Sun Yat-Sen Treatment Strategy for Enhancing Response in Muscle-invasive Bladder Cancer

Официальное название

Study on Immunotherapy Enhancement Strategies for Muscle-invasive Bladder Cancer

Обзор

This is a multicenter, prospective, open-label, Phase II, four-arm parallel study evaluating the efficacy and safety of different sensitization strategies combined with disitamab vedotin and toripalimab in patients with HER2-positive muscle-invasive urothelial carcinoma of the bladder (MIBC). Eligible patients with cT2-4aN0M0 HER2-positive urothelial carcinoma of the bladder will receive neoadjuvant disitamab vedotin plus toripalimab in combination with one of four sensitizing agents: sitagliptin, tazemetostat, tafolecimab, or ursodeoxycholic acid. After six cycles of neoadjuvant treatment, patients will undergo comprehensive response assessment, including imaging, cystoscopy, urine cytology, and complete transurethral resection of bladder tumor (cTURBT). Patients who achieve a clinical complete response (cCR) may enter a bladder-preservation treatment pathway, including additional disitamab vedotin plus toripalimab and subsequent toripalimab maintenance therapy. Patients who do not achieve cCR will be considered for salvage radical cystectomy. The primary objective is to evaluate the cCR rate of each treatment strategy. Secondary objectives include bladder-intact disease-free survival, overall survival, bladder preservation rate, safety, quality of life, treatment costs, and exploratory biomarker analyses.

Подробное описание

This is a Phase II, open-label, four-arm parallel study evaluating the efficacy and safety of sensitizing agents (sitagliptin, tazemetostat, tafolecimab, or ursodeoxycholic acid) combined with disitamab vedotin and toripalimab in patients with HER2-positive muscle-invasive urothelial carcinoma of the bladder (MIBC).

Disitamab vedotin, a HER2-targeted antibody-drug conjugate, combined with the PD-1 inhibitor toripalimab has shown promising anti-tumor activity in HER2-positive MIBC and may provide an opportunity for bladder preservation in selected patients. However, some patients remain insensitive or resistant to this treatment strategy and fail to achieve a clinical complete response. How to improve treatment sensitivity and enhance the efficacy of HER2-targeted and immune-based combination therapy remains an important clinical problem.

Preclinical studies from our center suggest that sitagliptin, tazemetostat, tafolecimab, and ursodeoxycholic acid may play a potentially important role in regulating the tumor immune microenvironment, inhibiting tumor growth, and enhancing the efficacy of PD-1 inhibitor-based treatment.

Based on these preclinical studies, the investigators designed this study to enroll patients with HER2-positive cT2-4aN0M0 MIBC and to explore, at the clinical level, the efficacy and safety of one sensitizing agent-sitagliptin, tazemetostat, tafolecimab, or ursodeoxycholic acid-combined with disitamab vedotin plus toripalimab, providing new combination treatment strategies for bladder preservation in patients with HER2-positive MIBC.

Вмешательства

• Препарат Disitamab vedotin
  Disitamab vedotin, a HER2-targeted antibody-drug conjugate, will be administered intravenously at 2 mg/kg on Day 1 of each 2-week cycle (Q2W). During the neoadjuvant phase, participants will receive 6 cycles in combination with toripalimab and the arm-specific sensitizing agent. Participants who achieve clinical complete response after cTURBT and comprehensive response assessment will receive an additional 6 cycles of disitamab vedotin plus toripalimab as consolidation therapy.
• Препарат Toripalimab
  Toripalimab, an anti-PD-1 monoclonal antibody, will be administered intravenously at 3 mg/kg on Day 1 of each 2-week cycle (Q2W). During the neoadjuvant phase, participants will receive 6 cycles in combination with disitamab vedotin and the arm-specific sensitizing agent. Participants who achieve clinical complete response after cTURBT will receive 6 additional cycles of toripalimab plus disitamab vedotin consolidation therapy, followed by toripalimab maintenance therapy at 240 mg intravenously
• Препарат Sitagliptin
  Sitagliptin phosphate, a DPP-4 inhibitor, will be administered orally at 100 mg once daily throughout the 6-cycle neoadjuvant treatment phase (approximately 3 months), in combination with disitamab vedotin and toripalimab.
• Препарат Zeprumetostat
  Zeprumetostat, an EZH2 inhibitor, will be administered orally at 350 mg twice daily throughout the 6-cycle neoadjuvant treatment phase (approximately 3 months), in combination with disitamab vedotin and toripalimab.
• Препарат Tafolecimab
  Tafolecimab, a PCSK9-targeting monoclonal antibody, will be administered by subcutaneous injection at 150 mg on Day 1 of each 2-week cycle (Q2W) for 6 neoadjuvant treatment cycles (approximately 3 months), in combination with disitamab vedotin and toripalimab.
• Препарат Ursodeoxycholic Acid
  Ursodeoxycholic acid will be administered orally at 250 mg twice daily throughout the 6-cycle neoadjuvant treatment phase (approximately 3 months), in combination with disitamab vedotin and toripalimab.
• Процедура Complete transurethral resection of bladder tumor
  Complete transurethral resection of bladder tumor (cTURBT) will be performed within 6 weeks after completion of 6 cycles of neoadjuvant therapy in all study arms. The procedure will be combined with imaging assessment, pathological evaluation, and urine cytology to determine clinical response, including clinical complete response, and to guide subsequent bladder-preservation management or salvage radical cystectomy.

Первичные конечные точки

• Clinical Complete Response Rate [Срок оценки: At completion of 6 cycles of neoadjuvant therapy and cTURBT assessment, approximately 18 weeks after enrollment.]

Вторичные конечные точки (7)

• Overall Survival [Срок оценки: From enrollment through 5 years.]
• Bladder-Intact Disease-Free Survival [Срок оценки: From enrollment through 5 years.]
• Bladder Preservation Rate at 1, 3, and 5 Years [Срок оценки: At 1, 3, and 5 years after enrollment.]
• Partial Response Rate [Срок оценки: At completion of 6 cycles of neoadjuvant therapy and cTURBT assessment, approximately 18 weeks after enrollment.]
• Change in Quality of Life Assessed by EORTC QLQ-C30 [Срок оценки: From baseline through 5 years after cTURBT.]
• Total Direct Medical Cost [Срок оценки: From enrollment through 5 years.]
• Incidence Rate of Adverse Events [Срок оценки: From first study treatment through 90 days after the last study treatment, up to approximately 18 months.]

Критерии участия

Критерии включения

• Voluntarily participate in this study, provide written informed consent, and be able to understand and agree to comply with the study requirements and assessment schedule.
• Age ≥18 years on the date of signing the informed consent form.
• Histologically confirmed and radiologically assessed cT2-T4aN0M0 urothelial carcinoma of the bladder according to the American Joint Committee on Cancer (AJCC) 8th edition TNM staging system. For tumors with mixed histology, urothelial carcinoma must be the predominant component (at least 50%).
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• HER2 expression ≥1+ confirmed by immunohistochemistry using a pretreatment tumor specimen tested at a local laboratory.
• Availability of tumor tissue obtained from transurethral resection of bladder tumor (TURBT), together with the corresponding pathology report. Fresh surgical tissue or unstained pathology slides may be submitted.
• Adequate organ function, as determined by the following screening laboratory values obtained within 14 days before enrollment:

a. For assessment of the following hematologic parameters, participants must not have received growth factor support within 14 days before sample collection: i. Absolute neutrophil count ≥1.5 × 10\^9/L; ii. Platelet count ≥90 × 10\^9/L; iii. Hemoglobin ≥90 g/L. b. International normalized ratio (INR) or activated partial thromboplastin time (aPTT) ≤1.5 × the upper limit of normal (ULN).

c. Total serum bilirubin ≤1.5 × ULN. For participants with Gilbert syndrome or indirect bilirubin elevation of extrahepatic origin, total bilirubin must be ≤3 × ULN.

d. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase ≤2.5 × ULN.

e. Pulmonary function indicating ability to tolerate surgery.

• Women who are not pregnant or women of childbearing potential must be willing to use highly effective contraception during the study and for at least 120 days after the last dose of disitamab vedotin or toripalimab, whichever occurs later, and must have a negative urine or serum pregnancy test within 7 days before enrollment. Non-sterilized male participants must be willing to use highly effective contraception during the study and for at least 120 days after the last dose of disitamab vedotin or toripalimab, whichever occurs later.

Критерии исключения

• Prior treatment with therapies targeting PD-1, PD-L1, PD-L2, CTLA-4, LAG-3, HER2, or Nectin-4, or with other antibodies or drugs specifically targeting T-cell co-stimulatory or checkpoint pathways.
• Receipt of other approved systemic anticancer therapy or systemic immunomodulators, including but not limited to interferon, interleukin-2, or tumor necrosis factor, within 28 days before enrollment.
• Prior radiotherapy for bladder cancer.
• Prior antitumor drug therapy, except for the following:

• For participants who previously received systemic chemotherapy, a treatment-free interval of at least 12 months from the last treatment to the start of neoadjuvant study treatment is required.
• Local intravesical chemotherapy or immunotherapy must have been completed at least 1 week before the start of neoadjuvant study treatment.
• Major surgery or major trauma within 28 days before enrollment. Placement of a vascular access device and TURBT are not considered major surgery.
• Severe chronic or active infection requiring systemic antibacterial, antifungal, or antiviral treatment within 14 days before enrollment. HBV infection will be assessed according to Exclusion Criterion 13.
• Receipt of a live vaccine within 28 days before enrollment. Seasonal injectable influenza vaccines are generally inactivated and are permitted; intranasal vaccines are live vaccines and are not permitted.
• Active autoimmune disease requiring systemic treatment and considered by the investigator to affect study treatment.
• Requirement for long-term high-dose corticosteroids or other immunosuppressive agents considered by the investigator to affect study treatment.
• Any history of uncontrolled systemic disease that, in the investigator's judgment, may affect treatment, including abnormal potassium, sodium, or calcium levels; hypoalbuminemia; interstitial lung disease; noninfectious pneumonitis; diabetes mellitus; hypertension; cardiovascular disease; or other uncontrolled systemic disease.
• For Arm A, any of the following:

• Treatment with a DPP-4 inhibitor within 60 days before the first administration of study treatment.
• Diabetes mellitus requiring any glucose-lowering medication, including long-acting or short-acting insulin, DPP-4 inhibitors, GLP-1 receptor agonists, or other glucose-lowering drugs.
• Fasting blood glucose <4 mmol/L.
• For Arm D, any of the following:

• Acute cholecystitis or cholangitis.
• Biliary obstruction.
• Recurrent biliary colic attacks.
• Radiopaque calcified gallstones.
• Impaired gallbladder function.
• Nonvisualization of the gallbladder on radiography.
• Untreated chronic hepatitis B or hepatitis B virus carrier status with HBV DNA ≥500 IU/mL (2500 copies/mL). Participants with inactive hepatitis B surface antigen carrier status or stable active HBV infection after continuous antiviral therapy, with HBV DNA <500 IU/mL, may be enrolled. HBV DNA testing is required only for participants positive for hepatitis B core antibody.
• Active hepatitis C. Participants with negative HCV antibody results, or participants with positive HCV antibody results but negative HCV RNA results during screening, may be enrolled. HCV RNA testing is required only for participants with positive HCV antibody results.
• History of immunodeficiency, including positive human immunodeficiency virus (HIV) testing, other acquired or congenital immunodeficiency disorders, prior allogeneic stem cell transplantation, or prior organ transplantation.
• Known allergy to other monoclonal antibodies.
• Known allergy to any study drug or excipient.
• Toxicities from any prior treatment that have not recovered to baseline or a stable level, unless the investigator determines that such toxicities are unlikely to pose a safety risk, for example alopecia, neuropathy, or specific laboratory abnormalities.
• Any underlying medical condition, alcohol or drug abuse, or dependence that may interfere with study drug administration, affect interpretation of study results, or place the participant at high risk of treatment complications.
• Concurrent participation in another interventional clinical study.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 1 центр

• Sun Yat-sen Memorial Hospital — Гуанчжоу

Идентификаторы

NCT: NCT07717242 · SYSKY-2026-461-02 · 2024ZD0525700

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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