Sun Yat-Sen Treatment Strategy for Enhancing Response in Muscle-invasive Bladder Cancer
Trial statusRecruiting
Trial phasePhase 2
Trial typeInterventional
Biological sexAll
Age18+
SponsorSun Yat-Sen Memorial Hospital of Sun Yat-Sen University
About this trial
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.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
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.
Disqualifiers
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.
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.
Trial design
Design model
Parallel
Treatments tested in this trial
Disitamab vedotin
DrugDisitamab 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
DrugToripalimab, 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
DrugSitagliptin 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
DrugZeprumetostat, 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
DrugTafolecimab, 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
DrugUrsodeoxycholic 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
Procedure/SurgeryComplete 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.
Treatment groups
80 Participants
are divided into 4 treatment groupsGroup A: Disitamab Vedotin + Toripalimab + Sitagliptin (Arm A)Experimental treatment 4 interventions
Group B: Disitamab Vedotin + Toripalimab + Zeprumetostat (Arm B)Experimental treatment 4 interventions
Group C: Disitamab Vedotin + Toripalimab + Tafolecimab (Arm C)Experimental treatment 4 interventions
Group D: Disitamab Vedotin + Toripalimab + Ursodeoxycholic Acid (Arm D)Experimental treatment 4 interventions
Trial outcomes
Primary outcomes
1
Clinical 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.Secondary outcomes
1
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.2
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.3
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.4
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.Sponsors and contacts
Click on the lead sponsor to view all of their trials.
Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
Lead sponsor
First Affiliated Hospital of Chongqing Medical University
Collaborator
Tianjin Medical University Second Hospital
Collaborator
Peking University First Hospital
Collaborator
Peking University People's Hospital
Collaborator
The First Affiliated Hospital with Nanjing Medical University
Collaborator
Shengjing Hospital
Collaborator
Fujian Provincial Hospital Affiliated to Fuzhou University
Collaborator
Source ClinicalTrials.gov