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

Pancreatic Cancer Clinical Trial

Official title:

A 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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05539430
• Other study ID #: LB1908-1001
• Status: Recruiting
• Phase: Phase 1
• Start date: April 18, 2023
• Est. completion date: December 2025

Study information

• Verified date: March 2024
• Source: Legend Biotech USA Inc
• Contact: Legend Biotech USA
• Phone: 17323175050
• Email: medical.information[@]legendbiotech.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a 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

Description:

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. Patients will be confirmed to have sufficient expression of Claudin 18.2 as part of a prescreening. The study comprises a dose-escalation component (Part A) and a dose-expansion component (Part B). In part A, patients with gastric, GEJ, or esophageal adenocarcinoma will be treated with LB1908 at protocol-defined dose level, with escalation to higher doses in subsequent patients guided by evaluation of protocol-defined dose limiting toxicities (DLTs). Part A will identify the recommended dose for expansion (RDE) to be tested in part B in two cohorts: a gastric, GEJ and esophageal adenocarcinoma cohort as well as a pancreatic adenocarcinoma cohort. Part B will aim to identify the recommended dose for phase 2 (RP2D).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 56
• Est. completion date: December 2025
• Est. primary completion date: July 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

1. Be willing and able to provide written informed consent

2. Be a female or male = 18 and = 75 years old at the time of signing of the informed consent

3. For Part A and B: subjects 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: subjects 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.

4. Subjects 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. Subjects 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.

5. Presence of CLDN18.2 positive tumors with staining intensity of = 1+ in = 50% of tumor cells by immunohistochemistry (performed by central laboratory during Prescreening)

6. Presence of = 1 radiologically measurable lesion per Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1.

7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

8. Life expectancy of at least 4 months per investigator judgment.

9. Have adequate organ function

10. Women of childbearing potential must have a negative pregnancy test at screening

11. All Subject 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.

12. 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:

1. Prior treatment with cellular immunotherapy (e.g., CAR-T) or gene therapy product.

2. Prior treatment with claudin 18.2-targeted therapy.

3. Antitumor therapy prior to apheresis during the protocol-defined window

4. Subjects who have a history of esophageal or gastric resection that the investigator considers is at increased risk of bleeding or perforation;

5. Unstable/active ulcer, varices, or digestive tract bleeding or recent digestive surgery that may have increased risk of bleeding;

6. Clinically significant ascites, pleural or peritoneal effusions requiring weekly clinical intervention at screening.

7. Patients requiring anticoagulant therapy such as warfarin or heparin

8. Patients requiring long-term antiplatelet therapy

9. Primary immunodeficiency

10. Known brain metastasis or leptomeningeal metastasis.

11. Subjects with heavy tumor burden such as significant lung disease or extensive liver metastases.

12. Active autoimmune disease receiving immunosuppressants (e.g., cyclosporine or high dose systemic steroids) within 2 weeks or 5 half-lives prior to screening

13. Impaired cardiac function or clinically significant cardiac disease as defined by the protocol

14. Previous or concurrent malignancy not meeting protocol-defined exceptions

15. 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:

16. Current known active infection with human immunodeficiency virus (HIV), hepatitis B, and/or hepatitis C virus (HBV/HCV).

17. Contraindications or life-threatening allergies, hypersensitivity, or intolerance to LB1908 excipients, such as dimethyl sulfoxide; or to fludarabine, cyclophosphamide, or tocilizumab.

18. Ongoing toxicity from previous anticancer therapy that has not resolved to Grade 2 or less, except for alopecia, fatigue, nausea, and constipation.

19. Major surgery within 4 weeks prior to apheresis, or planned within 4 weeks after LB1908 administration.

20. Pregnant or breast-feeding.

21. Plans to become pregnant or breastfeed, or father a child within 1 year after receiving a LB1908 infusion.

22. Previous history of allogeneic HSCT, organ transplant, or in preparation for organ transplant.

Related Conditions & MeSH terms

• Adenocarcinoma
• Esophageal Cancer
• Gastric Cancer
• Gastroesophageal-junction Cancer
• Pancreatic Cancer

Intervention

Biological:
• LB1908
Claudin 18.2-Targeted autologous Chimeric Antigen Receptor T-cells

Locations

Country	Name	City	State
United States	Roswell Park Comprehensive Cancer Center	Buffalo	New York
United States	OHSU Knight Cancer Institute	Portland	Oregon
United States	Fred Hutchinson Cancer Center	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Legend Biotech USA Inc

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To characterize the safety and tolerability of LB1908 and determine the optimal dose or recommended dose for expansion (RDE)	Multiple doses will be tested to establish a recommended dose.	28 days
Primary	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)	Treatment of additional patients at the recommended dose as identified in the initial dose escalation part of the study.	90 days
Secondary	To evaluate the preliminary efficacy of LB1908	Measured by Response Evaluation Criteria In Solid Tumors (RECIST)	Through study completion, a minimum of 2 years
Secondary	To characterize the pharmacokinetics of LB1908 in blood	CAR-positive T cell counts, CAR transgene level in blood	Through study completion, a minimum of 2 years
Secondary	To evaluate the immunogenicity of LB1908	Presence of anti-LB1908 antibodies	Through study completion, a minimum of 2 years