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

2026年6月17日 更新者：Ding-Wei Ye、Fudan University

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

調査の概要

状態

まだ募集していません

条件

介入・治療

詳細な説明

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.

研究の種類

介入

入学 (推定)

75

段階

  • フェーズ2

連絡先と場所

このセクションには、調査を実施する担当者の連絡先の詳細と、この調査が実施されている場所に関する情報が記載されています。

研究連絡先

研究連絡先のバックアップ

研究場所

  • 中国
    • Shanghai Municipality
      • Shanghai、Shanghai Municipality、中国、200032
        • Fudan University Shanghai Cancer Center
        • 主任研究者：
          • Yao Zhu
        • コンタクト：

参加基準

研究者は、適格基準と呼ばれる特定の説明に適合する人を探します。これらの基準のいくつかの例は、人の一般的な健康状態または以前の治療です。

適格基準

就学可能な年齢

  • 大人
  • 高齢者

健康ボランティアの受け入れ

いいえ

説明

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.

研究計画

このセクションでは、研究がどのように設計され、研究が何を測定しているかなど、研究計画の詳細を提供します。

研究はどのように設計されていますか？

デザインの詳細

  • 主な目的：処理
  • 割り当て：ランダム化
  • 介入モデル：並列代入
  • マスキング：なし（オープンラベル）

武器と介入

参加者グループ / アーム
介入・治療
実験的：Experimental
Patients receive sac-TMT (a Topo-I inhibitor-payload ADC) following failure of prior MMAE-based ADC therapy.
薬：Sacituzumab Tirumotecan
4.0 mg/kg intravenously administered on Day 1 every 2 weeks.
他の名前：
  • SKB264
  • MK-2870
  • 嚢-TMT
アクティブコンパレータ：Active Comparator
Patients receive an alternative MMAE-based ADC regimen as sequential therapy following progression on or intolerance to prior MMAE-based ADC treatment.
薬：MMAE-based ADC

EV (Enfortumab Vedotin): 1.25 mg/kg administered intravenously on Days 1, 8, and 15 of every 4 weeks.

DV (Disitamab Vedotin): 2.0 mg/kg administered intravenously on Day 1 of every 2 weeks.

他の名前：
  • DV
  • EV
他の：Observational
An observational cohort for patients who discontinued prior MMAE-ADCs due to neurotoxicity.
薬：Sacituzumab Tirumotecan (Observational Cohort)
4.0 mg/kg intravenously administered on Day 1 every 2 weeks.
他の名前：
  • SKB264
  • MK-2870
  • 嚢-TMT

この研究は何を測定していますか？

主要な結果の測定

結果測定
メジャーの説明
時間枠
Peripheral Neuropathy Progression Rate (PNPR)
時間枠：From randomization up to the end of treatment (approximately 24 months).

The PNPR is defined as the proportion of participants who experience their first occurrence of treatment-emergent peripheral neurotoxicity of Grade 2 or higher from the time of randomization until the end of treatment.

Neurotoxicity severity is graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0, a 5-point ordinal scale ranging from Grade 1 (mild; asymptomatic or mild symptoms, clinical or diagnostic observations only) to Grade 5 (death related to adverse event). Higher grades indicate worse outcomes (i.e., more severe neurotoxicity).

The difference in PNPR between treatment arms will be analyzed using the Cochran-Mantel-Haenszel (CMH) test, adjusted for stratification factors specified in the protocol.
From randomization up to the end of treatment (approximately 24 months).

二次結果の測定

結果測定
メジャーの説明
時間枠
Percent Change in NCS Parameters
時間枠：Baseline, and at protocol-specified time points (including the time of first occurrence of Grade ≥2 neurotoxicity symptoms) during the treatment period, up to approximately 24 months.
The NCS percentage change is calculated as the relative change in electrophysiological parameters from baseline to each post-baseline assessment. The formula used is: [(Post-baseline Value - Baseline Value) / Baseline Value] × 100%.
Baseline, and at protocol-specified time points (including the time of first occurrence of Grade ≥2 neurotoxicity symptoms) during the treatment period, up to approximately 24 months.
Cumulative Neurotoxicity Burden (CNB)
時間枠：From randomization up to the end of treatment (approximately 24 months).

Cumulative Neurotoxicity Burden (CNB) quantifies total peripheral neurotoxicity exposure, incorporating both severity and duration. Neurotoxicity grades are assigned using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0, a 5-point ordinal scale ranging from Grade 1 (mild) to Grade 5 (death); higher grades indicate worse outcomes.

Two complementary CNB metrics are calculated:

  1. Raw CNB: trapezoidal AUC of NCI-CTCAE grades plotted against time from randomization to end of treatment. Unit: grade-months.
  2. Time-Standardized CNB (CNB-TS): Raw CNB divided by total observation duration, expressed as mean grade per unit time. CNB-TS = AUC / T(observation). This standardizes burden across participants with differing treatment durations.

Higher values of both metrics indicate worse outcomes. Between-arm comparisons will use mixed-effects models adjusted for stratification factors.
From randomization up to the end of treatment (approximately 24 months).
Health-Related Quality of Life: EORTC QLQ-C30
時間枠：From randomization up to the end of treatment (approximately 24 months), assessed at baseline and at protocol-specified time points.
Health-related quality of life (HRQoL) is assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), a 30-item validated cancer- specific questionnaire comprising 5 functional scales (physical, role, emotional, cognitive, social functioning), 3 symptom scales (fatigue, nausea/vomiting, pain), 6 single-item symptom assessments, and a global health status/quality of life scale. All scores are linearly transformed to a 0-100 scale. For functional scales and the global health status/QoL scale, higher scores indicate better functioning or better quality of life (better outcomes). For symptom scales and single items, higher scores indicate a higher level of symptom burden (worse outcomes). Mean changes from baseline in EORTC QLQ-C30 subscale scores will be compared between treatment arms using a mixed-effects model for repeated measures (MMRM), adjusted for stratification factors.
From randomization up to the end of treatment (approximately 24 months), assessed at baseline and at protocol-specified time points.
Chemotherapy-Induced Peripheral Neuropathy Symptoms: EORTC QLQ-CIPN20
時間枠：From randomization up to the end of treatment (approximately 24 months), assessed at baseline and at protocol-specified time points.

Patient-reported peripheral neuropathy symptoms are assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Chemotherapy-Induced Peripheral Neuropathy 20-item module (EORTC QLQ-CIPN20), a validated 20-item instrument designed to specifically capture sensory, motor, and autonomic symptoms of chemotherapy-induced peripheral neuropathy.

Items are rated on a 4-point Likert scale (1 = "Not at all" to 4 = "Very much"). Raw scores are linearly transformed to a 0-100 scale. Higher scores indicate a higher level of peripheral neuropathy symptom burden (worse outcomes).

Mean changes from baseline in EORTC QLQ-CIPN20 sensory, motor, and autonomic subscale scores will be compared between treatment arms using a mixed-effects model for repeated measures (MMRM), adjusted for stratification factors.
From randomization up to the end of treatment (approximately 24 months), assessed at baseline and at protocol-specified time points.
Objective Response Rate (ORR)
時間枠：From randomization up to the end of treatment (approximately 24 months).
The proportion of participants who achieve a Complete Response (CR) or Partial Response (PR) based on RECIST v1.1.
From randomization up to the end of treatment (approximately 24 months).
Disease Control Rate (DCR)
時間枠：From randomization up to the end of treatment (approximately 24 months).
The proportion of participants with CR, PR, or Stable Disease (SD) maintained for at least 6 weeks.
From randomization up to the end of treatment (approximately 24 months).
Progression-Free Survival (PFS)
時間枠：From randomization up to the end of treatment (approximately 24 months).
The time from randomization to the first disease progression (per RECIST v1.1) or death from any cause, whichever occurs first.
From randomization up to the end of treatment (approximately 24 months).
Overall Survival (OS)
時間枠：From randomization up to the end of treatment (approximately 24 months).
The time from randomization to death from any cause.
From randomization up to the end of treatment (approximately 24 months).
Duration of Response (DoR)
時間枠：From randomization up to the end of treatment (approximately 24 months).
The time from the first documented CR or PR until the first documented disease progression or death.
From randomization up to the end of treatment (approximately 24 months).
Adverse Events (AEs)
時間枠：From randomization up to the end of treatment (approximately 24 months).
Assessment of AEs graded by NCI-CTCAE v5.0 including incidence, type, severity, duration, and relationship to study drug.
From randomization up to the end of treatment (approximately 24 months).

その他の成果指標

結果測定
メジャーの説明
時間枠
Serum Neurofilament Light Chain (sNfL) Levels
時間枠：Baseline, and at protocol-specified time points during treatment (including the time of first occurrence of Grade ≥2 neurotoxicity symptoms), up to approximately 24 months.

Serum neurofilament light chain (sNfL) is a blood-based biomarker of neuronal axonal injury. Elevated sNfL levels reflect ongoing axonal damage and have been validated as a biomarker for chemotherapy-induced peripheral neuropathy and other neurodegenerative conditions.

sNfL concentration is measured in serum using a quantitative single-molecule array (Simoa) immunoassay. Results are reported in picograms per milliliter (pg/mL). Higher sNfL levels indicate greater axonal injury (worse neurological outcomes).

Outcomes assessed include: (1) absolute sNfL concentration at each time point, (2) change from baseline in sNfL concentration, and (3) fold change in sNfL from baseline. Between-arm comparisons will be performed using mixed-effects model for repeated measures (MMRM) on log-transformed values.
Baseline, and at protocol-specified time points during treatment (including the time of first occurrence of Grade ≥2 neurotoxicity symptoms), up to approximately 24 months.

協力者と研究者

ここでは、この調査に関係する人々や組織を見つけることができます。

スポンサー

Fudan University

研究記録日

これらの日付は、ClinicalTrials.gov への研究記録と要約結果の提出の進捗状況を追跡します。研究記録と報告された結果は、国立医学図書館 (NLM) によって審査され、公開 Web サイトに掲載される前に、特定の品質管理基準を満たしていることが確認されます。

主要日程の研究

研究開始 (推定)

2026年7月15日

一次修了 (推定)

2028年12月1日

研究の完了 (推定)

2029年12月1日

試験登録日

最初に提出

2026年5月10日

QC基準を満たした最初の提出物

2026年6月17日

最初の投稿 (実際)

2026年6月23日

学習記録の更新

投稿された最後の更新 (実際)

2026年6月23日

QC基準を満たした最後の更新が送信されました

2026年6月17日

最終確認日

2026年6月1日

詳しくは

本研究に関する用語

キーワード

追加の関連 MeSH 用語

その他の研究ID番号

  • FUSCC-SPARE-UC-01

個々の参加者データ (IPD) の計画

個々の参加者データ (IPD) を共有する予定はありますか?

いいえ

医薬品およびデバイス情報、研究文書

米国FDA規制医薬品の研究

いいえ

米国FDA規制機器製品の研究

いいえ

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