efficacy and safety of tyra-300 in participants with fgfr3 altered low grade, intermediate risk non-muscle invasive bladder cancer

Conditions: Low-grade NMIBC; FGFR Gene Amplification; FGFR Gene Alterations; FGFR3 Gene Alteration; FGFR3 Gene Mutation; FGFR3 Gene Fusions

Summary: phase 2 study of tyra-300 in fgfr3 altered low grade, intermediate risk nmibc

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

Eligibility criteria:
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: 1. ta low grade 2. t1 low grade * participants must have intermediate risk nmibc, defined as having any of the following characteristics (aua guidelines, 2024) 1. recurrence within 1 year, lg ta 2. solitary lg ta \>3cm 3. lg ta, multifocal 4. 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 \ 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

Keywords: fgfr3 gene alterations fgfr3 gene mutations fgfr3 gene fusions fgfr3 non-muscle invasive bladder cancer