A Study of SHR-1501 Alone or in Combination With BCG in Subjects With NMIBC

Study Overview
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Brief Summary
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The study is to evaluate the safety and tolerability of SHR-1501 alone or in combination with BCG intravesical therapy in the patients with NMIBC, and to determine the RP2D of SHR-1501 in combination with BCG. To evaluate the preliminary efficacy of SHR-1501 alone or in combination with intravesical BCG in the treatment of NMIBC.

Official Title
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Phase I/II Clinical Study of Dose Escalation and Dose Expansion of SHR-1501 Alone or in Combination With Bacille de Calmette Guerin （BCG）in the Treatment of Non-muscle Invasive Bladder Cancer（NMIBC）

Conditions
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High-risk NMIBC

Intervention / Treatment
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* Drug: SHR-1501


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Voluntarily participate in this clinical study, understand the research procedures and be able to sign the informed consent in writing; Age ≥ 18 years old, gender is not limited; Eastern Cooperative Oncology Group (ECOG) performance status score ≤2; Expected survival time ≥ 2 years; High-risk NMIBC diagnosed by previous pathological biopsy Cystoscopy within 6 weeks before the first administration shows that the lesion has been completely removed, or the residual lesion is only carcinoma in situ; for T1 stage lesions, postoperative pathological results must show the presence of bladder muscle tissue; ineligible or unwilling to undergo radical cystectomy; The level of organ function is good. Female or male subjects of childbearing age who did not undergo surgical sterilization shall agree to use contraceptive measures (such as intrauterine device and contraceptive pill) during the study treatment period and within 3 months after the end of the study treatment period, and the female subject and the female partner of the male subject should use highly effective contraceptive methods; the female subject of childbearing age without surgical sterilization must be negative for serum HCG within 7 days before the first administration and must be non-lactating. Exclusion Criteria: Received surgery or radiotherapy for bladder lesions within 2 weeks before the first administration; Those who have previously received the following treatments and have not experienced disease progression before enrolment t as assessed by the investigator: Intravesical instillation of cytotoxic chemotherapy or other drugs; Immune checkpoint inhibitor; Other investigational products for the treatment of NMIBC. Currently receiving study treatment in other clinical trials or less than 4 weeks from last participation to the first administration of this study; Upper urinary tract tumor detected by CTU or MRU during screening period, urethral prostate tumor detected by cystoscopy, or other concomitant malignant tumors within 5 years before the first administration; Previous medical history or examination suggests active tuberculosis within 1 year prior to the first dose; Severe infections requiring antibiotic, antiviral or antifungal drug control; patients with definite urinary tract infection, gross hematuria; Patients who discontinued treatment due to adverse reactions such as toxemia, systemic infection or urinary incontinence during previous BCG treatment History of clinically significant cardiovascular disease A history of immunodeficiency, including HIV seropositive, other acquired or congenital immunodeficiency diseases, a history of organ transplantation, or those who are using immunosuppressants; With a history of active autoimmune disease； Patient with active hepatitis B (HBeAg positive and HBV DNA ≥ 500 IU/mL), hepatitis C (HCV antibody positive and HCV RNA higher than the detection limit of the analytical method); Known allergic or intolerance to study drug, BCG (Phase Ib and Phase II subjects only) or excipients; The presence of other serious physical or mental illness, abnormal laboratory tests, and other factors that may increase the risk of participating in the study, or interfere with the results of the study; and any other conditions that the investigator deems inappropriate to participate in this study.

Ages Eligible for Study
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Minimum Age: 18 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: Single Group .Dose escalation and expansion of SHR-1501 alone or in combination with intravesical BCG in the treatment of NMIBC
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SHR-1501<br>Phase I：Phase Ia and Ib： Phase Ia include SHR-1501 dose escalation and expansion; Phase Ib ： SHR-1501 in combination with BCG dose escalation Phase II：SHR-1501 in combination with BCG dose expansion in NMIBC Cohort 1: No previous BCG treatment (n=15); Cohort 2: CIS (with or without Ta or T1) with or without prior BCG response (n=30); Cohort 3: BCG-unresponsive Ta or T1 (without CIS) (n=30) | Drug: SHR-1501<br>* SHR-1501 single agent dose escalation will consist of 3 dose groups: 200 μ g、400 μ g and 600 μ g, and in combination of BCG. The administration method is intravesical instillation.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicity |  | 21 Days | 
| Maximum tolerated dose |  | Approximately 2years | 
| Recommended Phase 2 dose (RP2D) |  | Approximately 2 years. | 
| CR Rate (cohort 2) |  | Approximately 4 years. | 
| 12-month DFS Rate (cohort 3) |  | Approximately 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment-Related Adverse Events as assessed by CTCAE v5.0 |  | Approximately 4 years. | 
| Duration of CR (DoR) |  | Approximately 4 years. | 
| CR rate at 6 months and 12 months |  | Approximately 4 years. | 
| DFS |  | Approximately 4 years. | 
| Time to cystectomy, |  | Approximately 4 years. | 
| Radical cystectomy rate; |  | Approximately 4 years. | 
| The amount of drug recovered in perfusate and urine after SHR-1501 perfusion |  | Approximately 5 years. | 
| Maximum concentration (Cmax) of SHR-1501 |  | Approximately 2 years, if applicable | 
| Time to maximum concentration (Tmax) of SHR-1501 |  | Approximately 2 years，if applicable | 
| Areas under the concentration-time curve from time zero to the time of last quantifiable concentration (AUClast) of SHR-1501 |  | Approximately 2 years，if applicable | 
| Areas under the concentration-time curve from time zero extrapolated to infinity (AUCinf) of SHR-1501 |  | Approximately 2 years，if applicable | 
| Half-life (t1/2) of SHR-1501 |  | Approximately 2 years, if applicable | 
| Apparent clearance (CL/F) of SHR-1501 |  | Approximately 2 years, if applicable | 
| Apparent volume of distribution (V/F) of SHR-1501 |  | Approximately 2 years, if applicable | 
| Concentration of SHR-1501 in Urine |  | Approximately 2 years, if applicable | 
| Anti-drug antibody of SHR-1501 |  | Approximately 2 years | 
| Neutralizing antibody of SHR-1501 |  | Approximately 2 years |