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

A Randomized, Open-label, Phase II Study Evaluating the Neurotoxicity and Efficacy of Sacituzumab Tirumotecan (Sac-TMT) Versus MMAE-based ADCs in Patients With Advanced Urothelial Carcinoma: The SPARE-UC-01 Trial

The main goal of this clinical trial is to learn if a new targeted cancer drug called sacituzumab tirumotecan (sac-TMT) works to treat cancer while causing less nerve damage in patients with advanced urothelial carcinoma who have progressed on or could not tolerate previous treatment such as enfortumab vedotin plus pembrolizumab (EVP) or disitamab vedotin plus toripalimab (DVT).

The main question it aims to answer is: Does sac-TMT lower the risk of getting severe nerve damage, as measured together by doctors, machines, and the participants?

Researchers will compare sac-TMT to alternative MMAE-based ADC drugs (switching to a different MMAE-based ADC after the first one stopped working) to see if sac-TMT causes less nerve damage while still effectively treating the cancer. A small group of participants who had to stop their previous MMAE-based ADC treatment because of nerve damage will also receive sac-TMT to learn if the drug is safe for their nerves.

Participants will:

1. Receive either sac-TMT or another MMAE-based ADC drug
2. Have regular physical exams by a doctor to check their nerves
3. Have machine tests to measure how well their nerves work
4. Answer survey questions about their pain, numbness, and daily activities

Metastatic urothelial carcinoma (mUC) is associated with a poor prognosis, and traditional platinum-based chemotherapy offers limited clinical benefit with significant toxicity. In recent years, the emergence of antibody-drug conjugates (ADCs) has transformed the treatment landscape of mUC. Nectin-4-directed enfortumab vedotin (EV) and HER2-directed disitamab vedotin (DV) have demonstrated breakthrough survival benefits in multiple pivotal clinical studies. EV plus pembrolizumab (EVP) and DV plus toripalimab (DVT) have been approved and are increasingly adopted as first-line treatments for mUC, with growing utilization in Chinese clinical practice.

However, as patient survival extends, the long-term safety profile of ADCs has become a major clinical challenge. Both EV and DV utilize MMAE as their cytotoxic payload, a potent microtubule- targeting agent. Non-specific uptake of these ADCs may lead to the release of MMAE within peripheral nerves, potentially causing microtubule dysregulation. By interfering with microtubule dynamics and inhibiting microtubule-dependent axonal transport, MMAE is thought to contribute to the development of peripheral neuropathy. Clinical data indicate that EV and DV cause a high incidence of peripheral neuropathy. Numbness, pain, and motor dysfunction significantly impair patients' activities of daily living (ADLs). Given the absence of effective prophylactic or therapeutic agents for peripheral neuropathy, clinical management is currently limited to dose reductions or complete treatment discontinuation, which will inevitably diminish anti-tumor efficacy.

Sacituzumab tirumotecan (sac-TMT) is a novel TROP2-directed ADC delivering a topoisomerase I (Topo-I) inhibitor payload. This payload induces DNA double-strand breaks within the cell nucleus, completely avoiding interference with the cytoskeletal microtubule system. This mechanistic difference fundamentally eliminates the biological basis for axonal transport blockade. Preliminary data from the Phase 1/2 MK-2870-001/KL264-01 study showed that sac-TMT achieved an overall objective response rate (ORR) of 31% and a median overall survival (OS) of 12.1 months in previously treated mUC patients, demonstrating a favorable efficacy profile. Notably, no typical drug-related peripheral neurotoxicity events were observed, highlighting a neuroprotective advantage.

The SPARE-UC-01 study is a head-to-head, Phase II clinical trial to compare the neurotoxicity and anti-tumor efficacy of sac-TMT versus sequential MMAE-based ADC therapy. The study targets a population that has progressed on or is intolerant to prior EVP or DVT. By comparing sac-TMT to the sequential use of alternative MMAE-based ADCs, the research aims to provide an evidence-based sequential treatment strategy. The study utilizes an integrated evaluation system designed to quantitatively capture the spectrum of neurotoxicity. This includes investigator-assessed NCI-CTCAE v5.0 scoring of Peripheral Neuropathy Progression Rate (PNPR), instrument-based nerve conduction studies (NCS), and patient- reported quality-of-life outcomes (PROs). Such a three-dimensional paradigm ensures that both structural nerve damage and functional disability are accurately documented. In view of the substantial population of patients who undergo discontinuation of MMAE-ADCs due to cumulative neurotoxicity, an observational cohort has been established within this study. This cohort aims to characterize the clinical utility of sac-TMT in these patients. Given that its payload does not target the microtubule system, sac-TMT is expected to provide effective treatment without introducing additional neurotoxicity.

Inclusion Criteria

1. Must voluntarily sign the written Institutional Review Board (IRB)/Ethics Committee (EC) approved informed consent form (ICF) prior to any screening procedures.

2. Age > 18 years at the time of signing the ICF.

3. 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%).

4. 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).

5. 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.

6. 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).

7. ECOG Performance Status of 0 or 1 at screening.

8. Expected survival > 3 months.

9. 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.

Exclusion Criteria

1. Prior treatment with TROP2-targeted ADCs, topoisomerase I inhibitors (e.g., irinotecan, topotecan), or ADCs containing topoisomerase I inhibitor payloads.
2. Patients previously treated with both Enfortumab Vedotin (EV) and Disitamab Vedotin (DV) are excluded from Cohorts A and B (eligible for Cohort C only).
3. 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.
4. 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.
5. 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.
6. 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.
7. Active keratitis, corneal ulcer, or severe dry eye syndrome.
8. 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.
9. Hypersensitivity: Known severe hypersensitivity to sac-TMT, EV, DV, or their excipients.
10. Any severe or uncontrolled systemic disease that, in the investigator's opinion, increases the risk to the participant.
11. HbA1c ≥ 8% (Patients with well-controlled blood glucose, fasting glucose ≤ 10 mmol/L, and investigator approval are eligible).
12. History of allogeneic stem cell transplant or solid organ transplant.
13. Pregnant or breastfeeding females.