NCT07142200

A Clinical Study Evaluating the Efficacy and Safety of Disitamab Vedotin Combined With PD-1 Inhibitor and Radiotherapy as Bladder-preserving Therapy in Patients With Localized HER2-high Expressing Muscle-invasive Bladder Urothelial Carcinoma Following Maximal Transurethral Resection

• Status: Not Yet Recruiting
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 45 (estimated)
• Sponsor: RenJi Hospital · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

This is a prospective, open label, multicenter clinical study of vediximab combined with PD-1 and radiation therapy for bladder preservation in MIBC patients with HER-2 high expression (IHC 2+or 3+), conducted in accordance with Good Clinical Practice (GCP). Each patient received treatment with Vediximab injection \[2.0 mg/kg, Q2W, iv\] and Triprolizumab injection \[3mg/kg, Q2W, iv\] for one cycle, followed by concurrent radiotherapy in the second cycle. Assuming a 20% improvement in the efficacy of conventional TMT bladder protection treatment, i.e. an increase in CR rate from 60% to 80%, alpha of 0.05, and beta of 0.2, a sample size of 36 is required. Considering a 20% dropout rate, 45 subjects need to be enrolled. The subjects need to undergo maximum transurethral resection of the bladder (TURBT) and imaging diagnosis, and collect urine samples before treatment. The researchers judged that localized myometrial invasive bladder cancer with high HER2 expression could be treated with bladder conserving therapy by maximizing TURBT. The patient will receive treatment with vediximab combined with PD-1 and radiotherapy after TURBT surgery (without the need for secondary resection). The subjects should receive treatment with vediximab combined with PD-1 every two weeks for a total of 12 treatment cycles, and receive radiation therapy simultaneously. The specific number of treatment cycles will be determined by the researchers based on the patient's response to the treatment, tolerance to the regimen, and overall judgment of the condition. Patients with safety intolerance caused by any drug treatment will be reduced or discontinued according to the dosage adjustment plan specified in the regimen. After completing the above treatments, the pathology, imaging, and cytology of the tumor site were obtained through diagnostic TURBT or cystoscopy for tumor evaluation to assess whether complete remission was achieved. The first tumor efficacy evaluation was conducted 3 months after receiving treatment, and the researcher judged whether to continue treatment based on the patient's treatment status. After completing the treatment for the next 3 months, another tumor efficacy evaluation was conducted. After completing all 12 treatment cycles (6 months), the patient underwent two tumor evaluations at the 6th month (from the 12th month of treatment) and the 12th month (from the 24th month of treatment), respectively.

Detailed description

MIBC has a poor prognosis, and even with radical surgery, the 5-year survival rate is less than 60%. Although immune checkpoint inhibitors have made rapid progress in the treatment of advanced bladder and urinary tract epithelial cancer in the past year, many drugs have been approved for market both domestically and internationally. Immunosuppressants targeting PD-1 or its ligand PD-L1, including Nivolumab, Pembrolizumab, Trastuzumab, and Triprolizumab, have been proven to be a promising approach for tumor immunotherapy. The Phase III clinical trial of Pembrolizumab compared with chemotherapy for the treatment of advanced bladder and urinary tract epithelial cancer has been successful. Nivolumab has an objective efficacy rate of 24.4% in patients with advanced bladder and urinary tract epithelial cancer who have previously failed treatment. Domestic trastuzumab (targeting high PD-L1 expression) and terilelizumab have significantly improved ORR and OS in patients who have failed platinum based chemotherapy, and the DoR of beneficiary patients has been significantly prolonged. Therefore, the efficacy of anti-PD-1 monoclonal antibody in advanced bladder and urinary tract epithelial cancer has been validated. In PURE-01, Pembrolizumab achieved a complete disease response rate of 42% in preoperative neoadjuvant therapy for MIBC, greatly changing the treatment status. Terriptylimab also achieved a pCR rate of 40% in neoadjuvant therapy for MIBC. Whether the bladder can be preserved in patients with localized MIBC has always been a hot topic in clinical research. The ANZUP 1502 study is a phase II clinical trial evaluating the combination of Pembrolizumab and concurrent chemoradiotherapy for the treatment of MIBC, with 90% of patients achieving complete remission after 24 weeks. At the same time, TMT combined with immunotherapy achieved good bladder preservation effects in both the IMMUNOPRESSE-SOGUG study (electrocautery durvalumab+Treme radiotherapy, 12 week cCR rate of 81%) and the BTCR-GU15-023 study (durvalumab+radiotherapy, cCR rate of 54.5%). Therefore, based on the excellent results of phase II clinical studies, there are currently multiple phase III clinical studies underway, including KEYNOTE-992, SWOG1806, SunRISe-2, INTACT studies, etc. Vidiximab for injection (product code: RC48, RC48-ADC) is an innovative new therapeutic biologic developed to meet the needs of patients with HER2 expressing malignant solid tumors. The injection of vediximab mainly exerts anti-tumor effects through two pathways: one is to inhibit the activation of HER2 downstream signaling pathways (such as PI3K/AKT) by binding to HER2 molecules on the surface of tumor cells, thereby interfering with cell transcription, growth, and proliferation; The second is through the action of small molecule MMAE on microtubule proteins during mitosis, which interferes with the formation of microtubules in cells, mainly manifested as depolymerization of microtubules and induction of cell cycle arrest in the G2/M phase. RC48-C005/C09 is a combined analysis of two clinical studies, C005 and C009. The trial enrolled a total of 107 patients with advanced urothelial carcinoma who had previously received first-line or above systemic therapy but failed. Among all 107 patients, the ORR evaluated by IRC was 50.5% (95% CI: 40.6, 60.3), and the BOR evaluation results showed that 2 patients achieved CR and 52 patients achieved PR. From a biological perspective, the combination of targeted therapy and immunotherapy can simultaneously block the HER2 signaling pathway and PD-1/PD-L1 signaling pathway, bridge PD-1 expressing T lymphocytes and HER2 expressing tumor cells, and assist T cells in recognizing and killing tumor cells. In addition, the warhead of ADC drugs can cause tumor cell destruction through cytotoxic effects (especially the destruction of microtubules by MMAE), and the release of calcitonin, heat shock proteins, and other substances on the surface of apoptotic cells can induce immunogenic cell death (ICD), thereby activating T cells. MMAE and other microtubule protein stabilizers (MSA) can directly activate antigen-presenting cells (such as dendritic cells), promote DC maturation, enhance T cell recruitment, and reduce immune suppression in tumor tissues. Therefore, the combination of anti-HER2ADC and PD-1/L1 drugs has a synergistic effect, which can improve the immunosuppressive effect in the tumor microenvironment and enhance the infiltration of immune cells into the tumor. In the RC48-C014 study, the combination of vediximab (RC48) and terilelimab (JS001) was used for mUC with previous first-line treatment failure or intolerance/unwillingness to receive cisplatin chemotherapy. The study results showed an objective response rate of 73.2%, with an objective response rate of 76% in the first-line population, including HER2 IHC (2+/3+) and PD-L1 (+); The objective response rates of HER2 IHC (2+/3+) and PD-L1 (-) patients were 75% and 87.5%, respectively. Meanwhile, there was no significant increase in treatment-related adverse reactions compared to monotherapy. In the first phase of this study, 6 patients did not experience any DLT events within 28 days after receiving the study drug and radiotherapy. According to the definition of the first phase study, this protocol is considered safe. In the first stage of patients, the CR rate reached 83% in March, which has preliminarily returned to normal for its effectiveness. Therefore, based on the results of the first stage, further research will be conducted in the second stage.

Conditions

• Bladder (Urothelial, Transitional Cell) Cancer

Interventions

Type	Name	Description
DRUG	Disitamab Vedotin	Each patient will receive Disitamab Vedotin injection \[2.0 mg/kg, Q2W, iv\], with an expected total of 12 courses of treatment. The specific number of treatment cycles is determined by researchers based on the patient's response to the treatment, tolerance to the treatment plan, and comprehensive assessment of the condition. Patients with safety intolerance caused by any drug treatment should reduce or discontinue the medication according to the dosage adjustment plan specified in the plan. The medication is diluted with physiological saline and administered intravenously for one hour.
DRUG	PD-1 inhibitor	Each patient will receive Triprolizumab injection \[3mg/kg, Q2W, iv\], with an expected total of 12 courses of treatment. The specific number of treatment cycles is determined by researchers based on the patient's response to the treatment, tolerance to the treatment plan, and comprehensive assessment of the condition. Patients with safety intolerance caused by any drug treatment should reduce or discontinue the medication according to the dosage adjustment plan specified in the plan. The medication is diluted with physiological saline and administered intravenously for one hour.
RADIATION	radiotherapy	1. Whole bladder treatment, recommended scope of application: T2 Suggestion: The total bladder radiotherapy dose is 2Gy/day, five times a week, up to a dose of 50Gy/25 times, to cover at least 95% of the planned target volume (PTV full bladder). The radiation dose for shrinking the field to bladder tumors is 2Gy/day, five times a week, with a total dose of 14Gy/7 times, to cover at least 95% of the planned target dose (PTV bladder tumors). 2. Whole pelvic radiotherapy (whole bladder+selective pelvic lymph node radiotherapy), applicable range: T3-T4a Suggestion: Whole pelvic radiotherapy at 2Gy/day, five times a week, up to a dose of 46Gy/23 times, to cover at least 95% of the planned target dose. Reduce the dosage to 2Gy/day for the entire bladder and up to 4Gy/twice. Bladder tumor (PTV bladder tumor) 2Gy/day, five times a week, with a total dose of 14Gy/7 times, to cover at least 95% of the planned target volume. The above radiotherapy plan is a suggestion, and the specific plan will

Timeline

• Start date: 2025-09-01
• Primary completion: 2026-06-30
• Completion: 2027-12-31
• First posted: 2025-08-26
• Last updated: 2025-08-26

Locations

1 site across 1 country: China