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

Inclusion Criteria:

For inclusion in the study, all of the following inclusion criteria must be fulfilled.

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 theprescreening ICF.

3. For Part A and Part B Cohort MR1 only:

4. Subjects with histologically/cytologically confirmed unresectable, locallyadvanced or metastatic adenocarcinoma of the GC/GEJC/EC for which standardtreatment is considered intolerable, unlikely to confer significant clinicalbenefit, is no longer effective, or subject is ineligible or declines standardtherapy.

5. Subjects must have received prior therapy as follows:

• Previous treatment must have included a fluoropyrimidine and/or platinumcontaining regimen. Subjects with HER2-neu-positive (HER2+) disease musthave also received prior anti-HER2+ therapy.
• Neoadjuvant/adjuvant treatment will be considered as a prior regimen ifdisease progression occurred during treatment or within 6 months ofcessation of treatment.For Part B Cohort MR2 only:

3. Subjects with histologically/cytologically confirmed unresectable, locallyadvanced or metastatic PDAC for which standard treatment is consideredintolerable, unlikely to confer significant clinical benefit, is no longereffective, or subject is ineligible or declines standard therapy.

4. Subjects must have received prior therapy as follows:

• Previous treatment must have included fluoropyrimidine and/or gemcitabinecontaining regimen.
• Neoadjuvant/adjuvant treatment will be considered as a prior regimen ifdisease progression occurred during treatment or within 6 months ofcessation of treatment.For Part B Cohort CR1 only:

5. Subjects with histologically/cytologically confirmed metastatic GC/GEJC/EC withRECIST v1.1 SD or PR at the initial response evaluation during first-line SOCtreatment.

6. Subjects with locally advanced, unresectable disease for whom radiation is notplanned may be eligible with Sponsor approval.

7. Subjects who develop metachronous metastatic disease after prior (neo)adjuvanttreatment for previously localized disease are eligible if at least 6 monthshave elapsed since completion of prior chemotherapy (and disease status issatisfied, as above).

8. Subjects must be clinically suitable to continue at least part of the initialfirst-line regimen during LB1908 manufacturing.

9. Negative for human epidermal growth factor receptor 2 (HER2) or ineligible toreceive HER2-directed therapy.

10. Subjects must have received prior therapy as follows:

• Acceptable SOC first-line regimens include (but are not limited to)leucovorin/fluorouracil/oxaliplatin (FOLFOX; modifications allowed) andcapecitabine/oxaliplatin (CAPOX), with or without an approved immunecheckpoint inhibitor.
• Zolbetuximab is allowable as part of first-line SOC (subjects withprior zolbetuximab exposure require Sponsor approval prior toenrollment)

11. No investigational therapies in first-line therapy, unless the investigationalproduct is discontinued prior to enrollment on this trial.For Part B Cohort CR2 only:

12. Subjects with metastatic PDAC with RECIST v1.1 SD or PR at the initial responseevaluation during first-line SOC treatment.

13. Subjects with locally advanced, unresectable disease for whom radiation is notplanned may be eligible with Sponsor approval.

14. Subjects who develop metachronous metastatic disease after prior (neo)adjuvanttreatment for previously localized disease are eligible if at least 6 monthshave elapsed since completion of prior chemotherapy (and disease status issatisfied, as above).

15. Subjects must be clinically suitable to continue at least part of the initialfirst-line regimen during LB1908 manufacturing.

16. Subjects must have received prior therapy as follows:

• Acceptable SOC first-line regimens include (but are not limited to)leucovorin/fluorouracil/irinotecan/oxaliplatin (FOLFIRINOX),nabpaclitaxel/ gemcitabine, and liposomalirinotecan/fluorouracil/leucovorin/oxaliplatin (NALIRIFOX).
• Prior investigational therapies are exclusionary.

17. No investigational therapies in first-line therapy, unless the investigationalproduct is discontinued prior to enrollment on this trial.

18. Presence of CLDN18.2 positive tumors with staining intensity of ≥ 1+ in ≥ 50% oftumor cells by immunohistochemistry (IHC) (Performed during Prescreening).

• Subject has available formalin-fixed, paraffin-embedded (FFPE) tumor specimenin a tissue block or unstained serial slides accompanied by an associatedpathology report prior to enrollment. Archival or fresh biopsy tissue isrequired.

• If a subject had prior CLDN18.2 targeted therapy, subject may be required tohave a formalin-fixed, paraffin-embedded tumor specimen in a tissue block orunstained serial slides accompanied by an associated pathology report that wasobtained after exposure to CLDN18.2 targeted therapy, prior to enrollment, andfulfill criteria as outlined (>50% expression) as directed by Sponsor.

5. Presence of ≥ 1 radiologically measurable lesion per RECIST v1.1.

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

7. Life expectancy of at least 4 months per Investigator judgment.

Exclusion Criteria:

Subjects are not eligible for this study if they fulfill any of the following exclusion criteria:

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

2. Antitumor therapy prior to Screening as follows (Part A and Part B MonotherapyRegimen [second- or later-line subjects] subjects only):

• Any systemic anticancer therapy (including investigational) within 7 days or atleast 5 halflives, whichever is shorter.

• Monoclonal antibody therapy within 2 weeks. Type of monoclonal antibody shouldbe communicated with Sponsor. Palliative radiotherapy is permitted with a safety break, the length of which is atthe discretion of the Investigator. Radiotherapy directed at sites of diseaseassessment is also permitted at the discretion of the Investigator and exclusion ofthe radiated site for disease assessments.

3. Unstable/active ulcer, varices, or digestive tract bleeding or recent digestivesurgery that may have increased risk of bleeding.

4. Clinically significant ascites, pleural or peritoneal effusions requiring weeklyclinical intervention at screening.

5. Subjects who are on therapeutic anticoagulation. (Note: subjects who are ontherapeutic antiplatelet therapy or prophylactic anticoagulation are permitted toparticipate if deemed to not be at an increased risk of bleeding from theirunderlying disease or procedures and are required to obtain approval from Sponsor.Similarly, subjects who can have therapeutic anticoagulation de-escalated toprophylactic dosing prior to LB1908 infusion are also eligible).

6. Known inherited or acquired immune deficiency without the ability of medical controlor normalization.

7. History or known brain metastasis or leptomeningeal metastasis. Part B Cohorts MR1and MR2: Subjects can have brain metastases if previously treated and confirmedstable for at least 4 weeks prior to study entry.

8. Subjects with heavy tumor burden such as significant lung disease or extensive livermetastases (e.g., > 5 liver lesions or a single dominant lesion > 5 cm in maximaldimension).

9. Active autoimmune disease receiving immunosuppressants (e.g., cyclosporine or highdose systemic steroids) prior to screening as follows:

• Within 2 weeks or 5 half-lives, whichever is longer (those with inhaled ortopical steroids recently or currently are not excluded.)

• Immune-related AEs due to prior immune checkpoint therapy must be ≤ Grade 1with no ongoing immunosuppression, including a systemic steroid dose ≤ 20 mgdaily of prednisone equivalent.

10. Impaired cardiac function or clinically significant cardiac disease including:

• Unstable angina or myocardial infarction or coronary artery bypass graft (CABG)within 6 months prior to apheresis.

• New York Heart Association (NYHA) Stage III or IV congestive heart failure.

• History of medically uncontrolled clinically significant cardiac arrhythmia (e.g., ventricular tachycardia), complete left bundle branch block, high-gradeatrioventricular (AV) block, or third-degree AV block.

11. Prior or active malignancy other than the study indication requiring active therapyand/or in the judgment of the Investigator or Sponsor may affect the interpretationof the study endpoints, including the following exceptions:

• Smoldering low grade malignancies may be acceptable as long as the Investigatorassesses them of having a significant longer life expectancy than theunderlying gastric/pancreatic tumor, after discussion with the Sponsor.Carcinoma in situ.

• Non-melanoma skin cancer (e.g., basal cell or squamous cell carcinoma).

12. Serious and/or uncontrolled medical condition that, in the Investigator's judgment,would cause unacceptable safety risk, interfere with study procedures or results, orcompromise compliance with the protocol, such as:

• Active, uncontrolled, viral, bacterial, or systemic fungal infection.

• Requirement of supplemental oxygen to maintain oxygen saturation.

• Clinical evidence of dementia or altered mental status.

13. Active central nervous system (CNS) disorder, stroke or seizure within 6 months ofscreening.

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

• For subjects who are known carriers of HBV, active hepatitis B infection mustbe ruled out based on negative serologic testing and/or determination of HBVdeoxyribonucleic acid (DNA) viral load per institutional guidelines.

• For subjects with known history of HCV infection, confirmation of sustainedvirologic response (SVR) is required for study eligibility, defined as ≥24weeks from initiation of antiviral therapy.

15. Contraindications or life-threatening allergies, hypersensitivity, or intolerance toLB1908b excipients, such as dimethyl sulfoxide (DMSO); or to fludarabine,cyclophosphamide, or tocilizumab.

16. Ongoing toxicity from previous anticancer therapy that has not resolved to Grade 2or less, except for alopecia, fatigue, nausea, and constipation. For Part B Cohorts CR1 and CR2: toxicity from ongoing chemotherapy that isreversible and expected to resolve (based on the discretion of the treatingphysician) by the time of LD chemotherapy is not necessarily exclusionary.

17. Any prior ≥ Grade 3 gastritis or gastric mucosal injury with zolbetuximab, or lowergrade events that have not recovered to Grade 1 or baseline.

18. Major surgery within 4 weeks prior to enrollment, failure to adequately recover fromrecent surgery, or planned surgery within 4 weeks after LB1908 administration.

19. Pregnant or breast-feeding.

20. Plans to become pregnant or breastfeed, or father a child within 1 year afterreceiving a LB1908 infusion.

21. Previous history of allogeneic hematopoietic stem cell transplantation (HSCT), majororgan transplant or in preparation for organ transplant.