A Study of RC48-ADC Combined With Toripalimab For First-line Treatment of Urothelial Carcinoma

Study Overview
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Brief Summary
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This is a Phase 3, Open-Label, Multicenter, Randomised, Controlled Study designed to compare RC48-ADC in Combination With JS001 to Chemotherapy Alone in Previously Untreated HER2-Expressing Unresectable Locally Advanced or Metastatic Urothelial Carcinoma.

Detailed Description
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This is a Phase 3, Open-Label, Multicenter, Randomised, Controlled Study to evaluate the efficacy and safety of RC48-ADC,a recombinant humanized anti-HER2 monoclonal antibody-Monomethyl auristatin E (MMAE) conjugate, in Combination With JS001,a PD-1 monoclonal antibody, for the treatment of Previously Untreated HER2-Expressing Unresectable Locally Advanced or Metastatic Urothelial Carcinoma.

Official Title
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A Open-Label, Multicenter, Randomised, Controlled Phase 3 Study of RC48-ADC Plus Toripalimab Versus Chemotherapy Alone in Previously Untreated Unresectable Locally Advanced or Metastatic Urothelial Carcinoma With HER2-Expressing

Conditions
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Urothelial Carcinoma, HER2-expressing

Intervention / Treatment
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* Drug: RC48-ADC
* Drug: Toripalimab
* Drug: Gemcitabine
* Drug: Cisplatin
* Drug: Carboplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Expected survival ≥12 weeks. Locally advanced unresectable or metastatic UC with histopathological confirmation, including UC originating from the renal pelvis, ureters, bladder, or urethra. Participants must not have received prior systemic therapy for locally advanced or metastatic urothelial carcinoma with the following exceptions: Participants that received neoadjuvant chemotherapy with recurrence >6 months from completion of therapy are permitted; Participants that received adjuvant chemotherapy following cystectomy with recurrence >6 months from completion of therapy are permitted. At least one measurable lesion based on RECIST version 1.1 HER2-expressing status determined by the central laboratory to be IHC 1+, 2+ or 3+. ECOG performance status score: 0 or 1. Adequate cardiac, bone marrow, hepatic, renal, and coagulation functions. Exclusion Criteria: Known hypersensitivity to RC48-ADC or Toripalimab or any of its components. History of major surgery within 4 weeks of planned start of trial treatment. Toxicity from a previous treatment has not returned to Grade 0-1. Prior ADCs or PD-1/PD-L1 inhibitor therapy. Active central nervous system (CNS) metastases. Known active hepatitis B, active hepatitis C, or human immunodeficiency virus (HIV) infection. History of other malignancy within the previous 5 years, except for low-risk localized prostate cancer, appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or cancers with a similar curative outcome as those mentioned above. Other serious, uncontrolled concomitant diseases that may affect protocol compliance or interpretation of outcomes, including active opportunistic infections or advanced (severe) infections, or uncontrolled diabetes. Active autoimmune diseases that require systemic therapy over the past 2 years. Replacement therapies (such as thyroxine, insulin, or physiological replacement of glucocorticoids due to renal or pituitary deficiency) are allowed. Assessed by the investigator to be unable or unwilling to comply with the requirements of the protocol.

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RC48-ADC + JS001<br>Participants will receive RC48-ADC + JS001 every 2 weeks (Q2W) until investigator assessed loss of clinical benefit, unacceptable toxicity, investigator or participant decision to withdraw from therapy, or death (whichever occurs first). | Drug: RC48-ADC<br>* 2.0 mg/kg IV every 2 weeks<br>* Other names: Disitamab Vedotin;Drug: Toripalimab<br>* 3.0 mg/kg IV every 2 weeks<br>* Other names: JS001;|
| Active Comparator: Gemcitabine + cisplatin/carboplatin<br>Participants will receive Gemcitabine + cisplatin or carboplatin every 3 weeks (Q3W) for maximum 6 weeks or until investigator assessed loss of clinical benefit, unacceptable toxicity, investigator or participant decision to withdraw from therapy, or death (whichever occurs first). | Drug: Gemcitabine<br>* 1000mg/m2 IV infusion on Days 1 and 8 of every 3 week cycle<br>Drug: Cisplatin<br>* 70mg/m2 IV infusion on Day 1 of every 3 week cycle<br>Drug: Carboplatin<br>* AUC=4.5, IV infusion on Day 1 of every 3 week cycle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS), evaluated by independent review committee | Progression-free survival (PFS) refers to the time from the date of randomization to the first researcher's evaluation of disease progression or death (calculated by the event that occurred first). The disease progression will be evaluated by independent review committee according to the RECIST 1.1 standard. | Up to approximately 3 years | 
| Overall survival (OS) | Overall survival (OS) refers to the time from the date of randomization to the date of death of the subject. | Up to approximately 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective remission rate (ORR) | The objective response rate will be mainly analyzed by the independent efficacy evaluation committee according to the RECIST 1.1 standard tumor evaluation (the evaluation by the investigator will also be performed). | Up to approximately 3 years | 
| Progression-free survival (PFS), evaluated by the investigator | Progression-free survival (PFS) refers to the time from the date of randomization to the first researcher's evaluation of disease progression or death (calculated by the event that occurred first). The disease progression will be evaluated by the researchers according to the RECIST 1.1 standard. | Up to approximately 3 years | 
| Duration of relief (DOR) | DOR is defined as the time from the first documented objective response (CR or PR) to the first documented disease progression or death | Up to approximately 3 years | 
| Disease control rate (DCR) | Disease control rate (DCR) is defined as cases where objective remission (assessed as complete remission or partial remission according to RECIST 1.1 standard) or stable disease during the study. | Up to approximately 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Urothelial Carcinoma, HER2-expressing, RC48, First-Line