Active Surveillance Versus Definitive Local Therapy for Patients Showing Clinical Complete Response Following Neoadjuvant Therapy for Muscle Invasive Bladder Cancer
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 688
- 试验地点
- 2
- 主要终点
- Metastasis free survival at 2 years (phase 3)
研究概览
简要总结
Invasive bladder cancer is managed with neoadjuvant therapy followed by bladder removal (cystectomy). Research shows that approximately 40% of patient will have no remaining cancer left in their bladder after completion of the initial systemic treatment, and perhaps could have avoided the surgery. However, currently physicians lack the ability to identify these patients.
The investigators believe that by using advanced imaging (MRI), bladder biopsies and novel biomarkers that detect tumor DNA in blood, they can better identify participants without any remaining cancer after chemotherapy. This will make active surveillance of these participants safer. In this study, participants without evidence of residual cancer will be randomized to active surveillance vs conventional bladder treatment (bladder removal, or chemo-radiation of the bladder). This study will be a pilot randomized control trial (RCT), and if successful, it will transition to a larger phase 3 RCT.
详细描述
Purpose To assess the feasibility to randomize patients with muscle-invasive bladder cancer (MIBC) who experience a complete clinical response (cCR) following neoadjuvant therapy (NAT), as defined by negative ctDNA, negative bladder MRI and negative repeat TURBT to active surveillance vs standard of care (SOC) with definitive bladder treatment.
Hypothesis The hypothesize is that the combination of bladder re-staging with MRI, repeat biopsy and the use of ctDNA will markedly enhance the ability to identified participant who achieve an excellent response to NAT (cCR) and who could safely be offered AS.
Justification:
Cisplatin-based neoadjuvant therapy (NAT) followed by radical cystectomy (RC), or alternatively in selected patient, a combination of chemo-radiation (trimodal therapy, TMT), are the current standards of care for treatment of MIBC. However, both have significant potential toxicity that can impact quality of life. Clinical trials have demonstrated that up to 38% of patients have a pathologic complete response (pCR) to NAT. Those patients could potentially avoid RC or TMT. Unfortunately, the clinical tools to predict pCR are still considered inadequate and definitive local therapy is advised. Retrospective data and now prospective phase 2 trials have reported promising outcomes in selected patients undergoing active surveillance. A prospective randomized trial is still lacking to ensure non-inferiority of active surveillance over the standard of care.
Primary Objectives:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 19 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female >18 years
- •Primary urothelial or predominantly (>50%) urothelial carcinoma of the bladder with histologic evidence of muscularis propria invasion.
- •Clinical stage T2-T4aN0M0 (Radiographic lymphadenopathy greater than 1.5 cm in short axis by imaging must be proven by biopsy to be free of cancer)
- •No concomitant multifocal carcinoma in situ; a single focus is allowed.
- •ECOG performance status 0, 1, or
- •Participants must be able to undergo pelvis MRI.
- •Medically appropriate candidate for radical cystectomy (assessed by uro-oncologist) or chemo-radiation (assess by radiation-oncologist and medical-oncologist)
- •Participants must be candidate to received standard of care (SOC) neoadjuvant systemic treatment at time of enrolment (assessed by medical-oncologist): 4 or more cycles of cisplatin-based chemotherapy (gemcitabine/cisplatin (GC) or methotrexate/vinblastine/Adriamycin/cisplatin (MVAC) or dose-dense MVAC (ddMVAC). If SOC evolves from the time of trial design and enrolment, eligibility to any SOC NAT (for example immunotherapy and/or antibody drug conjugate, as per NCCN guideline) will be allowed.
- •Adequate bladder function and/or absence of significant urethral stricture to allow cystoscopic surveillance, as evaluate by urologist.
排除标准
- •Any component of small cell or plasmacytoid histology.
- •Prior systemic chemotherapy or immunotherapy (an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways) or antibody-drug conjugate (NECTIN-4, HER2 or other) : Participants who have received any previous systemic therapy for urothelial carcinoma or cytotoxic chemotherapy, immunotherapy or other targeted therapy for another malignancy within 2 year of study entry are ineligible.
- •No available bladder tumor tissue from prior TURBT for tumor sequencing.
- •Prior or concurrent malignancy of any other site EXCEPT for non-melanoma skin cancer OR low risk malignancy not requiring treatment (such as prostate cancer Grade Group 1 under adequate surveillance, carcinoma in situ of the breast, cervix, etc.) AND unless free of disease for ≥ 5 years. Other cancers at low risk of recurrence may be allowed after review by principal investigator.
- •Prior radiation therapy for bladder cancer.
- •Participants who have received experimental agents within 4 weeks of study entry.
- •Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection (defined by current oral or intravenous antibiotic therapy), symptomatic congestive heart failure (NYHA >2), unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
- •Pregnancy. People of childbearing potential must have a negative serum pregnancy test before general anesthesia procedure and MRI
- •No concurrent treatment on another clinical trial; supportive care trials or non-therapeutic trials (e.g., quality of life) are allowed.
结局指标
主要结局
Metastasis free survival at 2 years (phase 3)
时间窗: 24 months
Time to metastasis, defined as \>cN1 (more than 1 clinically suspicious lymph nodes), cT4a (unresectable disease), or M1 disease or death.
Proportion of patients found to have a cCR and randomized on the number of patients enrolled (pilot-RCT ; phase 2)
时间窗: 24 months
Feasibility to randomized patients with cCR to either active surveillance or definitive bladder treatment.
次要结局
- Bladder-intact event-free survival(24 months)
- Proportion of cCR patient with ypT0(24 months)
- Overall survival(24 months)
- Acceptance rate to treatment allocation(6 months)
- Quality of life measure by EORTC-QLQ-C30 in participants according to treatment received(24 months)
- Quality of life measure by EORTC QLQ BLM-30 in participants according to treatment received(24 months)
研究者
Peter Black
Professor
University of British Columbia