Safety and Efficacy of Camrelizumab for High-risk NMIBC Failing BCG Treatment

Study Overview
=================
Brief Summary
-----------------
This study will evaluate the safety and efficacy of bladder intravesical Camrelizumab in patients with high-risk non-muscle-invasive bladder cancer who failed BCG therapy.

Official Title
-----------------
A Phase I/II Single Arm Study of Intravesical Administration With Camrelizumab for High-risk Non-muscle Invasive Bladder Cancer(NMIBC) Failing in BCG Treatment

Conditions
-----------------
Urinary Bladder Neoplasms, Immunotherapy

Intervention / Treatment
-----------------
* Drug: Camrelizumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥ 18 years. Histologically-confirmed diagnosis of high risk non-muscle-invasive urothelial cell carcinoma of the bladder (mixed histology tumors allowed if urothelial carcinoma histology is >50%). Fully resected disease at study entry (residual CIS acceptable). BCG-unresponsive high risk non-muscle-invasive bladder cancer after treatment with adequate BCG therapy(at least five times a week during the induction phase and at least two times a week during the maintenance phase). Ineligible for radical cystectomy or refusal of radical cystectomy. Consent to tissue specimen retrieval and testing. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Adequate normal organ and marrow function as defined below: Haemoglobin (HB) ≥ 90 g/L Absolute neutrophil count (ANC) ≥1.5×10^9/L(no granulocyte colony-stimulating factor support for 2 weeks before day 1 of cycle 1) Lymphocyte count≥0.500×10^9/L Platelet count ≥100×10^9/L(No blood transfusions within 2 weeks before day 1 of cycle 1) 4.0×10^9/L≤White Blood Cell Count (WBC)≤15×10^9/L AST (SGOT)/ALT (SGPT)/Alkaline phosphatase ≤ 2.5 x institutional upper limit of normal(ULN) (excluded Gilbert's disease patients, whose serum bilirubin level ≤ 3x ULN) INR/aPTT≤1.5×ULN(Which only applies to patients not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be given a stable dose) Serum creatinine (Cr) ≤ 1.5 times the upper institutional limit of normal (ULN) or Serum creatinine Cl>60 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) Women of childbearing potential who have a negative serum pregnancy test within 72 hours prior to the first dose should consent to and must use effective contraception during and for 6 months after the end of the study. Men should consent to patients who must use contraception during the study and for 6 months after the end of the study period. The subject is personally willing and able to provide written informed consent to be able to comply with the protocol. Exclusion Criteria: Muscle-invasive, locally advanced nonresectable, or metastatic urothelial carcinoma. Concurrent extra-vesical (i.e., urethra, ureter, or renal pelvis)urothelial cell carcinoma. Have participated in a clinical trial of an investigational drug or device within 4 weeks prior to receiving the first treatment in this project. Received chemotherapy, targeted small molecule therapy, immunotherapy or radiation therapy following a recent cystoscopy or transurethral resection of a bladder tumour. History of other malignancies within the last 5 years. Active autoimmune disease that has required systemic treatment in the past 2 years. History of idiopathic pulmonary fibrosis (including pneumonia), drug-induced pneumonia, histoplasmosis (i.e. occlusive bronchiolitis, cryptogenic histoplasmosis), or evidence of active pneumonia on chest CT scan (history of fibrosis in radiation pneumonia), patients with active tuberculosis. Active infection requiring systemic therapy,therapeutic oral or intravenous (IV) antibiotics within 14 days prior to enrolment (patients receiving prophylactic antibiotics (e.g. for the prevention of urinary tract infections or chronic obstructive pulmonary disease) can be enrolled). Patients who are pregnant or breastfeeding, or expecting to conceive . Previous treatment with anti-PD-1 monoclonal antibody, PD-L1 monoclonal antibody, CTLA-4 monoclonal antibody, or other drugs that act on T-cell co-stimulation or any other antibody of the checkpoint pathway. Patients with known positive test for human immunodeficiency virus (HIV) infection or known acquired immunodeficiency syndrome (AIDS). Patients with known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (Hepatitis B reference: HBsAg positive and HBV DNA ≥ 500 IU/ml; Hepatitis C reference: HCV antibody positive and HCV viral copy number > upper limit of normal value). Received a live virus vaccine within 30 days of planned start of study treatment. Has had an allogeneic tissue/solid organ transplant. Long-term oral steroids, more than 10 mg/day of methandrostenolone or similar, must be stopped for 28 days before entry into the group. Evidence of apparently uncontrolled concomitant disease that may affect compliance with the protocol or interpretation of the results, including significant liver disease (e.g. cirrhosis, uncontrolled major seizures or superior vena cava syndrome). Significant cardiovascular disease, such as New York Heart Association heart attack (class II or higher), myocardial infarction, unstable arrhythmia or unstable angina within 3 months prior to study entry. Patients who have had major surgery within 4 weeks prior to study entry, or who are expected to require major surgery during the course of the study, except diagnostic procedures such as TURBT or biopsy. History of autoimmune diseases, including but not limited to severe muscle weakness, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, angio-thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, dry syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. History of severe allergy, sensitisation or other hypersensitivity reactions to chimeric or humanised antibodies or fusion proteins. Patients who, in the opinion of the investigator, are otherwise unable to participate in this trial.

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intravesical therapy group<br>Camrelizumab(SHR-1210) is administered on the first day of each treatment cycle (D1) at a dose up to 200 mg. The recommended phase II dose(RP2D) to be decided after safety run-in. The cycle is divided into an induction course and a maintenance course. The induction course is initiated 2 weeks after TURBT and repeat once a week for 6 weeks . After that, the maintenance course starts every 3 weeks. The maximum duration of dosing is 2 years. | Drug: Camrelizumab<br>* Solution for Infusion (Intravesical)<br>* Other names: SHR-1210;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The maximum dose of Camrelizumab for intravesical treatment | The maximum tolerated dose (MTD) of Camrelizumab that will be given intravesically to patients with BCG-refractory NMIBC(de-escalated doses of 200/150/100mg) and recommended for phase II studies (RP2D). | 3 months after trial initiation(Phase I) | 
| Event-Free Survival (EFS) | Recurrence of high-grade cancer (TaHG, T1HG, CIS), or disease progression to stage T2 or beyond or lymph node metastasis or distant metastasis, or the need for other treatment (including systemic chemotherapy, radical cystectomy, radiation therapy), and death from any cause. | 3 months after patient treatment (Phase II) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events | Incidence of adverse events and treatment-related adverse events | Until progressive disease or death | 
| Assessment of HGRF | High grade cancer recurrence free rate (HGFR) at 6 months and 1 year of treatment. | 6 months and 1 year after patient enrollment | 
| Assessment of RFS | Recurrence free survival (RFS) at 6 months and 1 year of treatment. | 6 months and 1 year after patient enrollment | 
| Assessment of PFS | Progression free survival (PFS) at 6 months and 1 year of treatment. | 6 months and 1 year after patient enrollment | 
| the predictive value of PD-1 expresssion | the predictive value of PD-L1 expression assessed in tumor tissue and urine sample obtained before and after Camrelizumab instillation. | 1 year after patient enrollment |