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

PRIMARY OUTCOMES

Primary Outcome 1 - Measure: To assess the efficacy of TYRA-300 in LG IR-NMIBC participants

Primary Outcome 1 - Timeframe: at 3 months

CONDITION

• Low-grade NMIBC
• FGFR Gene Amplification
• FGFR Gene Alterations
• FGFR3 Gene Alteration
• FGFR3 Gene Mutation
• FGFR3 Gene Fusions

ELIGIBILITY

Inclusion Criteria:
* Participants age ≥18 at time of informed consent and willing and able to comply with all required study procedures

- * Able to understand and given written informed consent

- * Participants with histologically confirmed low-grade NMIBC within 8 weeks prior to C1D1 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 8.1.6) residual visible tumor as a marker lesion(s) left behind:
1. Ta low grade

- 2. T1 low grade

- * Participants must have protocol-defined intermediate risk NMIBC and meet at least one of the following criteria
1. Recurrence within 1 year, LG Ta

- 2. Solitary LG Ta >3cm

- 3. LG Ta, multifocal

- 4. LG T1

- * Documented negative voiding urine cytology within 2 weeks of C1D1

- * Documented activating FGFR3 alteration (mutation or fusion)

- * Have undergone bladder mapping and identification of visible marker lesion(s) within 8 weeks prior to C1D1 (refer to Inclusion Criterion #8)

- * No evidence of urothelial carcinoma of the upper urinary tract (confirmed by imaging) or prostatic urethra within 6 months of C1D1.

- * No prior BCG administration within 3 months of the date of most recent consent.

- * No intravesical chemotherapy within 8 weeks prior to C1D1.

- * Eastern Cooperative Oncology Group Performance Status (ECOG PS) 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 as defined as:
a. 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 b. Liver function: i. Total bilirubin < or = ULN ii. Alanine aminotransferase (ALT) < or = ULN iii. Aspartate aminotransferase (AST) < or = ULN c. Renal function: i. estimated glomerular filtration rate >30 mL/min calculated using the modification of diet in renal disease equation or CKD-EPI formula j. Serum Phosphate level < or = ULN d. 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 must refrain from donating sperm until 3 months 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. - * 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 active hepatitis B virus (HBV) infection should be on a suppressive antiviral therapy prior to C1D1. Note: participants with no history of chronic HBC infection do not need serology testing at Screening. - * Participants with a history of hepatitis C virus (HCV) infection should have completed curative antiviral treatment or be on stable treatment and must have a HCV viral load below the limit of quantification. Note: participants with no history of chronic HCV infection do not need serology testing at Screening.
Exclusion Criteria:
* 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

- * Current or prior history of pelvic external beam radiotherapy for bladder cancer

- * Current or history of receiving a prior FGFR inhibitor

- * Systemic immunotherapy for treatment of cancer within 6 months prior to C1D1

- * Treatment with an investigational agent within 30 days or 5 half-lives from C1D1, 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 a previous bladder cancer therapy or any toxicity that would impact the interpretability of study results per the Investigator's discretion.

- * 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 during Screening as well as any active ocular abnormality at baseline (during Screening) that may increase the chance of ocular toxicity.

- * History of or current uncontrolled cardiovascular disease

- * Gastrointestinal disorders that will affect oral administration or absorption of TYRA-300

- * Other malignancy within 3 years of signing ICF, except for skin cancer (e.g. basal cell, squamous cell, melanoma in situ with negative margins) and cured and/or active surveillance malignancies (i.e., prostate, breast, and others in consultation with the Sponsor).

- * Known allergy to TYRA-300 or any excipients of the formulated product

- * Participants taking moderate and strong inhibitors and/or inducers of CYP3A4 enzyme and inhibitors of P-gp and BCRP.

- * History of prolonged QT syndrome or baseline heart rate-corrected QT interval using Fridericia formula (QTcF) interval >470 ms

Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

OFFICIAL INFORMATION

Name: Doug Warner, MD

Role: Study Chair

Affiliation: Tyra Biosciences, Inc

Overall Contact

Name: Gina Risdall

Phone: 619-824-2509

Email: [email protected]

LOCATION