An Exploratory Clinical Study of LDP Combined With CDP1 in Patients With Advanced Malignant Tumor

Study Overview
=================
Brief Summary
-----------------
This is an exploratory clinical study of Human Anti-PD-L1 Monoclonal Antibody Injection (LDP) combined with Recombinant Anti-EGFR Human Mouse Chimeric Monoclonal Antibody Injection (CDP1) in patients with advanced malignant tumor.

Detailed Description
-----------------
This is an open, dose-escalation and dose-extension exploratory clinical study for patients with advanced malignancy who have failed standard therapy. In the dose-escalation phase, a fixed dose of CDP1 will be given once a week, while LDP will be given every two weeks with dose climbing. Then, cohort studies (cohorts 1 to 5) will be conducted during the dose-expansion phase. The purpose is to preliminarily evaluate the safety and efficacy of LDP combined with CDP1 in the treatment of patients with advanced malignant tumor, and to determine the recommended dose for clinical trial.

Official Title
-----------------
An Exploratory Clinical Study of Human Anti-PD-L1 Monoclonal Antibody Injection (LDP) Combined With Recombinant Anti-EGFR Human Mouse Chimeric Monoclonal Antibody Injection (CDP1) in Patients With Advanced Malignant Tumor

Conditions
-----------------
Advanced Malignant Tumor

Intervention / Treatment
-----------------
* Drug: Human Anti-PD-L1 Monoclonal Antibody Injection (LDP) Combined with Recombinant Anti-EGFR Human Mouse Chimeric Monoclonal Antibody Injection (CDP1)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 1. Age ≥ 18 (inclusive), no gender limitation; 2. The estimated survival time is more than 3 months. 3. At least one assessable tumor lesion according to RECIST1.1 (in cohort 1, evaluate lesion is accept); 4. ECOG physical strength score 0-2; 5. No serious abnormal blood system, liver function, kidney function or coagulation function: ANC≥1.5×109 / L, PLT≥75×109 / L, Hb≥9g/dL; TBIL≤1.5×ULN, ALT≤2.5×ULN, AST≤2.5×ULN; Cr ≤ 1.5 × ULN, and creatinine clearance ≥ 50 ml /min(according to Croft Gault formula),Urinary protein ≤2+;or 24-hour urinary protein ≤1g; APTT≤ 1.5 ×ULN, PT ≤ 1.5 × ULN, INR ≤ 1.5 × ULN; 6.Blood or urine pregnancy tests are negative in women of childbearing age within 7 days before the first dose.Male subjects and female subjects of reproductive age must use adequate contraception and have no plans to donate sperm or eggs within 3 months from the date of signing informed consent for the study to the date of the last study drug treatment. 7. Subjects must give informed consent to this study before the study, and voluntarily sign a written informed consent; 8.Locally advanced or metastatic malignancies diagnosed by histopathology, which have failed standard treatment, have no standard treatment regimen, or are not suitable for standard treatment at this stage. In the dose-expansion phase: cohort 1: head and neck squamous cell carcinoma;Cohort 2: colorectal cancer, RAS genotype was wild type;Cohort 3: esophageal squamous cell carcinoma;Cohort 4: Penile cancer;Cohort 5: Female reproductive system tumors (endometrial, cervical, ovarian). Exclusion Criteria: 1. 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. 2. Major organ surgery (excluding puncture biopsy) or significant trauma occurred within 4 weeks prior to the first administration. 3. The adverse effects of previous antitumor therapy have not recovered to CTCAE 5.0 ≤grade1 (except for alopecia) 4. 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 5. Patients who had previously received PD-1 or PD-L1 inhibitors or anti-EGFR monoclonal antibody or other immune checkpoint inhibitors and failed; 6. Immunorelated adverse events ≥ Grade 3 were observed in previous immunotherapy; 7. Patients with active or previous autoimmune diseases (such as systemic lupus erythematosus, rheumatoid arthritis, vasculitis, interstitial lung disease, etc.); 8. 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; 9. 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. 10. 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; 11. Known alcohol or drug dependence; 12. Mental disorder or poor compliance; 13. Women who are pregnant or lactating; 14. Have received live attenuated vaccine within 4 weeks before the first administration or scheduled to receive during the study period. 15. The Investigator considers that the subject is unsuitable to participate in this study because of any clinical or laboratory test abnormalities or other reasons. 16.A malignant tumor that has been active in the past two years (Except for tumors in this study, cured stage Ib cervical cancer or lower, non-invasive basal cell or squamous cell skin cancer, malignant melanoma with complete response (CR) > for 10 years, and other malignant tumors with complete response (CR) BBB>r 5 years)

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

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

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

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

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental Arms<br>All participants will receive treatment with LDP combined with CDP1. In the dose-escalation phase, a fixed dose of CDP1 will be given once a week, while LDP will be given every two weeks with dose climbing. Then, cohort studies (cohorts 1 to 5) will be conducted during the dose-expansion phase. | Drug: Human Anti-PD-L1 Monoclonal Antibody Injection (LDP) Combined with Recombinant Anti-EGFR Human Mouse Chimeric Monoclonal Antibody Injection (CDP1)<br>* In the dose-escalation phase, CDP1 400 mg/ m2 will be given in the first week, then 250 mg/m2 will be given evert week. LDP will be given every two weeks with dose climbing of 5 mg/kg, 10 mg/kg, 20 mg/kg. Dose in the dose-expansion phase according to the assesment in the dose-escalation phase.<br>* Other names: LDP combined with CDP1;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 combined of CDP1 through 30 days after last dose, up to 5 months. | 
| Dose Limiting Toxicities (DLT) | Number of participants with dose limiting toxicity (DLT) | Time Frame: 28 days after first dose of LDP combined of CDP1, up to 24 months. | 
| Recommended dose for clinical trials | A comprehensive evaluation of the results from the dose escalation/expansion phase was conducted to determine the recommended dose for the clinical trial. | up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | From first dose of LDP combined of CDP1, 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 combined of CDP1, an average of 6 months. | 
| 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 combined of CDP1, 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 combined of CDP1, an average of 6 months. | 
| Maximum plasma concentrations (Cmax) | Pharmacokinetic parameter, Observed Maximum Serum Concentration (Cmax) of LDP and CDP1. | an average of 6 months | 
| Area under the plasma concentration-time curve from zero to last concentration time (AUC0-t) | Pharmacokinetic Parameters, Area Under the Serum Concentration-time Curve From Time Zero to the Last Sampling Time (AUC0-t) of LDP and CDP1. | an average of 6 months | 
| Half-life (t1/2) | Pharmacokinetic parameters,Apparent Terminal Half-life (t1/2) of LDP and CDP1. | an average of 6 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. | an average of 6 months |