Tilelizumab Combined With Nab-Paclitaxel for High-Risk Non-Muscle-Invasive Urothelial Bladder Carcinoma Which is Not Completely Resectable: a Multi-center Study

Study Overview
=================
Brief Summary
-----------------
This is a phase II study to determine the safety and efficacy of tislelizumab when given in combination with nab-paclitaxel as treatment for patients with high-risk non-muscle-invasive bladder cancer (HR NMIBC) which is not completely resectable. Patients will receive treatment with tislelizumab in combination with nab-paclitaxel every 3 weeks for 4 treatment cycles over 12 weeks followed by transurethral resection biopsy.

Official Title
-----------------
An Open Label, Single-arm, Phase 2 Study of Tislelizumab Combined With Nab-Paclitaxel for Patients With High-Risk Non-Muscle-Invasive Urothelial Bladder Carcinoma Which is Not Completely Resectable: a Multi-center Study

Conditions
-----------------
High-Risk Non-Muscle Invasive Bladder Urothelial Carcinoma

Intervention / Treatment
-----------------
* Drug: Tislelizumab Nab paclitaxel


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Willing and able to provide written informed consent; Ability to comply with the protocol; Age ≥ 18 years; High-risk non-muscle-invasive urothelial carcinoma or high-risk non-muscle-invasive urothelial carcinoma as the main pathological component > 50%, difined as following: a. T1 b. High-grade Ta c.Carcinoma in situ(CIS); Multi-point biopsy of bladder shows there are more than 2 section and over 3 points of pathological specimens are diagnosed as above, meanwhile, the tumor has to be diagnosed as not completely resectable by at least 2 senior urologist; Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2; Agreed to provide tissue examination samples (for detection of PD-L1 expression, tumor mutation load, IHC, detection of DNA and RNA, etc;) Organ function level must meet the following requirements: Hematological indexes: neutrophil count >= 1.5x10^9/L, platelet count >= 80x10^9/L, hemoglobin >= 6.0 g/dl (can be maintained by blood transfusion); Liver function: total bilirubin <=1.5 ULN, alanine aminotransferase and aspartate aminotransferase <=2.5 ULN; The subjects volunteered to join the study, signed informed consent, and had good compliance with follow-up; Exclusion Criteria: Receive live attenuated vaccine within 4 weeks before treatment or during the study period; Active, known or suspected autoimmune diseases; History of primary immunodeficiency; Known history of allogeneic organ transplantation and allogeneic hematopoietic stem cell transplantation; Pregnant or lactating female patients; Untreated acute or chronic active hepatitis B or hepatitis C infection. Under the condition of monitoring the virus copy number of patients receiving antiviral treatment, doctors can judge whether they are in line with the patients' individual conditions; Prior use of immunosuppressive drugs within 4 weeks prior to the start of treatment, excluding nasal and inhaled corticosteroids or physiological doses of systemic steroids (i.e. not more than 10 mg / day prednisolone or other corticosteroids with the same physiological dose); Known or suspected allergy to tislelizumab and albumin paclitaxel; Have a clear history of active tuberculosis; Received PD-1 / PD-L1 / CTLA-4 antibody or other immunotherapy in the past; Participating in other clinical researchers; Men with reproductive capacity or women who are likely to become pregnant do not take reliable contraceptive measures; Uncontrolled concurrent diseases, including but not limited to: HIV infected (HIV antibody positive); Severe infection in active stage or poorly controlled; Evidence of serious or uncontrollable systemic diseases (such as severe mental, neurological, epilepsy or dementia, unstable or uncompensated respiratory, cardiovascular, liver or kidney diseases, uncontrolled hypertension [i.e. hypertension greater than or equal to CTCAE grade 2 after drug treatment]); Patients with active bleeding or new thrombotic disease

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tislelizumab and Nab-Paclitaxel<br>Tislelizumab 200mg IV on day 1 in combination with nab-paclitaxel 200mg IV on day 2 every 3 weeks for 3 or 4 cycles followed by transurethral resection biopsy. | Drug: Tislelizumab Nab paclitaxel<br>* Tislelizumab 200mg will be administered on Day 1 of each cycle for 4 treatment cycles;Nab-paclitaxel 200mg will be administered on Day 2 of each cycle for 4 treatment cycles.<br>* Other names: BGB-A317;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response (CR) Rate for tilelizumab combined with nab-paclitaxel |  | At the time of transurethral resection biopsy (within 9 or 12 weeks of the first dose of tislelizumab) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cystectomy-Free Survival (CFS) | defined from D1 of treatment until cystectomy | up to 3 years | 
| Duration of Response (DOR) |  | up to 3 years | 
| Number of adverse events and severity by grade (CTCAE) Number of adverse events and severity by grade (CTCAE) | Safety and toxicity will be characterized according to the reported adverse event (AE) profile using NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0, as well as a patient questionnaire derived from the Patient Reported Outcomes (PRO)-CTCAE and Patient Reported Outcomes Measurement Information System (PROMIS). | 12 weeks of treatment plus 30 days for toxicity followup | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Tislelizumab Nab-Paclitaxe