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.
Men or women aged ≥ 18 years old;
ECOG PS:0～1;
The subjects need to undergo maximum TURBT surgery (no need for secondary resection) and imaging diagnosis. The researchers have determined that MIBC (urothelial carcinoma as the main pathological component>50%) is present, and plan to undergo radical cystectomy, lymph node dissection, and urinary diversion surgery;
cT2-T4a N0 M0 （CT/MRI ± PET/CT）;
Previous treatment with anti-PD-1, anti-PD-L1, and anti-PD-L2, including adjuvant therapy phase;
Individuals known to be allergic to recombinant humanized anti-PD-1 monoclonal antibody drugs and their components;
Those who have received systemic chemotherapy, radiation therapy, or other anti-tumor treatments (including corticosteroid therapy, immunotherapy) or participated in other clinical studies within 4 weeks before the start of treatment, or have not yet recovered from the previous toxicity (excluding 2nd degree hair loss and 1st degree neurotoxicity);
Pregnant or lactating women;
Single group
Disitamab Vedotin
DrugEach 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.
PD-1 inhibitor
DrugEach 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.
radiotherapy
Radiation1. 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
3-month Complete Response (3-month CR)
Three months after the start of treatment, if there is no visible tumor detected by imaging examination, the pathological evaluation of the tumor site obtained by diagnostic TURBT/cystoscopy is negative, and the urine cytology(for example, urine TCT) is negative, it is defined as CR. For the primary efficacy endpoint CR, the exact binomial distribution method will be used to provide point estimates, 95% confidence intervals, and p-values for testing response rates higher than the historical control (20%).
6/12/24-month Complete Response (6/12/24-month CR)
The complete response rate (CR) after 6/12/24 months of treatment initiation is defined as the absence of visible tumors on imaging examinations, negative pathological evaluation of tumor site obtained by diagnostic TURBT/cystoscopy, and negative urine cytology( for example: urine TCT ) in subjects after treatment. For the primary efficacy endpoint CR, the exact binomial distribution method will be used to provide point estimates, 95% confidence intervals, and p-values for testing response rates higher than the historical control (20%).
Bladder Intact Event-Free Survival (BI-EFS)
Record the survival time of patients with preserved bladder function after treatment and no specific adverse events (such as tumor recurrence, metastasis, death, or the need for bladder resection). Provide Kaplan Meier (KM) curves and median estimates as appropriate.
Relapse-Free Survival (RFS)
During the treatment and follow-up period, the recurrence of previously disappeared tumors was suspected by urine cytology (such as tct), imaging (such as MRI) and confirmed by cystoscopy or pathology, which is defined as recurrence. If there is a recurrence, record the local recurrence time and distant recurrence time. For statistical analysis of results, provide Kaplan Meier (KM) curves and median estimates as appropriate
Cancer-Specific Survival (CSS)
From the first treatment (surgery, TURBT), record whether these patients died of bladder cancer (for example, due to tumor progression, metastasis or cancer related complications, such as renal failure or sepsis secondary to obstruction), and calculate the time. And exclude (non CSS events): death from unrelated conditions (such as myocardial infarction, stroke, trauma) or secondary primary cancer due to the following reasons (unless it is proved to be metastasis or recurrence of bladder cancer). Tumors are detected every 3/6 months through urine cytology (such as TCT), imaging (such as CT, MRI), and confirmed by cystoscopy or pathology.
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