Sacituzumab Tirumotecan vs MMAE-ADCs in Advanced Urothelial Carcinoma (FUSCC-SPARE-UC-01)

Prior treatment

• Prior treatment with TROP2-targeted ADCs, topoisomerase I inhibitors (e.g., irinotecan, topotecan), or ADCs containing topoisomerase I inhibitor payloads.
• Patients previously treated with both Enfortumab Vedotin (EV) and Disitamab Vedotin (DV) are excluded from Cohorts A and B (eligible for Cohort C only).
• Treatment with any investigational anti-tumor agents, chemotherapy, immunotherapy, monoclonal antibodies, targeted therapy, or radical radiotherapy within 2 weeks or 5 half-lives (whichever is shorter) prior to the first dose. Major surgery within 4 weeks prior to the first dose.
• Active CNS or meningeal metastases. Patients with previously treated CNS metastases are eligible if clinically stable for ≥ 4 weeks, off systemic corticosteroids for ≥ 2 weeks (physiological replacement ≤ 10 mg/day prednisone equivalent is allowed), and no evidence of radiographic progression.
• QTcF interval \> 470 ms (females) or \> 450 ms (males). Within 6 months prior to the first dose: myocardial infarction, unstable angina, severe arrhythmia requiring intervention, uncontrolled hypertension, stroke, or TIA. NYHA Class III or IV congestive heart failure.
• Active Hepatitis B (HBsAg positive and HBV-DNA \> 2000 IU/mL; patients with lower HBV-DNA must receive antiviral therapy); Active Hepatitis C (HCV antibody and RNA positive); Known HIV infection; Severe infection requiring IV antibiotics within 2 weeks prior to first dose.

Other illness

• History of non-infectious pneumonitis/interstitial lung disease (ILD) requiring steroids. Current ILD or suspected ILD on screening chest CT (even if asymptomatic). Severe COPD, severely impaired lung function, or requirement for long-term oxygen therapy.
• Active keratitis, corneal ulcer, or severe dry eye syndrome.
• Hypersensitivity: Known severe hypersensitivity to sac-TMT, EV, DV, or their excipients.
• Any severe or uncontrolled systemic disease that, in the investigator's opinion, increases the risk to the participant.
• History of allogeneic stem cell transplant or solid organ transplant.

Lab values

• HbA1c ≥ 8% (Patients with well-controlled blood glucose, fasting glucose ≤ 10 mmol/L, and investigator approval are eligible).

Other

• Pregnant or breastfeeding females.

• Must voluntarily sign the written Institutional Review Board (IRB)/Ethics Committee (EC) approved informed consent form (ICF) prior to any screening procedures.
• Age \> 18 years at the time of signing the ICF.
• Histologically or cytologically confirmed locally advanced (unresectable) or metastatic urothelial carcinoma (UC), including bladder, ureter, renal pelvis, or urethra. Participants with mixed histology are eligible provided that UC is the predominant component (\> 50%).
• Must have received at least one prior line of systemic therapy for locally advanced or metastatic UC (e.g., Enfortumab Vedotin plus Pembrolizumab, Disitamab Vedotin plus Toripalimab, platinum-based chemotherapy, immune checkpoint inhibitors, Nectin-4 ADCs, HER2 ADCs, FGFR inhibitors, or other palliative chemotherapy regimens).
• Neuropathy Status:
  • Cohort A/B: Baseline peripheral neuropathy (PN) Grade 0-1 (per NCI-CTCAE v5.0) with stable nerve function confirmed by Nerve Conduction Study (NCS) during screening.
  • Cohort C (Observational): Baseline PN Grade 2, or a history of PN \> Grade 2 where the investigator deems the patient unsuitable for MMAE-based ADC treatment.
• At least one measurable lesion per RECIST v1.1. (Lesions in previously irradiated areas are considered target lesions only if clear progression is documented after radiotherapy).
• ECOG Performance Status of 0 or 1 at screening.
• Expected survival \> 3 months.
• Must have adequate organ and bone marrow function (no blood transfusion, growth factors, or albumin support within 14 days prior to screening):
  • Hematological: ANC \>= 1.5 x 10\^9/L; Platelets \>= 75 x 10\^9/L; Hemoglobin \>= 90 g/L.
  • Hepatic: ALT and AST \<= 2.5 x ULN (or \<= 5 x ULN for patients with liver metastases); Total Bilirubin \<= 1.5 x ULN (if Total Bilirubin \> 1.5 x ULN, Direct Bilirubin must be \<= ULN).
  • Coagulation: INR \<= 1.5; APTT \<= 1.5 x ULN; PT \< ULN + 4 seconds.
  • Renal: Creatinine Clearance (CrCl) \>= 30 mL/min, or Serum Creatinine \<= 1.5 x ULN.