Efficacy and Safety of TYRA-300 in Participants With FGFR3 Altered Low Grade, Intermediate Risk Non-Muscle Invasive Bladder Cancer

A Phase 2 Multicenter, Open-Label Study Evaluating the Efficacy and Safety of TYRA-300 in Participants with FGFR3 Altered Low Grade, Intermediate Risk Non-Muscle Invasive Bladder Cancer

Inclusion criteria

• Participants age 18 and over of informed consent and willing and able to comply with all requires study procedures
• Able to understand and given written informed consent
• Participants with histologically confirmed low-grade NMIBC within 6 weeks prior to randomization with prior diagnostic biopsy/TURBT to confirm stage and grade and with at least 3 mm and no more than 12 mm total (1/2 a resectoscope loop to 2 loops, refer to Section 8.1.5) residual visible tumor as a marker lesion(s) left behind:

• Ta low grade
• T1 low grade
• Participants must have intermediate risk NMIBC, defined as having any of the following characteristics (AUA Guidelines, 2024)

• Recurrence within 1 year, LG Ta
• Solitary LG Ta >3cm
• LG Ta, multifocal
• LG T1
• Documented activating FGFR3 mutation or fusion (Appendix 4)
• Have undergone bladder mapping and identification of visible marker lesion(s) within 6 weeks prior to randomization (refer to Inclusion Criterion #3)
• No evidence of urothelial carcinoma of the upper urinary tract (confirmed by imaging) or prostatic urethra within 6 months of randomization
• No prior BCG administration within 1 year of date of consent.
• No intravesical chemotherapy within 8 weeks prior to C1D1.
• ECOG 0-1
• Pathology consistent with pure urothelial carcinoma; if mixed histology, ensure that at least 80% of the sample is urothelial
• Adequate bone marrow, liver, and renal function:

b. Bone marrow function: i. Absolute neutrophil count (ANC) > or = 1,500/mm3 ii. Platelet count > or = 75,000/mm3 iii. /hemoglobin > or = 10.0 g/dL e. Liver function: i.Total bilirubin < or = ULN ii. Alanine aminotransferase (ALT) < or = ULN iii. Aspartate aminotransferase (AST) < or = ULN f. Renal function: i. estimated glomerular filtration rate >60 mL/min calculated using the modification of diet in renal disease equation or CKD-EPI formula ii. Serum Phosphate level < or = ULN prior to starting treatment g. Coagulation i. International normalized ratio (INR) < or = 1.5 x ULN

• Ability to swallow tablets
• Participants (male and female) of child-bearing potential (including females who are post-menopausal for less than 1 year) must be willing to practice effective contraception while on treatment and be willing and able to continue contraception for 3 months (males) and 6 months (females) after the last dose of study treatment. Potential male participants should consider the potential impact of TYRA-300 on their ability to father a child and discuss options with the site study staff.
• Potential participants who are positive for human immunodeficiency virus (HIV) must have a viral load below the limits of detection and on stable antiretroviral therapy for at least 3 months prior to C1D1. NOTE: some of the compounds in antiretroviral therapy may be on the prohibited medications list. Allowances will be made to ensure the participant's HIV treatment continues uninterrupted following a discussion with the Sponsor's medical monitor. A discussion of the impact of the antiretroviral therapy on TYRA- 300 needs to be discussed with the potential participant prior to C1D1.
• Potential participants with chronic hepatitis B virus (HBV) infection with active disease should be on a suppressive antiviral therapy prior to C1D1.
• Potential participants patients with a history of hepatitis C virus (HCV) infection should have completed curative antiviral treatment and must have a HCV viral load below the limit of quantification.
• Potential participants with a history of HCV infection and on current treatment must have a HCV viral load below the limit of quantification

Exclusion criteria

• Presence of tumor in ureter or prostatic urethra:
• Current or previous history of muscle invasive bladder cancer
• Current or previous history of lymph node positive and/or metastatic bladder cancer
• Evidence of pure squamous cell carcinoma, pure adenocarcinoma or pure undifferentiated carcinoma of the bladder
• Currently receiving systemic cancer therapy (cytotoxic, immunotherapy, targeted)
• Currently receiving treatment with a prohibited therapy (refer to Section 6.7.1)
• Current or prior history of pelvic external beam radiotherapy
• Current or history of receiving a prior FGFR inhibitor
• Systemic immunotherapy within 6 months prior to randomization
• Treatment with an investigational agent within 30 days or 5 half-lives from randomization, whichever is shorter; compounds with an unknown half-life will default to the 30 days.
• Prior treatment with an intravesical agent within 8 weeks prior to C1D1
• Current ongoing toxicity from previous therapy
• Had major surgery within 4 weeks prior to C1D1
• Any reason that in the view of the investigator, would substantially impair the ability of the participant to comply with study procedures and/or risk to the participant (i.e., uncontrolled diabetes)
• Females who are pregnant, breastfeeding or planning to become pregnant within 6 months after the last dose of TYRA-300 and males who plan to father a child while enrolled in this study or within 3 months after the last dose of TYRA-300
• Has impaired wound healing capacity
• Serum phosphate levels above the upper limit of normal during screening
• Any ocular condition likely to increase the risk of eye toxicity
• Current evidence of central serous retinopathy or retinal pigmented epithelial detachment of any grade at time of baseline examination.
• History of or current uncontrolled cardiovascular disease
• Gastrointestinal disorders that will affect oral administration or absorption of TYRA-300
• Known history of HIV infection, or active hepatitis B or C
• History of a second primary malignancy within 3 years of signing ICF, except for nonmelanoma skin cancer and cured and active surveillance malignancies (i.e., prostate, breast) .
• Known allergy to TYRA-300 or any excipients of the formulated product
• Participants taking strong inhibitors and/or inducers of CYP3A4 enzyme
• History of prolonged QT syndrome or baseline heart rate-corrected QT interval using Fridericia formula (QTcF) interval >470 ms