Clinical Trial 23257

• Overview

  Study Title:

  Phase 1, Open-Label, Dose Escalation and Expansion, Multicenter Study of Claudin 18.2-Targeted Chimeric Antigen Receptor T-Cells in Subjects with Unresectable, Locally Advanced, or Metastatic Gastric, Gastroesophageal Junction (GEJ), Esophageal, or Pancreatic Adenocarcinoma

  Summary:

  This is a Phase 1, open label, multicenter study to evaluate Claudin 18.2-targeting CAR-T cells (LB1908) in adult subjects with unresectable, locally advanced or metastatic gastric, GEJ, esophageal, or pancreatic adenocarcinoma.

  Objective:

  Primary Objective: Part A: Dose-escalation: To characterize the safety and tolerability of LB1908 and determine the optimal dose or recommended dose for expansion (RDE) Part B: Dose-expansion To further characterize the safety and tolerability of LB1908 with the RDE identified in the dose escalation and determine the recommended Phase 2 dose (RP2D) Secondary Objectives: Secondary Objectives Endpoints To evaluate the preliminary efficacy of LB1908 To characterize the pharmacokinetics of LB1908 in blood To evaluate the immunogenicity of LB1908 Exploratory Objectives: To evaluate the additional preliminary efficacy of LB1908 To characterize the distribution of LB1908 in target tissues and effusions (ascitic fluid and pleural fluid) To evaluate Claudin 18.2 expression levels in target tissues and effusions (ascitic fluid and pleural fluid) over time To explore whether the phenotypic compositions of the infused CAR-positive T cell subset of LB1908 impacts the LB1908 pharmacokinetics, pharmacodynamics, safety, and efficacy To explore whether there are predictive biomarkers of safety, response, resistance or relapse to LB1908 To determine whether replication competent lentivirus is present in subjects who receive LB1908

• Treatments

  Therapies:

  Cell Therapy; Chemotherapy (NOS)

  Medications:

  LB1908 (); cyclophosphamide (); cytoxan (cyclophosphamide); fludarabine (Fludarabine phosphate)

• Inclusion Criteria

  Inclusion Criteria:
  • Be willing and able to provide written informed consent
  • Be a female or male between 18 and 75 years of age at the time of signing of the informed consent
  • For Part A and B: Participants with histologically/cytologically confirmed unresectable, locally advanced or metastatic adenocarcinoma of the stomach, GEJ, or distal esophagus for which standard treatment is considered intolerable, unlikely to confer significant clinical benefit, is no longer effective, does not exist, or subject is ineligible or declines standard therapy.
  • For Part B only: Participants with histologically/cytological confirmed unresectable, locally advanced or metastatic adenocarcinoma of the pancreas for which standard treatment is considered intolerable, unlikely to confer significant clinical benefit, is no longer effective, does not exist, or subject is ineligible or declines standard therapy.
  • Participants must have received prior therapy as follows: For gastric, GEJ, or esophageal adenocarcinoma, previous treatment must have included a fluoropyrimidine and/or platinum containing regimen. Patients with HER2-neu-positive (HER2+) disease must have also received prior anti-HER2+ therapy; For pancreatic adenocarcinoma, previous treatment must have included fluoropyrimidine and/or gemcitabine containing regimen.
  • Presence of CLDN18.2 positive tumors with staining intensity of 1+or more in 50% or greater of tumor cells by immunohistochemistry (performed by central laboratory during Prescreening)
  • Presence of 1 or more radiologically measurable lesion per Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1.
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
  • Life expectancy of at least 4 months per investigator judgment.
  • Have adequate organ function
  • Women of childbearing potential must have a negative pregnancy test at screening
  • All Participants must agree to practice a highly effective method of contraception from the time of signing the ICF to 1 year after receiving a LB1908 infusion.
  • Women and men must agree not to donate eggs (ova, oocytes) or sperm, respectively, until at least 1 year after receiving a LB1908 infusion.

• Exclusion Criteria

  Exclusion Criteria:
  • Prior treatment with cellular immunotherapy (e.g., CAR-T) or gene therapy product.
  • Prior treatment with claudin 18.2-targeted therapy.
  • Antitumor therapy prior to apheresis during the protocol-defined window
  • Participants who have a history of esophageal or gastric resection that the investigator considers is at increased risk of bleeding or perforation;
  • Unstable/active ulcer, varices, or digestive tract bleeding or recent digestive surgery that may have increased risk of bleeding;
  • Clinically significant ascites, pleural or peritoneal effusions requiring weekly clinical intervention at screening.
  • Patients requiring anticoagulant therapy such as warfarin or heparin
  • Patients requiring long-term antiplatelet therapy
  • Primary immunodeficiency
  • Known brain metastasis or leptomeningeal metastasis.
  • Participants with heavy tumor burden such as significant lung disease or extensive liver metastases.
  • Active autoimmune disease receiving immunosuppressants (e.g., cyclosporine or high dose systemic steroids) within 2 weeks or 5 half-lives prior to screening
  • Impaired cardiac function or clinically significant cardiac disease as defined by the protocol
  • Previous or concurrent malignancy not meeting protocol-defined exceptions
  • Serious and /or uncontrolled medical condition that, in the Investigator's judgment, would cause unacceptable safety risk, interfere with study procedures or results, or compromise compliance with the protocol:
  • Current known active infection with human immunodeficiency virus (HIV), hepatitis B, and/or hepatitis C virus (HBV/HCV).
  • Contraindications or life-threatening allergies, hypersensitivity, or intolerance to LB1908 excipients, such as dimethyl sulfoxide; or to fludarabine, cyclophosphamide, or tocilizumab.
  • Ongoing toxicity from previous anticancer therapy that has not resolved to Grade 2 or less, except for alopecia, fatigue, nausea, and constipation.
  • Major surgery within 4 weeks prior to apheresis, or planned within 4 weeks after LB1908 administration.
  • Pregnant or breast-feeding.
  • Plans to become pregnant or breastfeed, or father a child within 1 year after receiving a LB1908 infusion.
  • Previous history of allogeneic HSCT, organ transplant, or in preparation for organ transplant.

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