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

Phase 1

Recruiting

• Conditions: Urothelial Carcinoma; Solid Tumor, Adult; Non-muscle-invasive Bladder Cancer; Advanced Urothelial Carcinoma; Locally Advanced Urothelial Carcinoma; Metastatic Urothelial Carcinoma; Advanced Solid Tumor; Solid Tumor; Urinary Tract Cancer; Urinary Tract Tumor
• Interventions: Drug: TYRA-300

• Registration Number: NCT05544552
• Lead Sponsor: Tyra Biosciences, Inc

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.

Study Timeline

• Study First Submitted: 2022-09-06
• Study First Submitted QC: 2022-09-15
• Study First Posted: 2022-09-16
• Study Start: 2022-11-22
• Status Verified: 2024-10
• Last Update Submitted: 2024-10-01
• Last Update Posted: 2024-10-03
• Primary Completion: 2026-11
• Study Completion: 2027-06

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 310

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 18 years of age or older.

• ECOG performance status of 0-2 or Karnofsky Performance Scale (KPS) >70.

• 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.

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Phase 1 Part A - dose escalation	TYRA-300	TYRA-300 taken once daily by mouth in 28-day cycles starting at 10 mg daily.
Phase 1 Part B - dose expansion	TYRA-300	TYRA-300 taken once or twice daily by mouth in 28-day cycles.
Phase 2	TYRA-300	TYRA-300 taken once or twice daily by mouth in 28-day cycles at doses determined during Phase 1.

Primary Outcome Measures

Name	Time	Method
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 1 Part A: To determine the maximum tolerated doses (MTD).	Initiation of study treatment through 28 days.
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

Name	Time	Method
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.
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).
Pharmacokinetics: maximum plasma concentration (Cmax).	Initiation of study treatment through Cycle 3 Day 1 (each cycle is 28 days).
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: time to reach maximum plasma concentration (Tmax).	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).
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)].
Pharmacokinetics: area under the plasma concentration-time curve (AUC).	Initiation of study treatment through Cycle 3 Day 1 (each cycle is 28 days).

Trial Locations

Locations (21)

Cleveland Clinic - Main Campus; 🇺🇸 Cleveland, Ohio, United States

Dana Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

UMass Memorial Medical Center; 🇺🇸 Worcester, Massachusetts, United States

Macquarie University; 🇦🇺 Macquarie Park, New South Wales, Australia

Princess Alexandra Hospital; 🇦🇺 Woolloongabba, Queensland, Australia

Institut de Cancerologie de L'Ouest (ICO); 🇫🇷 Saint Herblain, France

Institut Claudius Regaud, IUCT-Oncopole; 🇫🇷 Toulouse, France

Memorial Sloan Kettering Cancer Center (MSKCC); 🇺🇸 New York, New York, United States

Gustave Roussy (Institut de Cancerologie Gustave-Roussy); 🇫🇷 Villejuif, France

NEXT Barcelona - Hospital Quironsalud Barcelona; 🇪🇸 Barcelona, Spain

NEXT Madrid - Hospital Universitario Quironsalud Madrid; 🇪🇸 Madrid, Spain

Vall d'Hebron Institut d'Oncologia (VHIO); 🇪🇸 Barcelona, Spain

Florida Cancer Affiliates - Ocala - Main (Ocala Oncology - Ocala); 🇺🇸 Ocala, Florida, United States

Prisma Health Cancer Institute - Faris; 🇺🇸 Greenville, South Carolina, United States

Seattle Cancer Care Alliance (SCCA) - South Lake Union; 🇺🇸 Seattle, Washington, United States

Peter MacCallum Cancer Research Unit; 🇦🇺 Melbourne, Victoria, Australia

Linear Clinical Research Limited; 🇦🇺 Nedlands, Western Australia, Australia

Duke Cancer Institute (DCI) - Duke Cancer Center; 🇺🇸 Durham, North Carolina, United States

Vanderbilt University Medical Center (VUMC) - Vanderbilt-Ingram Cancer Center (VICC) - Nashville; 🇺🇸 Nashville, Tennessee, United States

Tasman Oncology; 🇦🇺 Southport, Queensland, Australia

Austin Health; 🇦🇺 Heidelberg, Victoria, Australia