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

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.

Inclusion criteria

• 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.

Exclusion criteria

• 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.