Safety and Preliminary Anti-Tumor Activity of TYRA-300 in Advanced Urothelial Carcinoma and Other Solid Tumors With FGFR3 Gene Alterations

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of TYRA-300 in cancers with FGFR3 activating gene alterations, including locally advanced/metastatic urothelial carcinoma of the bladder and urinary tract and other advanced solid tumors.

Detailed Description
-----------------
This is a single arm, multi-part, phase 1/2 global trial studying TYRA-300, a novel, potent fibroblast growth factor receptor (FGFR) 3-selective tyrosine kinase inhibitor, in advanced/metastatic urothelial carcinoma of the bladder and urinary tract, that contain activating gene alterations of FGFR3. Phase 1 is a dose-escalation study to evaluate the safety, tolerability, and PK of TYRA-300 to determine the optimal and maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Phase 2 will evaluate the preliminary antitumor activity of TYRA-300 in cancers with FGFR3 activating gene alterations, including locally advanced/metastatic urothelial carcinoma of the bladder and urinary tract and other advanced solid tumors.

Official Title
-----------------
A Multicenter, Open-label Phase 1/2 Study of TYRA300 in Advanced Urothelial Carcinoma and Other Solid Tumors With Activating FGFR3 Gene Alterations (SURF301)

Conditions
-----------------
Solid Tumor, Adult, Locally Advanced Urothelial Carcinoma, Metastatic Urothelial Carcinoma, Solid Tumor, Urothelial Carcinoma, Bladder Cancer, Non-muscle-invasive Bladder Cancer, FGFR3 Gene Mutation, FGFR3 Gene Alteration, Advanced Solid Tumor, Advanced Urothelial Carcinoma, Urinary Tract Cancer, Urinary Tract Tumor, Urinary Tract Carcinoma

Intervention / Treatment
-----------------
* Drug: TYRA-300


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Phase 1 Part A and Part B Men and women 18 years of age or older. Eastern Cooperative Oncology Group (ECOG) performance status of ≤1. Histologically confirmed advanced solid tumor who have exhausted standard therapeutic options. Evaluable (Part A) or measurable (Part B) disease according to RECIST v1.1. Histologically confirmed advanced solid tumor with an eligible FGFR3 gene mutation or fusion (Part B). Phase 2 Men and women 12 years of age or older. ECOG performance status of 0-2 or Karnofsky Performance Scale (KPS) >70 for participants aged 12 to 17 years. At least 1 measurable lesion by RECIST v1.1. Histologically confirmed locally advanced/metastatic tumor in one of the following categories: Urothelial carcinoma with an eligible FGFR3 gene mutation or rearrangement who have progressed on a prior FGFR inhibitor and presence of a resistance mutation or other kinase domain mutation. Urothelial carcinoma with an eligible FGFR3 gene mutation or rearrangement who has not received a prior FGFR inhibitor. Any solid tumor with an eligible FGFR3 gene mutation or rearrangement. Exclusion Criteria (All Phases): 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-300. Females who are pregnant, breastfeeding, or planning to become pregnant and males who plan to father a child while enrolled in this study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 Part A - dose escalation<br>TYRA-300 taken once daily by mouth in 28-day cycles starting at 10 mg daily. | Drug: TYRA-300<br>* TYRA-300 is an oral, novel potent FGFR 3-selective tyrosine kinase inhibitor that targets tumors that contain activating gene alterations of FGFR3.<br>|
| Experimental: Phase 1 Part B - dose expansion<br>TYRA-300 taken once daily by mouth in 28-day cycles. | Drug: TYRA-300<br>* TYRA-300 is an oral, novel potent FGFR 3-selective tyrosine kinase inhibitor that targets tumors that contain activating gene alterations of FGFR3.<br>|
| Experimental: Phase 2<br>TYRA-300 taken once daily by mouth in 28-day cycles at doses determined during Phase 1. | Drug: TYRA-300<br>* TYRA-300 is an oral, novel potent FGFR 3-selective tyrosine kinase inhibitor that targets tumors that contain activating gene alterations of FGFR3.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1 Part A: To determine the maximum tolerated doses (MTD). |  | Initiation of study treatment through 28 days. | 
| Phase 1 Part B: To determine the recommended Phase 2 dose (R2PD). |  | Initiation of study treatment through 28 days (up to approximately 18 months). | 
| Phase 2: Overall Response Rate (ORR), defined by RECIST v1.1. |  | Initiation of study treatment until disease progression, death, unacceptable toxicity, or withdrawal (up to 2 years). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events (AEs) and serious adverse events (SAEs) as a measure of safety and tolerability. |  | Initiation of study treatment through 28-days post treatment (up to 2 years). | 
| Frequency in changes in laboratory parameters and physical signs of toxicity. |  | Initiation of study treatment through 28-days post treatment (up to 2 years). | 
| Pharmacokinetics: maximum plasma concentration (Cmax). |  | Initiation of study treatment through Cycle 3 Day 1 (each cycle is 28 days). | 
| Pharmacokinetics: time to reach maximum plasma concentration (Tmax). |  | Initiation of study treatment through Cycle 3 Day 1(each cycle is 28 days). | 
| Pharmacokinetics: area under the plasma concentration-time curve (AUC). |  | Initiation of study treatment through Cycle 3 Day 1 (each cycle is 28 days). | 
| Pharmacokinetics: half-life of TYRA-300 (t1/2). |  | Initiation of study treatment through Cycle 3 Day 1 (each cycle is 28 days). | 
| ORR is 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 will be 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 is 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 is defined as time to first CR or PR that is subsequently confirmed according to RECIST v1.1. |  | Up to 5 years. | 
| Progression-free survival is 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)]. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
bladder, FGFR3 gene activation, FGFR3 gene alterations, FGFR3 gene fusion/rearrangement, FGFR3 gene mutation, FGFR3 gene translocation, FGFR3 positive, Fibroblast growth factor receptor 3 (FGFR3), Fibroblast growth factor receptor 3 alterations, locally advanced cancer, metastatic cancer, solid tumors, urothelial cancer, urothelial carcinoma, Urinary tract cancer, Urinary tract tumor, Urinary tract carcinoma