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.
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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
80
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.
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 every 3 weeks (Q3W) for up to 1 year or until recurrence or study withdrawal.
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.
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.
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.
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.
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.
Sun Yat-sen Memorial Hospital
Guangzhou, Guangdong, China
RECRUITINGClinical Complete Response Rate
Clinical complete response (cCR) rate is defined as the proportion of participants who have no visible tumor on imaging, no evidence of malignancy on cystoscopy and/or complete transurethral resection of bladder tumor (cTURBT) biopsy, and negative urine cytology after completion of 6 cycles of neoadjuvant treatment. Clinical response will be determined by comprehensive assessment using imaging, pathology, cystoscopy/cTURBT findings, and urine cytology.
Time frame: At completion of 6 cycles of neoadjuvant therapy and cTURBT assessment, approximately 18 weeks after enrollment.
Overall Survival
Overall survival (OS) is defined as the time from enrollment to death from any cause. Participants who are alive at the time of analysis will be censored at the date of last known follow-up.
Time frame: From enrollment through 5 years.
Bladder-Intact Disease-Free Survival
Bladder-intact disease-free survival (BI-DFS) is defined as the time from enrollment to the first occurrence of intravesical recurrence, regional lymph node recurrence, distant metastasis, salvage radical cystectomy, or death from any cause, as assessed by imaging, urine cytology, and cystoscopy.
Time frame: From enrollment through 5 years.
Bladder Preservation Rate at 1, 3, and 5 Years
Bladder preservation rate is defined as the proportion of participants who remain free from radical cystectomy and retain an intact, functioning bladder at 1, 3, and 5 years after enrollment.
Time frame: At 1, 3, and 5 years after enrollment.
Partial Response Rate
Partial response (PR) rate is defined as the proportion of participants who, after completion of 6 cycles of neoadjuvant treatment, have a reduction of at least 30% in the sum of diameters of target lesions on imaging, with residual disease no deeper than pT1 confirmed by cystoscopy and/or cTURBT biopsy, and no evidence of locally advanced or metastatic disease. Participants achieving clinical complete response are not included in the partial response rate.
Time frame: 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
Quality of life will be assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). Changes in global health status, functional scales, and symptom scales from baseline will be evaluated over time. Higher scores on the global health status and functional scales indicate better quality of life, whereas higher scores on symptom scales indicate greater symptom burden.
Time frame: From baseline through 5 years after cTURBT.
Total Direct Medical Cost
Total direct medical cost is defined as the cumulative pre-reimbursement medical cost incurred from enrollment through the last follow-up visit. Costs include inpatient and outpatient costs, surgical costs, study treatment and concomitant medication costs, supportive care costs, laboratory and imaging examination costs, pathological examination costs, radiotherapy-related costs, and other medically related costs.
Time frame: From enrollment through 5 years.
Incidence Rate of Adverse Events
The incidence rate of adverse events (AEs) is defined as the percentage of participants who experience at least one AE after initiation of study treatment. The numerator is the number of participants with at least one AE, and the denominator is the number of participants in the safety analysis set. AEs will be coded and summarized by type, severity, seriousness, and relationship to study treatment. Drug-related AEs will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI-CTCAE v5.0).
Time frame: From first study treatment through 90 days after the last study treatment, up to approximately 18 months.
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