the Efficacy and Safety of LDP in Patients With Urinary and Male Genital Tumors

Study Overview
=================
Brief Summary
-----------------
This is a single-arm,open, multicenter, phase II clinical study of the efficacy and safety of human anti-PD-L1 monoclonal antibody Injection (LDP) in the treatment of urinary and male genital tumors.

Detailed Description
-----------------
This trial is a single arm, open, multicenter, Ⅱ period clinical research. Three cohorts were included, 127 subjects were enrolled (Cohort 1: about 60 subjects with surgically suitable muscular-invasive bladder cancer; Cohort 2: about 40 subjects with advanced Non-clear Cell Renal Carcinoma; Cohort 3: about 27 subjects with advanced penile carcinoma. After confirmation of inclusion, intravenous infusion of 10mg/kg human anti-PD-L1 monoclonal antibody injection (LDP) was given. The initial efficacy and safety of drugs in different tumor species in the cohort above will be observed.

Official Title
-----------------
A Single-arm, Open, Multicenter, Phase II Clinical Study of the Efficacy and Safety of Human Anti-PD-L1 Monoclonal Antibody Injection (LDP) in the Treatment of Urinary and Male Genital Tumors

Conditions
-----------------
Bladder Cancer, Renal Carcinoma, Advanced Penile Carcinoma

Intervention / Treatment
-----------------
* Drug: Human Anti-PD-L1 Monoclonal Antibody Injection (LDP)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥ 18 (inclusive), ≤18 (inclusive) Patients with muscular-infiltrating bladder cancer suitable for surgery; advanced opaque cell renal carcinoma; advanced penile carcinoma The estimated survival time is more than 3 months. At least one assessable tumor lesion according to RECIST1.1 (in cohort 1, evaluate lesion is accept); ECOG physical strength score 0-1; Enough organ function: Blood routine (no blood transfusion or colony stimulating factor (G-CSF) treatment within 14 days):ANC≥1.5×109 / L, PLT≥75×109 / L, Hb≥80g/L; Liver function: TBIL≤1.5×ULN, ALT≤2.5×ULN, AST≤2.5×ULN (ALT,AST≤5×ULN for liver metastasis patients); Renal function: Cr ≤ 1.5 × ULN, and creatinine clearance > 50 ml /min(according to Croft Gault formula) ; Coagulation function: APTT≤ 1.5 ×ULN, PT ≤ 1.5 × ULN, INR ≤ 1.5 × ULN; Eligible patients (male and female) with fertility must agree to use reliable methods of contraception (hormone or barrier or abstinence) during the trial period and at least 6 months after the last dose; The blood or urine pregnancy test within 7 day before being selected must be negative for the female patients of childbearing age; Subjects must give informed consent to this study before the study, and voluntarily sign a written informed consent; Exclusion Criteria: Received radiotherapy, chemotherapy, targeted therapy, endocrine therapy or immunotherapy within 4 weeks before the first administration, or other unlisted clinical trial drug therapy (mitomycin and nitrosourea are 6 weeks from the last administration, oral fluorouracil drugs such as Tegiol and Capecitabine are at least 2 weeks from the last administration, small molecule targeted drugs are at least 2 weeks or at least interval 5 half-life (Subject to the longer time) from the last administration, and traditional Chinese medicine with antitumor indications are at least 2 weeks from the last administration. Major organ surgery (excluding puncture biopsy) or significant trauma occurred within 4 weeks prior to the first administration. The adverse effects of previous antitumor therapy have not recovered to CTCAE 5.0 ≤grade1 (except for alopecia) Patients with clinical symptoms of brain metastases, spinal cord compression, cancerous meningitis, or other evidence of uncontrolled brain or spinal cord metastases are not suitable for inclusion as judged by the investigator Patients who had previously received PD-1 or PD-L1 inhibitors; Immunorelated adverse events ≥ Grade 3 were observed in previous immunotherapy except for PD-1 or PD-L1 inhibitors; Patients have any active autoimmune diseases or a history of autoimmune diseases (e.g., but not limited to: systemic lupus erythematosus, autoimmune hepatitis, interstitial pneumonia, uveitis, enteritis, hypophysitis, vasculitis, nephritis, hyperthyroidism, vitiligo, etc.); Complete remission of asthma in childhood can be included if in adults without any intervention;Asthma patients requiring bronchodilators for medical intervention were excluded); Patients who received systemic corticosteroid (prednisone > 10mg/ day or equivalent) or other immunosuppressive therapy within 14 days prior to initial dosing; Exceptions include: topical, ocular, intraarticular, intranasal, and inhaled corticosteroids;Short-term use of corticosteroids for preventive treatment, such as before the use of contrast agents; Malignancies that were active within the last 2 years prior to initial administration (except for the tumors targeted in this study); Uncontrolled active hepatitis B (HBsAg positive with HBV DNA copy number > 103/ mL or HBV DNA titer >200 IU/ mL); Hepatitis C; Syphilis infection (syphilis antibody positive) and HIV positive patients. A history of serious cardiovascular disease, including ventricular arrhythmias requiring clinical intervention;Acute coronary syndrome, congestive heart failure, stroke, or other grade 3 or higher cardiovascular events within 6 months;New York Heart Association (NYHA) cardiac function grade ≥II or left ventricular ejection fraction (LVEF) < 50%;Patients with clinically uncontrolled hypertension who are not suitable for the trial as determined by the investigator; Patients with a history of other serious systemic diseases who have been determined by the investigator to be unsuitable for participation in clinical trials; Known alcohol or drug dependence; Mental disorder or poor compliance; Women who are pregnant or lactating; Have received live attenuated vaccine within 4 weeks before the first administration or scheduled to receive during the study period. The Investigator considers that the subject is unsuitable to participate in this study because of any clinical or laboratory test abnormalities or other reasons.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental Arms<br>All participants will receive treatment with LDP 10mg/kg once every two weeks, every 2 weeks will be a cycle. In Cort 1, surgical treatment will be performed within 2 weeks after the end of 3 cycles of treatment. | Drug: Human Anti-PD-L1 Monoclonal Antibody Injection (LDP)<br>* All participants will receive treatment with LDP 10mg/kg once every two weeks, every 2 weeks will be a cycle. In Cort 1, surgical treatment will be performed within 2 weeks after the end of 3 cycles of treatment.<br>* Other names: LDP;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Case complete response （pCR） | The pCR is defined as the case complete response in Cohort 1 (muscular-infiltrating bladder cancer suitable for surgery) | At the end of the cycle 3 of treatment (each cycle is 14 days). | 
| Objective response rate (ORR) | The ORR is defined as the proportion of subjects with confirmed CR or confirmed PR, based on RECIST Version 1.1 in Cohort 2 (Non-clear Cell Renal cell Carcinoma) and Cohort 3 (advanced penile carcinoma) | From first dose of LDP through 21 days after last dose of LDP up to 2 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrence-free survival (RFS) | Recurrence-free survival (RFS) is defined as the time from the start of surgery to the earliest evidence of recurrence. | One year after surgery or disease progression or intolerant toxicity, up to 2 years. | 
| Progression-free survival （PFS） | Progression-free survival (PFS) is defined as the time elapsed from the day the study drug was first administered until the first imaging assessment of disease progression (PD) or death from any cause. | From first dose of LDP, up to 2 years. | 
| Disease control rate (DCR) | Disease control rate (DCR) is defined as the proportion of the optimal time response of CR, PR, disease stable (SD) (i.e. CR+PR+SD) between initiation of the trial drug and withdrawal from the trial, as assessed according to RECIST1.1 criteria. | From first dose of LDP, up to 2 years. | 
| Duration of response (DOR) | The duration of response (DOR) is defined as the time from the beginning of the first tumor assessment as PR or CR to the first assessment as PD or death from any cause. | From first dose of LDP, up to 2 years. | 
| Overall survival (OS) | Overall survival (OS) is defined as the time between the date of first use of the study drug and death from any cause. | From first dose of LDP, up to 2 years. | 
| Incidence of adverse events | Adverse events (AEs) refer to all adverse medical events that occur when subjects sign the informed consent, which may be manifested as symptoms, signs, diseases or abnormal laboratory tests, but not necessarily causally related to the investigational drug. | From first dose of LDP through 30 days after last dose of LDP, up to 5 months. | 
| Incidence of abnormal vital signs | Vital signs (including temperature, respiration, heart rate and blood pressure) can be measured. The time window for each vital sign measurement is ±10 minutes. | From first dose of LDP through 30 days after last dose of LDP, up to 5 months. | 
| Incidence of abnormal ECOG scores | ECOG physical strength rating is based on ECOG physical strength rating criteria. | From first dose of LDP through 30 days after last dose of LDP, up to 5 months. | 
| Incidence of abnormal laboratory tests results | Descriptive analysis of laboratory results for safety analysis. | From first dose of LDP through 30 days after last dose of LDP, up to 5 months. | 
| Incidence of abnormal physical examinations | Descriptive analysis of physical examination for safety analysis. | From first dose of LDP through 30 days after last dose of LDP, up to 5 months. | 
| anti-drug antibody (ADA) | Anti-drug antibody (ADA) is tested for immunogenicity assessment , titer and neutralizing antibody analysis were performed when ADA was positive, and immunocomplex (CIC) and complement analysis were performed. | In Cohort 1: before administration ,before surgery; In Cohort 2, 3: before administration, up to 4 months. |