An Open-label, Single-arm, Multicenter Phase II Clinical Study： Evaluating RC48-ADC Combined With Triplizumab in the Neoadjuvant Treatment of Her2-positive Muscle-invasive Bladder Cancer

Study Overview
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Brief Summary
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An Open-label, Single-arm, Multicenter Phase II Clinical Study： Evaluating RC48-ADC Combined With Triplizumab in the Neoadjuvant Treatment of Her2-positive Muscle-invasive Bladder Cancer.It's arm to evaluate the neoadjuvant treatment of Her2-positive Muscle-invasive Bladder Cancer in patients with objective response rate (ORR),Duration of response (DoR) , progression-free survival (PFS), overall survival (OS), and safety.

Detailed Description
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Objective response rate (ORR), Duration of response (DoR) (according to RECIST 1.1 Standard Edition)，progression-free survival (PFS), overall survival (OS), quality of life (QoL)and safety. Evaluation once every 2 weeks before cystectomy, If the efficacy results of the evaluation are complete response (CR) or partial response (PR), confirmed imaging efficacy at 9 weeks after the initial assessment ， efficacy evaluation time window of ± 14 days.

Official Title
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An Open-label, Single-arm, Multicenter Phase II Clinical Study： Evaluating RC48-ADC Combined With Triplizumab in the Neoadjuvant Treatment of Her2-positive Muscle-invasive Bladder Cancer

Conditions
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Neoadjuvant Treatment of Her2-positive Muscle-invasive Bladder Cance

Intervention / Treatment
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* Drug: RC48- ADC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The subject is volunteer to participate, and the subject must signed an informed consent form (ICF), indicating that it understands the purpose of this study and the required procedures, and is willing to participate in the study. Subjects must be willing and abide by prohibition and restrictions specified in the research program; Subjects are willing and able to follow the trial and follow-up procedures Patients with invasive bladder cancer are prepared for radical cystectomy (standard lymph node dissection); Age ≥ 18 years old and ≤ 75 years old; Clinical stage T2-T4aN0M0 (assessed by CT/MR/PET-CT); Pathological was confirmed urothelial carcinoma by TURBT, HER2 overexpression confirmed by pathological biopsy: IHC2+ or IHC3+(central laboratory verification) andthe physical condition was not suitable for neoadjuvant chemotherapy ( pathological permit urothelial carcinoma Combined with other variant subtypes, with urothelial carcinoma as the main type) or refused neoadjuvant chemotherapy; ECOG score ≤ 1; After TURBT, residual tumor (measurable according to RECIST 1.1 criteria) is present; The important laboratory examination indexes meet the following requirements: Hemoglobin ≥ 90g/L. Absolute neutrophil count (ANC) ≥ 1.5 × 109 / L. Platelet ≥ 100 × 109 / L. 3.5mmol/L ≤ serum potassium ≤ 5.5mmol/L. Liver function index: ALT, AST ≤ 1.5 times the upper limit of normal value (ULN), TBIL ≤ 1.5ULN. Subjects with Serum creatinine≤ 1.5× ULN The left ventricular ejection fraction (LVEF) was 50%. Female subjects should be surgically sterilized or postmenopausal, or agree to use at least one medically approved contraceptive method (such as intrauterine device, contraceptive or condom) during the study treatment and within 6 months after the end of the study treatment period. The blood pregnancy test must be negative within 7 days before the study, and it must be non-lactation. Male subjects should agree to use at least one medically approved contraceptive method (such as condoms, abstinence, etc.) during the study treatment period and within 6 months after the end of the study treatment period. Exclusion Criteria: Had received live attenuated vaccine or had serious infection or planned to receive any vaccine during the study period4 weeks before entering the group. Received antineoplastic therapy within 6 months before the start of the study, including chemotherapy, radiotherapy, targeted therapy, immunotherapy and clinical research antineoplastic drug therapy. Uncontrollable concomitant diseases, including, but not limited to, persistent infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, arrhythmia, interstitial lung disease, severe chronic gastrointestinal disease associated with diarrhoea, or mental illness / social conditions, which will limit compliance with research requirements, significantly increase the risk of AE or impair the patient's ability to write informed consent.The results of HIVAb test were positive;with active bleeding or new thrombotic disease who are taking therapeutic anticoagulants or who have a tendency to bleed Patients with RC48-ADC /PD-1 allergy or hypersensitivity, patients with autoimmune diseases; HBsAg or HBcAb test results are positive, while HBVDNA copies are positive; HCVAb test results are positive (only if the PCR test result of HCVRNA is negative);Systemic corticosteroids or other systemic immunosuppressive drugs are used before enrollment, or systemic immunosuppressive drugs are expected to be needed during the trial; Serious arteriovenous thrombosis or cardio-cerebrovascular accidents occurred within 1 year before administration, such as deep venous thrombosis, pulmonary embolism, cerebral infarction, cerebral hemorrhage, myocardial infarction, etc., except for lacunar infarction that is asymptomatic and does not require clinical intervention;with active bleeding or new thrombotic disease who are taking therapeutic anticoagulants or who have a tendency to bleed. Active/known/suspected autoimmune disease, history of primary immunodeficiency,Previous allogeneic hematopoietic stem cell transplantation; Diagnosed with other malignancies within 5 years Pregnant or lactating women. Patients with missing main observation indicators, incomplete research data, incomplete follow-up data or failure to follow the research protocol

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: test group<br>RC48-ADC 2.0 mg/kg）D1,Triplizumab 3mg/kg D2，Q2W | Drug: RC48- ADC<br>* RC48-ADC 2.0 mg/kg D1,Triplizumab 3mg/kg D2，Q2W<br>* Other names: Triplizumab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological response (PaR) rate | Pathological response (PaR) rate per central pathology review | Up to approximately 6 months | 
| recommended dose for phase II safety (RP2D) | tolerability | Up to approximately 6 months | 
| Incidence of adverse events and serious adverse events | safety | Up to approximately 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The pathological complete response | The pathological complete response rate refers to all target lesions disappear | Up to approximately 6 months | 
| Progression free survival | Follow-up was made after the first month after the operation, and then with an every three months until the tumor relapsed or progress | Up to approximately 24 months | 
| Overall survival | The time from start of study treatment to date of death due to any cause | Up to approximately 48 months | 
| Duration of response | This is the time from when the tumor begins to respond to treatment until the disease gets worse | Up to approximately 24 months |