) as determined by the investigator using RECIST V1.1. [From enrollment, every 8 or 12 weeks (up to 2 years)]
• Duration of response defined as the time from the initial CR or PR to the time of relapse or death, whichever occurs first among participant with an objective response. [From enrollment, every 8 or 12 weeks (up to 5 years)]
• Disease control rate defined as the proportion of participants having a CR, PR or stable disease (SD) for >12 weeks. [From enrollment up to 5 years]
• Time to response defined as time to first CR or PR that is subsequently confirmed according to RECIST v1.1. [Up to 5 years]
• Progression-free survival defined as the time from the date of first study drug administration to the earliest date of documented disease progression or death. [From the date of the first dose of study drug until disease progression or death as assessed up to the last efficacy assessment for disease progression (up to 5 years)]

Sex: All, ages: 18 Years to any

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.

• Doug Warner, Study chair, Tyra Biosciences, Inc