A phase II study of risk-based stratification after chemotherapy combined with PD-1 antibody: Two various bladder-sparing modalities for muscle invasive bladder cancer therapy (ReBirth).

Abstract

TPS580 Background: Neoadjuvant chemotherapy plus radical cystectomy is the standard for cisplatin-eligible patients with cT2-4aN0M0 muscle invasive bladder cancer, however, some of them desperately need innate bladder. Developments in the last two decades suggest that well-documented Trimodal therapy(TMT) demonstrated durable oncologic control and long-term survival in selected patients. Nevertheless, personalized treatment based on responses of systematic treatment and biomarker are currently lacking. Additionally, concerning a balance between non-inferiority of hypofractionated radiation therapy in local control and late toxicity, the specified dose regimen combined with immunotherapy is worth exploring. "ReBirth" study was designed to evaluate the efficacy and tolerability of two various bladder-sparing modalities with risk-based stratification after chemotherapy combined with PD-1 antibody. Methods: This is a single-arm, phase II trial that includes cT2-4aN0-1M0 patients who aged 18-85 years and histologically confirmed bladder urothelial carcinoma. Other key inclusion criteria: no prior anti PD-(L)1 therapy; ECOG 0-2 and cisplatin eligible. The trial consists of two stages. In the first stage, eligible patients will receive tislelizumab 200 mg in day 1 (D1), cisplatin 70 mg/m2 D1, and gemcitabine 1000 mg/m2 D1 and D8 every 21 days for four cycles. Patients will then be divided into two cohorts in the second stage based on the cystoscopy, urine cytology, and imaging combined with utDNA (urine tumor DNA). Patients who achieve clinical complete response (cT0, cTa) will enter into cohort 1 and treated with tislelizumab 200 mg IV Q3 for up to 6 months, while patients who did not achieve clinical complete response will enter into cohort 2 and treated with tislelizumab 200 mg IV Q3W for up to 6 months and chemoradiotherapy for whole bladder 44Gy/16 fractionation, if lymph node is positive, it can be dosed to the maximum tolerable dose, such as tumor boost 11Gy/4fractionation, combined with DDP as radiosensitizer. The primary endpoint is BIDFS (bladder intact disease-free survival) at one year, which is defined as time from initiation of protocol therapy until the development of muscle-invasive bladder cancer recurrence, regional pelvic recurrence, distant metastases, bladder cancer-related death, or cystectomy. Secondary endpoints include metastatic free survival rate at two years, BIDFS at two years and safety graded according to CTCAE V5.0. Tissue samples will be collected for genomic profiling and utDNA will be collected and examined for biomarker exploring in this bladder preservation therapy. Till Sep.2022, 5 of planned 30 patients have been enrolled. Clinical trial information: NCT05531123 .