Phase 2A/2B Open‑Label Study of Dabogratinib (TYRA‑300) in Patients with FGFR3‑Altered Low‑Grade Upper Tract Urothelial Carcinoma

The primary objective of this phase 2A/2B trial is to assess the efficacy of dabogratinib in patients with low‑grade upper tract urothelial carcinoma harboring FGFR3‑altered tumors and, in the phase 2A portion, to identify the recommended dose for the subsequent phase 2B cohort.

• To evaluate the efficacy of dabogratinib in all participants with low‑grade upper tract urothelial carcinoma.
• To assess the therapeutic activity of dabogratinib.
• To evaluate the safety and tolerability of dabogratinib.
• To characterize the pharmacokinetic profile of dabogratinib.
• To determine the rate of renal preservation after treatment.
• To evaluate the change from unresectable to resectable disease following therapy.

The trial enrolled 200 participants diagnosed with Low Grade Upper Tract Urothelial Carcinoma and harboring FGFR3‑altered tumors. Eligible individuals were adults aged 18 years or older, encompassing both male and female patients, and included vulnerable subjects as defined by regulatory criteria. All participants were required to have an Eastern Cooperative Oncology Group performance status of 0‑2 and demonstrate adequate bone marrow, hepatic, and renal function. Inclusion mandated confirmation of low‑grade disease, the presence of a marker lesion of at least 5 mm left in situ, and availability of a recent genomic report or tissue sample for retrospective testing. Subjects could not have received Bacillus Calmette‑Guérin therapy within the preceding year, intravesical chemotherapy within 8 weeks, or systemic chemotherapy within 3 months before study entry. No specific dietary or physical‑activity restrictions were stipulated in the protocol.

The study is a multi‑center, open‑label Phase 2A/2B trial evaluating the oral tablet dabogratinib (TYRA‑300) 99 mg once daily in participants with Low Grade Upper Tract Urothelial Carcinoma harboring FGFR3 alterations. After informed consent, a screening visit confirms eligibility, including ECOG status, laboratory parameters, and collection of tumor tissue for genomic confirmation. Eligible participants enter a single‑arm treatment period lasting up to six months, with clinic assessments on Day 1 (baseline), then at Weeks 4, 8, 12, 16, 20, and 24 to monitor safety, pharmacokinetics, and tumor response; additional visits occur as needed for adverse‑event management. The end‑of‑study visit occurs at Week 24 or earlier if discontinuation criteria are met. Participants remain on study drug until documented complete response, disease progression, unacceptable toxicity, withdrawal of consent, or the six‑month treatment window, whichever occurs first. Early termination may be triggered by Grade 3 or higher treatment‑related adverse events, significant laboratory abnormalities, or intercurrent illness precluding continued therapy. The primary efficacy endpoint is complete response rate within six months; secondary endpoints include duration of response, safety profile, pharmacokinetic parameters, and surgical avoidance outcomes. Recruitment is planned from June 2026 to December 2030.

The investigational product, designated TYRA‑300‑B01, contains the active substance tyra‑300‑b01 (dabogratinib). It is formulated as a 99 mg oral tablet and is administered by the oral route in accordance with the study dosing schedule.

No placebo, standard‑of‑care therapy, or other comparator is incorporated in this open‑label trial; participants receive only the investigational tablet.

The trial enrolls individuals with Low Grade Upper Tract Urothelial Carcinoma harboring FGFR3 alterations.

Efficacy will be evaluated in participants with Low Grade Upper Tract Urothelial Carcinoma by determining the Complete Response rate at predefined intervals. The primary efficacy endpoint for both Phase 2A and Phase 2B is the proportion of participants achieving a complete response within six months of initiating dabogratinib therapy. Secondary efficacy assessments include the complete response rate at 12 months and 24 months, the duration of response in participants with FGFR3‑altered tumors, the proportion of participants who avoid nephrectomy or nephroureterectomy, and the proportion of participants with unresectable disease at baseline who convert to resectable disease or achieve a complete response as assessed by the Investigator.

Efficacy assessments will be performed using standard investigative procedures to evaluate tumor status, with assessments scheduled at baseline, six months, twelve months, and twenty‑four months. The investigator’s determination of complete response will be based on imaging and clinical criteria consistent with trial protocol. Duration of response will be calculated from the time of first documented complete response until disease progression or loss of response. All efficacy data will be analyzed descriptively, with response rates expressed as percentages of the treated population at each timepoint.