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）
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）
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
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.
Inclusion Criteria
Subjects must meet all of the following criteria to be eligible for enrollment:
1. Age between 18 and 75 years (inclusive), regardless of sex. 2.
Dose-Escalation Phase: Histologically or cytologically confirmed advanced malignant solid tumors.
Monotherapy Expansion Phase: Histologically or cytologically confirmed advanced gastric/gastroesophageal junction adenocarcinoma, pancreatic ductal adenocarcinoma, or other solid tumors that have failed standard treatment, or for which there is no standard treatment, or for whom standard treatment is currently unsuitable. 3.
Dose-Escalation Phase: At least one evaluable lesion based on RECIST v1.1.
Monotherapy Expansion Phase: At least one measurable lesion based on RECIST v1.1 (lesions previously treated with radiotherapy or localized therapy are not considered measurable unless they have clearly progressed or persisted for at least 3 months post-radiotherapy).
Monotherapy Expansion Phase: Must provide a prior Claudin 18.2 test report; if unavailable, archived or fresh tumor tissue samples must be submitted.
Cohort E: If Claudin 18.2 testing has been done previously, the result must show no Claudin 18.2 expression. If no test result is available and no sample can be provided, inclusion is allowed upon joint agreement between the sponsor and investigator.
Cohorts A, B, C: Require Claudin 18.2 expression (≥1% of tumor cells with staining intensity of 1+ or above).
Cohort D: Must be Claudin 18.2 negative.
Cohort E: Must not have known Claudin 18.2 expression (≥1% of tumor cells with staining intensity of 1+ or above).
5. ECOG performance status of 0-1. 6. Expected survival time of at least 3 months. 7. Adequate organ function:
Hematologic (no transfusion or hematopoietic growth factors within 14 days prior):
Liver Function:
Renal Function:
Coagulation:
APTT ≤ 1.5 × ULN
INR ≤ 1.5 × ULN 8. Fertile patients (male and female) must agree to use reliable contraception (e.g., hormonal, barrier, or abstinence) during the study and for at least 90 days after the last dose. Women of childbearing potential must have a negative blood or urine pregnancy test within 7 days prior to the first dose.
9. Subjects must voluntarily sign the written informed consent form after being informed about the study.
Exclusion Criteria:
Subjects meeting any of the following criteria will be excluded:
Received chemotherapy, biologic therapy, targeted therapy, or immunotherapy within 4 weeks prior to first dose; radiotherapy, endocrine therapy, or oral fluoropyrimidines within 2 weeks;traditional Chinese medicine with antitumor indications within 1 week;or nitrosoureas/mitomycin C within 6 weeks.
Participation in another investigational drug or therapy trial within 4 weeks prior to first dose.
Major surgery (excluding biopsy) or significant trauma within 4 weeks prior to first dose, or scheduled elective surgery during the study.
Prior treatment with IL-10-targeted agents.
Systemic corticosteroids (prednisone >10 mg/day or equivalent) or immunosuppressants within 14 days prior to first dose, except for: topical, ophthalmic, intra-articular, intranasal, or inhaled corticosteroids; short-term prophylactic steroids (e.g., to prevent contrast reactions).
Immunomodulatory agents (e.g., thymosin, IL-2, interferons) within 14 days prior to first dose.
Live or attenuated vaccines within 4 weeks prior to first dose.
Prior allogeneic stem cell or organ transplantation.
Unresolved adverse events from prior anticancer therapy (excluding alopecia, Grade 2 peripheral neuropathy, or well-controlled hypothyroidism), unless ≤ Grade 1 per CTCAE v5.0.
Meningeal metastases, spinal cord compression, or unstable brain metastases requiring steroids or anti-epileptic drugs within 4 weeks before enrollment. Stable brain metastases off steroids/anti-epileptics for ≥4 weeks are allowed.
Active infection requiring systemic treatment.
Tumor thrombus involving major blood vessels or adjacent organ invasion (e.g., stomach, aorta, trachea) posing high risk of bleeding/perforation, or existing bleeding/perforation/fistula.
Known gastrointestinal disorders such as irritable bowel syndrome with symptoms (e.g., chronic nausea, vomiting, diarrhea) or gastric outlet obstruction.
History of immunodeficiency, including HIV antibody positivity.
Active syphilis, active hepatitis B [HBsAg-positive and HBV DNA >200 IU/mL or above assay's lower limit of detection], or active hepatitis C (HCV antibody positive but HCV RNA below assay limit is allowed). Patients on non-interferon antiviral therapy are eligible.
Interstitial lung disease (excluding radiation-induced fibrosis not requiring steroids).
Serious cardiovascular or cerebrovascular conditions, including but not limited to:
Active or recurrent autoimmune disease (e.g., SLE, RA, Crohn's, UC, vasculitis), except for: hypothyroidism requiring hormone replacement or stable type 1 diabetes on insulin.
Prior immune-related adverse event (irAE) of Grade ≥3 due to immunotherapy.
Clinically uncontrolled third-space or pericardial effusion requiring repeated drainage.
Grade ≥3 infusion-related reaction to previous biologic/protein therapy.
Known alcohol or substance abuse.
Psychiatric illness or poor compliance.
Pregnant or breastfeeding women.
History of other malignancies within the past 3 years, except for: non- melanoma skin cancer, biopsy-confirmed cervical carcinoma in situ, squamous intraepithelial lesion on Pap test, localized prostate cancer (Gleason <6), or completely resected in situ melanoma. Other low-risk or in-situ cancers may be allowed after sponsor consultation. 26. Other serious systemic diseases or conditions deemed unsuitable by the investigator.
27. Known HER2 positivity, MSI-H/dMMR, or mutations (e.g., KRAS) for which approved targeted therapies are available per guidelines.
28. Grade IV myelosuppression related to prior antitumor therapy. 29. Primary or secondary platelet count decreased or platelet-destructive diseases (e.g., Fanconi anemia, congenital platelet count decreased without megakaryocytes, May-Hegglin anomaly, aplastic anemia, bone marrow infiltration, radiation to bone marrow, megakaryocytic hypoplasia, ITP). 30. Arterial or venous thrombotic events within 6 months, including stroke (TIA, cerebral hemorrhage, infarction), DVT, or pulmonary embolism.