A Study of RC48-ADC(Antibody Drug Conjugate) and JS001 to Evaluate the Safety and Pharmacokinetics of Subjects With Locally Advanced or Metastatic Urothelial Cancer

Study Overview
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Brief Summary
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This is an open-label, single-arm, Phase Ib/II investigator-initiated trial of RC48-ADC combined with JS001 to evaluate the safety and pharmacokinetics of subjects with locally advanced or metastatic urothelial cancer

Official Title
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A Open-label, Single-arm, Phase Ib/II Study of RC48-ADC and JS001 to Evaluate the Safety and Pharmacokinetics of Subjects With Locally Advanced or Metastatic Urothelial Cancer

Conditions
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Urothelial Carcinoma

Intervention / Treatment
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* Drug: RC48-ADC and JS001


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent form; Aged 18 years and above; ECOG(Eastern Cooperative Oncology Group) performance is 0 or 1; Life expectancy greater than 12 weeks; Patients with locally advanced or metastatic malignant urothelial carcinoma which is platinum naive and cisplatin ineligible, or progressed after at least one line standard systemic chemotherapy (including progression within 12 months of neo-/adjuvant therapy); Cisplatinum ineligible patients should meet one of the following criteria: Aged 70 years and above, and ECOG performance is 1; Serum creatinine >= 1.0xULN or CrCl<60ml/min; Lose of hearing >= Grade 2; Peripheral nerve disorder >= Grade 2 Patients with measurable and appreciable tumor lesions according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1); Willing to provide primary lesion samples for the purpose of PD-L1 and HER2 tests. Adequate organ function as defined by the following criteria: absolute neutrophil count(ANC) >= 1.5 x 10^9/L; platelets>=100* 10^9/L; Total serum creatinine <=1.5*ULN; serum aspartate transaminase (AST) and serum alanine transaminase (ALT) <=2.5*upper limit of normal (ULN), or AST and ALT<=5*ULN if liver function abnormalities are due to underlying malignancy; normal serum creatinine ; Left ventricular ejection fraction (LVEF) >=50% Hemoglobin>=9g/dl Women of child-bearing potential and men must agree to use adequate contraception (e.g., condoms, implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], complete sexual abstinence, or sterilized partner) prior to study entry and during the period of therapy and for 30 days after the last dose of study drug; Exclusion Criteria: Allergy to RC48-ADC, or JS001, or their components Received anti-cancer therapy including chemotherapy, radiotherapy, immunotherapy or other clinical trial treatments within 3 weeks of starting study treatment Unresolved toxicities from prior anti-cancer therapy, except for alopecia Previously treated with HER2-ADC and/or anti-PD-1 or anti-PD-L1 or anti PD-L2 therapies; Underwent major surgery within 4 weeks of first dose of study drug and not completely recovered; Received vaccine within 4 weeks of first dose of study drug Currently active clinically significant cardiovascular disease such as uncontrolled arrhythmia, congestive heart failure, or greater than or equal to Class 2 congestive heart failure as defined by the New York Heart Association Functional Classification, or history of myocardial infarction unstable angina, or acute coronary syndrome within 6 months prior to enrollment in the study; History of other neoplastic disease within 3 years prior to the study drug, with exception of resolved/curable cancers such as basal skin cancer or squamous cell skin cancer,. Metastasis to CNS(central nervous system) and/or carcinomatous meningitis, with exception for the patients who received treatment of metastasis to CNS and/or carcinomatous meningitis and had stable disease for at least 3 months, and no evidence of progression within 4 weeks of first dose of study treatment. No evidence of new or expanded metastasis, and untreated with radiotherapy, surgery or steroid therapy within 4 weeks of first dose of study treatment. History of allogeneic hematopoietic stem cell transplantation or organ transplantation; Patients who had received systemic steroid therapy within the last 2 years; Pregnancy or lactation; Positive results of HIV testing; Active HBV(hepatitis B virus) or HCV(hepatitis C virus) infection Active tuberculosis; Other disorders with clinical significance according to the researcher's judgment; Unwilling or unable to participate in all required study evaluations and procedures

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RC48-ADC and JS001<br> | Drug: RC48-ADC and JS001<br>* Recombinant Humanized anti-HER2(Human epidermal growth factor receptor-2) Monoclonal Antibody-MMAE(Monomethyl Auristatin E) Conjugate For Injection and JS001 Injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events | rate of adverse events | through study completion, an average of 1 year | 
| maximal tolerated dose | dose-limiting toxity | through study completion, an average of 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak Plasma Concentration(Cmax) | Maximum observed plasma concentration | through study completion, an average of 1 year | 
| Immunogenicity | Numbers of participants with anti-drug antibody positive | through study completion, an average of 1 year | 
| objective response rate | evaluated by RECIST 1.1 every 8 weeks | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first；assessed up to 60 months | 
| the area under the curve (AUC) | Area under the plasma concentration versus time curve | through study completion, an average of 1 year |