Clinical trial NCT05707676: A Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Immunogenicity of LB4330 in Patients With Advanced Solid Tumors（MEETCD8-001）
Official title: 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）
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Solid Tumor
Lead sponsor: L & L biopharma Co., Ltd., Shanghai China
Sponsor class: INDUSTRY
First posted: 2023-02-01
Enrollment: 66
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Age 18-80 (including boundary value) years old male or female.
2. 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.
3. (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).
4. (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.
5. ECOG performance score 0-1.
6. Expected survival time of more than 3 months.
7. Adequate organ function.
8. 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.
9. Patients must give informed consent to this study prior to the study and sign a written informed consent form voluntarily

Exclusion Criteria:

1. 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.
2. Have received other investigational agents or treatment within 4 weeks prior to the first dose of the study drug.
3. 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.
4. 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).
5. Have received allogeneic hematopoietic stem cell transplantation or organ transplantation.
6. 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.)
7. Patients with symptomatic parenchymal brain metastasis (BM) or leptomeningeal (LM) metastasis who are not suitable for treatment as judged by the investigator.
8. Patients with active infection which requires intravenous anti-infective therapy.
9. Patients with known lesions responsible for gastric bleeding or those considered by the investigator to have a greater risk for gastric bleeding.
10. irritable bowel syndrome with symptoms (such as chronic nausea, persistent repeated vomiting or diarrhea) and gastric outlet obstruction are known to exist.
11. Have a history of immunodeficiency, including HIV antibody test positive.
12. 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).
13. Patients with interstitial lung disease (excluding radiation-induced pulmonary fibrosis that does not require hormone treatment).
14. 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.
15. 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.
16. Have received immunotherapy and had ≥ grade 3 irAE.
17. Have experienced ≥ grade 3 infusion-related reactions to protein therapeutics.
18. Known history of other serious systemic diseases or other reasons that unsuitable for entry as determined by the investigator.

Primary outcomes:
measure: MTD/RP2D
timeFrame: through study completion, an average of 8 months.
measure: DLT occurrence and frequency (dose escalation phase)
timeFrame: 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)
measure: AE, SAE occurrence and frequency (according to NCI CTCAE 5.0)
timeFrame: up to 90 days following last dose
Secondary outcomes:
measure: Serum PK parameters
timeFrame: Up to finished treatment
measure: Pharmacodynamic index
timeFrame: through study completion, an average of 8 months.
measure: Immunogenicity
timeFrame: up to 90 days following last dose
measure: Overall response rate (ORR)
timeFrame: through study completion, an average of 8 months.
measure: Disease control rate (DCR)
timeFrame: through study completion, an average of 8 months.
measure: Progression-free survival (PFS)
timeFrame: through study completion, an average of 8 months.
measure: Duration of response (DOR)
timeFrame: through study completion, an average of 8 months.
measure: OS
timeFrame: through study completion，an average of 1 year
measure: Biomarker
timeFrame: through study completion, an average of 8 months.
Other outcomes:
Locations:
city: Shanghai
country: China
facility: Fudan University Shanghai Cancer Center
state: Shanghai
Study officials:
affiliation: Fudan University
name: Xianjun Yu, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: Fudan University
name: Jian Zhang, Doctor
role: PRINCIPAL_INVESTIGATOR
References: