A Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Immunogenicity of LB4330 in Patients With Advanced Solid Tumors（MEETCD8-001）

Study Overview
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Brief Summary
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This is a Phase I study designed to evaluate if LB4330, an anti-Claudin 18.2 and CD8 T cell activator fusion protein, is safe, tolerable and efficacious in participants with Advanced Solid Tumors

Detailed Description
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This first time in patients, open-label, multi-center study will have LB4330 administered intravenously (IV) in Patients with Advanced Solid Tumors. This study will have 2 parts: Part A which will have dose escalation cohorts and Part B which will have the dose expansion cohorts.

Official Title
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A Phase I，Dose Escalation and Expansion Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Immunogenicity of LB4330 in Patients With Advanced Solid Tumors（MEETCD8-001）

Conditions
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Solid Tumor

Intervention / Treatment
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* Drug: LB4330


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-80 (including boundary value) years old male or female. Patients with advanced malignant solid tumor confirmed by histology or cytology (dose escalation stage), patients with advanced gastric and gastroesophageal junction adenocarcinoma, pancreatic duct adenocarcinoma or other solid tumors confirmed by histology or cytology (single drug expansion stage) who have failed standard treatment, or for whom standard treatment is not available or applicable at this stage. (Dose escalation stage) At least one evaluable tumor lesion according to RECIST v1.1; (Single drug expansion stage) According to RECIST version 1.1, there is at least one measurable tumor lesion (tumor lesions located in the previous radiotherapy area or other local regional treatment areas are generally not regarded as measurable lesions, unless the lesions have a clear progression or persist three months after radiotherapy). (Single drug expansion stage) Archived or fresh tumor tissue samples can be provided, and Claudin18.2 expression can be detected by IHC in the central laboratory (a clear cut off value will be defined according to the results of the dose increasing stage); Patients who cannot provide tumor tissue samples are also allowed to be included if they can provide previous test reports that meet the definition of Claudin 18.2 expression in the study. ECOG performance score 0-1. Expected survival time of more than 3 months. Adequate organ function. Eligible patients of childbearing potential (both men and women) must agree to use a reliable method of contraception (hormonal or barrier or abstinence, etc.) with their partners during the trial and for at least 90 days after the last dose; female patients of childbearing potential must have a negative blood or urine pregnancy test within 7 days prior to the first dose of study drug. Patients must give informed consent to this study prior to the study and sign a written informed consent form voluntarily Exclusion Criteria: Have received anti-tumor treatment such as chemotherapy, radiotherapy, biological therapy, endocrine therapy, targeted therapy and immunotherapy within 4 weeks prior to the first dose of the study drug, except for the following: Herbal medicine with anti-tumor indications within 2 weeks prior to the first dose of study drug. Or received nitrosourea or mitomycin C within 6 weeks prior to the first dose of the study drug. Have received other investigational agents or treatment within 4 weeks prior to the first dose of the study drug. Have received major organ surgery (excluding needle biopsy) or have experienced significant trauma within 4 weeks prior to the first dose of study drug, or require elective surgery during the study period. Have received systemic steroid therapy (prednisone >10 mg/day or equivalent) or other forms of immunosuppressive therapy within 14 days prior to the first dose of study drug; Except: topical, ocular, intra-articular, intranasal, and inhaled steroid therapy; and short-term corticosteroid prophylaxis (e.g., to prevent an allergic reaction to contrast material). Have received allogeneic hematopoietic stem cell transplantation or organ transplantation. The adverse reactions caused by previous anti-tumor treatment have not recovered to ≤ grade 1 per CTCAE 5.0 (except for toxicities without safety risk as judged by investigators, such as alopecia, grade 2 peripheral neurotoxicity, hypothyroidism stabilized by hormone replacement therapy, etc.) Patients with symptomatic parenchymal brain metastasis (BM) or leptomeningeal (LM) metastasis who are not suitable for treatment as judged by the investigator. Patients with active infection which requires intravenous anti-infective therapy. Patients with known lesions responsible for gastric bleeding or those considered by the investigator to have a greater risk for gastric bleeding. irritable bowel syndrome with symptoms (such as chronic nausea, persistent repeated vomiting or diarrhea) and gastric outlet obstruction are known to exist. Have a history of immunodeficiency, including HIV antibody test positive. Active infection with hepatitis B (HBsAg-positive and HBV-DNA > 500 IU/ml or active infection with hepatitis C (patients with positive HCV antibody but HCV-RNA < lower limit of detection at the study site are allowed). (Note: enrollment of patients on prophylactic antiviral therapy other than interferon is permitted). Patients with interstitial lung disease (excluding radiation-induced pulmonary fibrosis that does not require hormone treatment). Known history of serious cardiovascular and cerebrovascular diseases, including but not limited to: Severe cardiac rhythm or conduction defects, such as arrhythmia requiring clinical intervention, second-degree to third-degree atrioventricular block, etc.; QT interval (QTcF) corrected by Fridericia method>470ms for female and> 450ms for male (see Appendix 8 for calculation formula);Acute coronary syndrome, congestive heart failure, aortic dissection, stroke or other ≥ grade 3 cardiovascular and cerebrovascular events within 6 months prior to the first dose of study drug; Symptomatic heart failure (New York Heart Association [NYHA] Functional Class II-IV) or left ventricular ejection fraction (LVEF) < 50%; Uncontrolled hypertension. Patients with an active autoimmune disease or a documented history of autoimmune diseases with a risk of relapse (e.g., systemic lupus erythematosus, rheumatoid arthritis, Crohn's disease, ulcerative colitis, vasculitis, etc.), except for patients with clinically stable autoimmune thyroid disease or type I diabetes. Have received immunotherapy and had ≥ grade 3 irAE. Have experienced ≥ grade 3 infusion-related reactions to protein therapeutics. Known history of other serious systemic diseases or other reasons that unsuitable for entry as determined by the investigator.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation<br>Up to 9 dose cohorts will be sequentially enrolled in the dose escalation part using an accelerated titration combined with the standard BOIN dose escalation algorithm approach. | Drug: LB4330<br>* LB4330<br>|
| Experimental: Single Drug Expansion<br>To further evaluate the safety, tolerance and preliminary clinical efficacy of LB4330 single drug in specific tumor species, the planned expanded cohort and number of subjects are as follows: Cohort A: LB4330 single drug therapy, 10 patients with advanced gastric and gastroesophageal junction adenocarcinoma with Claudin 18.2 expression;Cohort B: LB4330 single drug therapy, 5 patients with advanced pancreatic ductal adenocarcinoma with Claudin 18.2 expression; Cohort C: LB4330 single drug therapy, other advanced solid tumor patients with Claudin 18.2 expression, a total of 8-15 cases. | Drug: LB4330<br>* LB4330<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MTD/RP2D | The MTD will be determined using the method of sequential regression in the Bayesian optimal interval (BOIN) design. This calculation can be realized by Select MTD in BOIN online software. Specifically, the dose that the toxicity rate estimated by sequential regression is closest to the target toxicity rate is selected as the maximum tolerable dose (MTD); If two or more doses meet this condition, select the higher (when the maintenance regression estimate is lower than the target toxicity rate) or lower (when the maintenance regression estimate is equal to or higher than the target toxicity rate) dose group. | through study completion, an average of 8 months. | 
| DLT occurrence and frequency (dose escalation phase) | The DLT for this study is defined according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0 and will be evaluated in the dose escalation part, the first 28 days (Cycle 1) of treatment. | The first period of LB4330 treatment (28 days for the first subject in the first dose group, 21 days for the rest subjects. If the administration is delayed, the DLT evaluation period should be extended to 7 days after the third administration) | 
| AE, SAE occurrence and frequency (according to NCI CTCAE 5.0) | According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. | up to 90 days following last dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum PK parameters | AUC0-t and so on. | Up to finished treatment | 
| Pharmacodynamic index | Pharmacodynamic index: percentage of monocytes | through study completion, an average of 8 months. | 
| Immunogenicity | Immunogenicity index: positive rate, titer and duration of ADA and Nab (if ADA is positive) | up to 90 days following last dose | 
| Overall response rate (ORR) | Evaluation Criteria in Solid Tumors (RECIST) v 1.1 and Immunotherapeutics Response Evaluation Criteria in Solid Tumors (iRECIST). | through study completion, an average of 8 months. | 
| Disease control rate (DCR) | Evaluation Criteria in Solid Tumors (RECIST) v 1.1 and Immunotherapeutics Response Evaluation Criteria in Solid Tumors (iRECIST). | through study completion, an average of 8 months. | 
| Progression-free survival (PFS) | Evaluation Criteria in Solid Tumors (RECIST) v 1.1 and Immunotherapeutics Response Evaluation Criteria in Solid Tumors (iRECIST). | through study completion, an average of 8 months. | 
| Duration of response (DOR) | Evaluation Criteria in Solid Tumors (RECIST) v 1.1 and Immunotherapeutics Response Evaluation Criteria in Solid Tumors (iRECIST). | through study completion, an average of 8 months. | 
| OS | Total survival period (OS): It is defined as the time from the start of using the study drug to the death due to any reason. | through study completion，an average of 1 year | 
| Biomarker | Biomarker: relationship between Claudin 18.2 expression level in tumor tissue and clinical response | through study completion, an average of 8 months. |