Efficacy of Camrelizumab in High-risk Non-muscle-invasive Bladder Cancer Failing BCG Treatment

Lead Sponsor: Fudan University

Collaborator: Shanghai Shen Kang Hospital Development Center
Jiangsu Hengrui Pharmaceuticals Co.,Ltd

Bladder cancer is one of the most common malignancies of the genitourinary male system, with approximately 70% of patients diagnosed with non-muscle invasive bladder cancer at the first visit. Intravesical BCG vaccine is the first choice to treat high-risk non-muscle invasive bladder cancer, which can delay tumor progression, improve overall survival and reduce tumor recurrence. Immunotherapy is a tumor treatment method that has emerged in recent years. In advanced bladder cancer, immune checkpoint inhibitors, represented by PD-1 and PD-L1 monoclonal antibody, have been included in the guidelines and become routine treatment. However, whether immune checkpoint inhibitors have similar efficacy to advanced uroepithelial carcinoma in the treatment of early-stage non-muscle invasive bladder cancer is still unknown, and there is much room for clinical research to explore. Current treatment with immune checkpoint inhibitors (PD-1, PD-L1, and CTLA-4 antibodies) in all major human solid tumors is administered intravenously. However, given the biological characteristics of early stage bladder cancer, local bladder perfusion delivery (chemotherapeutic agents and BCG) using the body's natural lumen is the most commonly used treatment in clinical practice. Intra bladder delivery reduces and minimizes the side effects of systemic intravenous drug delivery. The use of immune checkpoint inhibitors to regulate the local microenvironment of bladder tumors to achieve immune normalization, tumor killing, and delaying recurrence is undoubtedly more clinically promising. After searching pubmed and clinicaltrials.gov, we found no relevant literature reports and no clinical studies in progress or to be enrolled. This study will evaluate the maximum tolerated dose(MTD) of cariolizumab bladder perfusion therapy in patients with high-risk non-muscle-invasive bladder cancer who have failed BCG infusion,as well as high-grade free recurrence （HGFR） 3 months after bladder irrigation or intravenous treatment with cariolizumab.

• Urinary Bladder Neoplasms
• Immunotherapy

Intervention Type: Drug

Intervention Name: Camrelizumab

Description: Solution for Infusion (Intravesical and Intravenous) 。The dose of bladder perfusion is determined by the results of the dose creep phase of RP2D.The dose of intravenous drip is 200mg per time.

Criteria:

Inclusion Criteria: 1. Age ≥ 18 years. 2. Histologically-confirmed diagnosis of high risk non-muscle-invasive (T1,TaG3,carcinoma in situ [CIS] and/or TaG1G2 tumors with multiple, recurrent and diameter of > 3 cm at the same time) transitional cell carcinoma of the bladder (mixed histology tumors allowed if uroepithelial carcinoma histology is >50%). 3. Fully resected disease at study entry (residual CIS acceptable) 4. 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) 5. Ineligible for radical cystectomy or refusal of radical cystectomy 6. Consent to tissue specimen retrieval and testing 7. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 8. Adequate normal organ and marrow function as defined below: 1. Haemoglobin (HB) ≥ 90 g/L 2. Absolute neutrophil count (ANC) ≥1500/uL(no granulocyte colony-stimulating factor support for 2 weeks before day 1 of cycle 1) 3. Lymphocyte count≥0.500×10^9/L 4. Platelet count ≥100×10^9/L(No blood transfusions within 2 weeks before day 1 of cycle 1) 5. 4.0×10^9/L≤White Blood Cell Count (WBC)≤15×10^9/L 6. AST (SGOT)/ALT (SGPT)/Alkaline phosphatase ≤ 2.5 x institutional upper limit of normal(ULN) unless patients with known Gilbert's disease, in which its case serum bilirubin level must be ≤ 3x ULN 7. INR/aPTT≤1.5×ULN(Which only applies to patients not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be given a stable dose) 8. 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) 9. 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. 10. Men should consent to patients who must use contraception during the study and for 6 months after the end of the study period 11. The subject is personally willing and able to provide written informed consent to be able to comply with the protocol. Exclusion Criteria: 1. Muscle-invasive, locally advanced nonresectable, or metastatic urothelial carcinoma 2. Concurrent extra-vesical (i.e., urethra, ureter, or renal pelvis) non-muscle invasive transitional cell carcinoma of the urothelium 3. Have participated in a clinical trial of an investigational drug or device within 4 weeks prior to receiving the first treatment in this project 4. Received chemotherapy, targeted small molecule therapy, immunotherapy or radiation therapy following a recent cystoscopy or transurethral resection of a bladder tumour 5. History of other malignancies within the last 5 years 6. Active autoimmune disease that has required systemic treatment in the past 2 years 7. 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 8. 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) 9. Patients who are pregnant or breastfeeding, or expecting to conceive 10. 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 11. Patients with known positive test for human immunodeficiency virus (HIV) infection or known acquired immunodeficiency syndrome (AIDS) 12. 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). 13. Received a live virus vaccine within 30 days of planned start of study treatment 14. Has had an allogeneic tissue/solid organ transplant 15. Long-term oral steroids, more than 10 mg/day of methandrostenolone or similar, must be stopped for 28 days before entry into the group. 16. 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) 17. 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 18. 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. 19. 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 20. History of severe allergy, sensitisation or other hypersensitivity reactions to chimeric or humanised antibodies or fusion proteins 21. Patients who, in the opinion of the investigator, are otherwise unable to participate in this trial

Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

Last Name: Dingwei Ye, MD

Phone: +86-13701663571

Email: [email protected]

China

January 2021

Type: Sponsor

• Urinary Bladder Neoplasms

Label: Camrelizumab bladder irrigation therapy group

Type: Experimental

Description: Camrelizumab(SHR-1210) is administered on the first day of each treatment cycle (D1) at a dose determined by the results of the dose creep phase of RP2D. The perfusion cycle is divided into an induction course and a maintenance course. The induction course is initiated 2 weeks after TURBT and is perfused once a week for 6 weeks with a minimum of 1 hour retention in the bladder each time. The maintenance course starts at 13 weeks after TURBT with 200mg every 3 weeks. The maximum duration of dosing is 2 years.

Label: Camrelizumab intravenous treatment group

Type: Active Comparator

Description: The Camrelizumab would be administered on the first day (D1) of each treatment cycle (21 days) at a dose of 200 mg by 30-min intravenous infusion, (the allowable error in infusion time is -5 min, +10 min), the method of preparation of Camrelizumab (SHR-1210) needs to be performed according to the instructions.

Allocation: Randomized

Intervention Model: Parallel Assignment

Intervention Model Description: Major research stage Bladder perfusion group:Carrilizumab is administered on the first day of each treatment cycle (D1) at a dose determined by the results of the dose creep phase of RP2D. The perfusion cycle is divided into an induction course and a maintenance course. The induction course is initiated 2 weeks after TURBT and is perfused once a week for 6 weeks with a minimum of 1 hour retention in the bladder each time. The maintenance course starts at 13 weeks after TURBT with 200mg every 3 weeks. The maximum duration of dosing is 2 years. Intravenous drip group:Administered on the first day (D1) of each treatment cycle (21 days) at a dose of 200 mg by 30 minute intravenous infusion. Maximum duration of dosing is 2 years

Primary Purpose: Treatment

Masking: None (Open Label)