Treating Muscle-invasive Bladder Cancer With A Non-surgical Method Consisting of Anti-PD-1 Therapy and Chemoradiation

Study Overview
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Brief Summary
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The goal of this Phase 2 trial is to evaluate a non-surgical bladder-preserving treatment mode which consists of induction chemotherapy plus anti-programmed cell death protein 1 (anti-PD-1) therapy followed by radiotherapy plus concurrent anti-PD-1 therapy. The main questions it aims to answer are: (i) whether the anti-PD-1 antibody, toripalimab, is effective in treating muscle-invasive bladder cancer (MIBC), when combined with chemoradiation; (ii) whether toripalimab is safe in combination with chemoradiation. Participants will receive 3 cycles of induction treatment containing chemotherapy with gemcitabine and cisplatin/carboplatin, plus toripalimab. Then the ones without progressive disease will receive radical radiotherapy plus 2 cycles of concurrent toripalimab.

Detailed Description
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Bladder cancer is the second most common malignancies over the world. At initial diagnosis, the cases with muscle-invasive bladder cancer (MIBC) accounts nearly 20% of all bladder cancer patients. And 40% of non-muscle-invasive bladder cancer could develop to MIBC. Currently, radical cystectomy (RC) is the golden standard to manage MIBC. Yet, it brings severe surgical injuries and post-surgical complications which impair life quality of the patients. Recently, bladder-preserving treatment based gradually becomes the second choice for MIBC. It consists of maximal transurethral resection of bladder tumor (TURBT) and chemoradiation. A series of clinical trials and meta-analyses supported that the bladder-preserving treatment has a similar therapeutic effect compared with RC. But it is noteworthy that this treatment mode does not really avoid surgery. TURBT could also cause complications, such as haemorrhage, infection, perforation, and even tumor dissemination. Moreover, the incidence of serious toxicities brought by concurrent chemoradiation is as high as 36%. In actual clinical work, it is hard for more than half patients to complete chemoradiation of standard intensity. Additionally, many patients are unsuitable for bladder preservation, including those with T stage > T2, diameter > 5 cm, hydronephrosis and positive lymph nodes. Hence, it calls for improvement of current bladder preservation mode, to make more MIBC patients receive radical treatment which brings better therapeutic experience and life quality. Many lab studies indicated that formation and progression of bladder cancer is a process of mutation accumulation. It provides biological fundamentals for immune checkpoint inhibitors, such as anti-programmed cell death protein 1 (anti-PD-1) antibodies. Based on available clinical studies, anti-PD-1 antibodies exhibits ideal therapeutic effects in bladder cancer of different stages and has an incidence of toxicities as low as 13%. Its toxicities mainly include arthralgia and hyponatremia, which are well tolerated. Currently, there are more than 10 clinical trials trying anti-PD-1 antibodies for bladder preservation. However, the treatment modes in most of them still contain TURBT. This phase 2 trial intended to evaluate the therapeutic and adverse effects of a non-surgical bladder-preserving treatment mode consisting of anti-PD-1 antibodies and chemoradiation, in a small patient cohort with MIBC. The results might provide an effective, non-invasive and low-toxic choice which improves patient experience and realizes bladder preservation.

Official Title
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A Single-arm, Phase II Clinical Trial to Treat Muscle-invasive Bladder Cancer With Induction Chemotherapy Plus Anti-PD-1 Therapy Followed by Radiotherapy Plus Concurrent Anti-PD-1 Therapy

Conditions
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Muscle-Invasive Bladder Carcinoma, Programmed Cell Death Protein 1 Inhibitor, Radiotherapy

Intervention / Treatment
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* Drug: Toripalimab
* Drug: Gemcitabine
* Drug: Cisplatin
* Drug: Carboplatin
* Radiation: Intensity-modulated radiation therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologically diagnosed bladder malignant tumor via biopsy Urothelial carcinoma as the primary histological component Pretreatment clinical TNM stage as T2-4aN0M0 or T1-4aN1-2M0 (UICC TNM staging classification, version 8) Age between 18 and 75 years old Karnofsky performance score ≥ 70 Creatinine clearance rate ≥ 30 ml/min Exclusion Criteria: Simultaneous tumors of the urethra or upper urinary tract Existence of small cell cancer component Uncontrolled tuberculosis, viral hepatitis or AIDS Autoimmune or mental diseases Severe cardiac, renal, hepatic or hematopoietic dysfunctions unsuitable for chemotherapy, radiotherapy or immune checkpoint inhibiting therapy Prior history of other malignancies within 5 years, except cured cervical carcinoma in situ and skin basal cell carcinoma Prior history of pelvic radiotherapy or chemotherapy Poor adherence to regular follow-up (cystoscopy, CT, MRI, etc.) Pregnant or lactating women Treatment with glucocorticoid or immunosuppressive drugs within 1 month Other situations for which the investigators consider a patient inappropriate to participate

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: This Phase 2 trial uses a single-arm, Simon's two-stage design.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Toripalimab plus chemoradiation<br>This study has only single arm in which the patients will receive induction chemotherapy plus anti-PD-1 therapy (toripalimab), followed by radiotherapy plus concurrent anti-PD-1 therapy | Drug: Toripalimab<br>* The patients in this arm will receive 3 cycles of induction treatment containing chemotherapy with gemcitabine and cisplatin/carboplatin, plus toripalimab. Then the ones without progressive disease will receive radical radiotherapy, plus 2 cycles of concurrent toripalimab. Toripalimab: 240 mg on Day 1, every 3 weeks, totally 3 and 2 cycles in the induction and concurrent phases, respectively.<br>* Other names: JS001;Drug: Gemcitabine<br>* The patients in this arm will receive 3 cycles of induction treatment containing chemotherapy with gemcitabine and cisplatin/carboplatin, plus toripalimab. Then the ones without progressive disease will receive radical radiotherapy, plus 2 cycles of concurrent toripalimab. Gemcitabine: 1 g/m2 on Days 1 and 8, repeated every 3 weeks, totally 3 cycles.<br>Drug: Cisplatin<br>* The patients in this arm will receive 3 cycles of induction treatment containing chemotherapy with gemcitabine and cisplatin/carboplatin, plus toripalimab. Then the ones without progressive disease will receive radical radiotherapy, plus 2 cycles of concurrent toripalimab. Cisplatin: Used when creatinine clearance rate ≥ 40 ml/min, 37.5 mg/m2 on Days 1 and 2, repeated every 3 weeks, totally 3 cycles.<br>Drug: Carboplatin<br>* The patients in this arm will receive 3 cycles of induction treatment containing chemotherapy with gemcitabine and cisplatin/carboplatin, plus toripalimab. Then the ones without progressive disease will receive radical radiotherapy, plus 2 cycles of concurrent toripalimab. Cisplatin: Used when creatinine clearance rate < 40 ml/min, area under curve = 2 on Days 1 and 2, repeated every 3 weeks, totally 3 cycles.<br>Radiation: Intensity-modulated radiation therapy<br>* The patients in this arm will receive 3 cycles of induction treatment containing chemotherapy with gemcitabine and cisplatin/carboplatin, plus toripalimab. Then the ones without progressive disease will receive radical radiotherapy, plus 2 cycles of concurrent toripalimab. Radiotherapy: performed by using the technique of intensity-modulated radiation therapy, with a total dose of 65 and 45 Gy for the gross tumor and lymphatic drainage regions.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical complete response (cCR) rate | The percentage of the cases attaining cCR of primary tumor and regional lymph nodes (confirmed by radiography and cystoscopy) | When the eligible patients complete the treatment and followed-up for half a year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological complete response (pCR) rate | The percentage of the cases attaining pCR of primary tumor (confirmed by multipoint biopsy under cystoscopy) | When the eligible patients complete the treatment and followed-up for half a year | 
| Overall survival (OS) | The percentage of the cases surviving over a given time period | When the eligible patients complete the treatment and followed-up for 1 and 2 years | 
| Bladder-intact event-free survival (BI-EFS) | The percentage of the cases surviving with intact bladder and without muscle-invasive recurrence, regional lymph node recurrence or distant metastasis, over a given time period | When the eligible patients complete the treatment and followed-up for 1 and 2 years | 
| Disease-free survival (DFS) | The percentage of the cases surviving without locoregional recurrence or distant metastasis over a given time period | When the eligible patients complete the treatment and followed-up for 1 and 2 years | 
| Local recurrence (LR) rate | The percentage of the cases with locoregional recurrence over a given time period | When the eligible patients complete the treatment and followed-up for 1 and 2 years | 
| Incidence of grade 3/4 (G3/4) acute toxicities | The percentage of the cases with any G3/4 toxicity during the period of treatment | Once a week for each patient, until the last day of treatment | 
| Bladder function | The quantitative score of bladder function at a given time point, based on the Quality of Life 30-item Questionnaire, Bladder Module (QLQ-BLM30) from the EORTC | Once per 3 months for each patient, until the last follow-up (2 years after treatment) | 
| Best objective response rate (ORR) | The percentage of the cases attaining clinical complete or partial response of primary tumor and regional lymph nodes (confirmed by radiography and cystoscopy) | A week before radiotherapy, a week before boost radiation, and once per 3 months until the last follow-up (2 years after treatment) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bladder Cancer, Programmed Cell Death Protein 1 Inhibitor, Radiotherapy, Chemotherapy, Bladder Preservation