A Study Evaluating Toripalimab Injection Combined With Standard Chemotherapy as a First-line Treatment for Locally Advanced or Metastatic Urothelial Carcinoma

Study Overview
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Brief Summary
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The study is being conducted to evaluate the efficacy and safety of Toripalimab Injection in combination with chemotherapy compared to placebo in combination with chemotherapy in subjects with PD-L1-positive unresectable locally advanced or metastatic urothelial carcinoma who have received no previous systemic therapy.

Official Title
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A Phase III, Randomized, Double-blind, Placebo-controlled, Multi-center Clinical Study to Evaluate the Efficacy and Safety of Toripalimab Injection (JS001) in Combination With Standard Chemotherapy Versus Placebo in Combination With Standard Chemotherapy as the 1st-line Therapy for Treatment-naive Subjects With PD-L1-positive Locally Advanced or Metastatic Urothelial Carcinoma

Conditions
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Locally Advanced or Metastatic Urothelial Carcinoma

Intervention / Treatment
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* Biological: Toripalimab Injection
* Drug: Gemcitabine Hydrochloride for Injection
* Drug: Cisplatin for Injection / Carboplatin Injection
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Have full knowledge on this study and are willing to sign informed consent form (ICF); Age 18-75 years at time of signing ICF, male or female; The investigator judged that the subject is eligible for platinum-based chemotherapy; Presence of histopathologically confirmed unresectable locally advanced (T4, any N; or any T, N2-3) or metastatic urothelial carcinoma; No prior systemic anti-tumor therapy; Subjects who are able to provide tumor tissue slides (≥ 5 slides) for PD-L1 test and the corresponding pathology report and whose PD-L1 test must be positive before randomization; With at least one measurable lesion as per RECIST 1.1 criteria; ECOG performance status score of 0-1; Adequate function of vital organs. Exclusion criteria Have received anti-tumor treatments, including chemotherapy, radiotherapy or investigational product within 28 days before randomization; Have received traditional Chinese medicines with anti-tumor activity or immunomodulators (eg. Interferon and Interleukin) within 14 days before randomization; Previous use of anti-PD-1/PD-L1 agent or a drug acting on another co-inhibitory T cell receptor; Subjects who are currently participating in or have participated in a study with investigational product within 4 weeks before administration; Having received systemic corticosteroid therapy (dose equivalent to prednisone > 10 mg/day) within 14 days before randomization; Subjects with active central nervous system (CNS) metastasis; Grade 2 or higher peripheral neuropathy or hearing loss.

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Toripalimab Injection + chemotherapy group<br> | Biological: Toripalimab Injection<br>* Toripalimab Injection 240 mg iv infusion on Day 1 of each 3-week cycle. The cumulative duration of Toripalimab Injection is up to 2 years.<br>Drug: Gemcitabine Hydrochloride for Injection<br>* Gemcitabine 1000mg/㎡ iv infusion, on Day 1 and Day 8 of each cycle, each treatment cycle is 3 weeks. The chemotherapy regimen will be administered for 6 cycles.<br>Drug: Cisplatin for Injection / Carboplatin Injection<br>* Cisplatin 70mg/㎡ iv infusion, on Day 1 or Day 2 of each cycle, each treatment cycle is 3 weeks. Carboplatin AUC 4.5 iv infusion, on Day 1 or Day 2 of each cycle, each treatment cycle is 3 weeks. The chemotherapy regimen will be administered for 6 cycles.<br>|
| Placebo Comparator: Placebo + chemotherapy group<br> | Drug: Gemcitabine Hydrochloride for Injection<br>* Gemcitabine 1000mg/㎡ iv infusion, on Day 1 and Day 8 of each cycle, each treatment cycle is 3 weeks. The chemotherapy regimen will be administered for 6 cycles.<br>Drug: Cisplatin for Injection / Carboplatin Injection<br>* Cisplatin 70mg/㎡ iv infusion, on Day 1 or Day 2 of each cycle, each treatment cycle is 3 weeks. Carboplatin AUC 4.5 iv infusion, on Day 1 or Day 2 of each cycle, each treatment cycle is 3 weeks. The chemotherapy regimen will be administered for 6 cycles.<br>Drug: Placebo<br>* Placebo iv infusion on Day 1 of each 3-week cycle. The cumulative duration of placebo is up to 2 years.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Investigator-assessed progression-free survival (INV-PFS) as per RECIST 1.1 criteria | To evaluate the investigator-assessed progression-free survival following Toripalimab Injection in combination with chemotherapy compared to placebo in combination with chemotherapy in subjects with PD-L1-positive unresectable locally advanced or metastatic urothelial carcinoma who have received no previous systemic therapy | Approximately 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| IRC-PFS | Independent central radiological review committee-assessed progression-free survival as per RECIST1.1 criteria | Approximately 3 years | 
| INV-ORR, IRC-ORR | Investigator- and IRC-assessed overall response rate | Approximately 3 years | 
| INV-DCR, IRC-DCR | Investigator- and IRC-assessed disease control rate | Approximately 3 years | 
| INV-DoR, IRC- DoR | Investigator- and IRC-assessed duration of response | Approximately 3 years | 
| OS | Overall survival | Approximately 5 years | 
| OS rate at 1 year | Overall survival rate at 1 year | Approximately 3 years | 
| OS rate at 2 years | Overall survival rate at 2 years | Approximately 4 years | 
| INV-PFS rate and IRC-PFS rate at 6 months | Investigator- and IRC-assessed progression-free survival rate at 6 months | Approximately 2.5 years | 
| INV-PFS rate and IRC-PFS rate at 1 year | Investigator- and IRC-assessed progression-free survival rate at 1 year | Approximately 3 years | 
| Incidence of AEs/SAEs | Study drug related adverse events, serious adverse events graded in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 | Approximately 4 years |