Esophageal Cancer, Gastric Cancer, Gastroesophageal-junction Cancer, Pancreatic Cancer
Conditions
Brief 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
Detailed description
This is a Phase 1, open label, dose escalation, 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 several cohorts: * Monotherapy regimen (MR) cohorts: treating second or later line gastric, GEJ, and esophageal adenocarcinoma or pancreatic adenocarcinoma patients as standalone treatment. * Consolidation regimen (CR) cohorts: treating frontline gastric, GEJ, and esophageal adenocarcinoma or pancreatic adenocarcinoma patients who have achieved disease control with standard of care chemotherapy. Part B will aim to identify the recommended dose for phase 2 (RP2D)and evaluate preliminary efficacy in these different treatment settings and patient populations.
Interventions
BIOLOGICALLB1908
Claudin 18.2-Targeted autologous Chimeric Antigen Receptor T-cells
Sponsors
Legend Biotech USA Inc
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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 the prescreening ICF. 3. For Part A and Part B Cohort MR1 only: 1. Subjects with histologically/cytologically confirmed unresectable, locally advanced or metastatic adenocarcinoma of the GC/GEJC/EC for which standard treatment is considered intolerable, unlikely to confer significant clinical benefit, is no longer effective, or subject is ineligible or declines standard therapy. 2. Subjects must have received prior therapy as follows: * 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. * Neoadjuvant/adjuvant treatment will be considered as a prior regimen if disease progression occurred during treatment or within 6 months of cessation of treatment. For Part B Cohort MR2 only: 3. Subjects with histologically/cytologically confirmed unresectable, locally advanced or metastatic PDAC for which standard treatment is considered intolerable, unlikely to confer significant clinical benefit, is no longer effective, 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 gemcitabine containing regimen. * Neoadjuvant/adjuvant treatment will be considered as a prior regimen if disease progression occurred during treatment or within 6 months of cessation of treatment. For Part B Cohort CR1 only: 5. Subjects with histologically/cytologically confirmed metastatic GC/GEJC/EC with RECIST v1.1 SD or PR at the initial response evaluation during first-line SOC treatment. 6. Subjects with locally advanced, unresectable disease for whom radiation is not planned may be eligible with Sponsor approval. 7. Subjects who develop metachronous metastatic disease after prior (neo)adjuvant treatment for previously localized disease are eligible if at least 6 months have elapsed since completion of prior chemotherapy (and disease status is satisfied, as above). 8. Subjects must be clinically suitable to continue at least part of the initial first-line regimen during LB1908 manufacturing. 9. Negative for human epidermal growth factor receptor 2 (HER2) or ineligible to receive 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) and capecitabine/oxaliplatin (CAPOX), with or without an approved immune checkpoint inhibitor. * Zolbetuximab is allowable as part of first-line SOC (subjects with prior zolbetuximab exposure require Sponsor approval prior to enrollment) 11. No investigational therapies in first-line therapy, unless the investigational product 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 response evaluation during first-line SOC treatment. 13. Subjects with locally advanced, unresectable disease for whom radiation is not planned may be eligible with Sponsor approval. 14. Subjects who develop metachronous metastatic disease after prior (neo)adjuvant treatment for previously localized disease are eligible if at least 6 months have elapsed since completion of prior chemotherapy (and disease status is satisfied, as above). 15. Subjects must be clinically suitable to continue at least part of the initial first-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 liposomal irinotecan/fluorouracil/leucovorin/oxaliplatin (NALIRIFOX). * Prior investigational therapies are exclusionary. 17. No investigational therapies in first-line therapy, unless the investigational product is discontinued prior to enrollment on this trial. 4. Presence of CLDN18.2 positive tumors with staining intensity of ≥ 1+ in ≥ 50% of tumor cells by immunohistochemistry (IHC) (Performed during Prescreening). * Subject has available formalin-fixed, paraffin-embedded (FFPE) tumor specimen in a tissue block or unstained serial slides accompanied by an associated pathology report prior to enrollment. Archival or fresh biopsy tissue is required. * If a subject had prior CLDN18.2 targeted therapy, subject may be required to have a formalin-fixed, paraffin-embedded tumor specimen in a tissue block or unstained serial slides accompanied by an associated pathology report that was obtained after exposure to CLDN18.2 targeted therapy, prior to enrollment, and fulfill 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To characterize the safety and tolerability of LB1908 and determine the optimal dose or recommended dose for expansion (RDE) | Through study completion, a minimum of 2 years | Multiple doses will be tested to establish a recommended dose. |
| 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) | Through study completion, a minimum of 2 years | Treatment of additional patients at the recommended dose as identified in the initial dose escalation part of the study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To evaluate the preliminary efficacy of LB1908 | Through study completion, a minimum of 2 years | Measured by Response Evaluation Criteria In Solid Tumors (RECIST) |
| To characterize the pharmacokinetics of LB1908 in blood | Through study completion, a minimum of 2 years | CAR-positive T cell counts, CAR transgene level in blood |
| To evaluate the immunogenicity of LB1908 | Through study completion, a minimum of 2 years | Presence of anti-LB1908 antibodies |
Countries
United States
Outcome results
None listed