Clinical Study of Cord Blood-Derived CAR-NK Cells in Gastric Cancer and Pancreatic Cancer

NCT06464965 | Completed Phase 1 DMC

• 1 other identifier: 2024-105
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

Main Objective: To study the maximum tolerated dose (MTD) and dose-dependent toxicity (DLT) of cord blood-derived CAR-NK cells (CB CAR-NK182) targeting Claudin18.2 in patients with advanced gastric cancer and advanced pancreatic cancer. Secondary Objective: To evaluate the efficacy of CB CAR-NK182 in patients with advanced gastric cancer and advanced pancreatic cancer: overall objective tumor response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), duration of response (DOR), etc. To evaluate the CAR-NK amplification and persistence of CB CAR-NK182 in the blood of patients with advanced gastric cancer and advanced pancreatic cancer;

Conditions

Gastric Cancer; Pancreas Adenocarcinoma

Keywords

Gastric Cancer; Pancreatic Adenocarcinoma; CAR-NK; Claudin18.2

Outcome Measures

Primary Outcomes (2)

• MTD

  Maximum Tolerated Dose

  1 month

• DLT

  Dose-Dependent Toxicity

  1 month

Secondary Outcomes (5)

• ORR

  3 years

• DCR

  3 years

• PFS

  3 years

• OS

  3 years

• DOR

  3 years

Study Arms (1)

CB CAR-NK182 Dose Escalation

EXPERIMENTAL

Participants will receive a lymphodepleting conditioning regimen (FC regimen) followed by three intravenous infusions of Claudin18.2-targeted umbilical cord blood-derived CAR-NK cells (CB CAR-NK182) on days 0, 3, and 7. The study follows a "3+3" dose-escalation design with three planned dose levels. Three dose levels: Dose Level 1 (2×10⁶ cells/kg/infusion on days 0, 3, and 7), Dose Level 2 (8×10⁶ cells/kg/infusion on days 0, 3, and 7), Dose Level 3 (16×10⁶ cells/kg/infusion on days 0, 3, and 7). 3-6 subjects will be enrolled per dose level. Each subject will be observed for at least 28 days after the first infusion, with a long-term follow-up period of 2 years post-first infusion. Standard "3+3" rules apply for DLT observation and dose escalation decisions.

Biological: CB CAR-NK18.2; Drug: Cyclophosphamide; Drug: Fludarabine

Interventions

CB CAR-NK18.2 BIOLOGICAL

Administered via intravenous infusion on Days 0, 3, and 7. Three dose levels are planned: Dose Level 1: 2×10\^6 cells/kg/infusion Dose Level 2: 8×10\^6 cells/kg/infusion Dose Level 3: 16×10\^6 cells/kg/infusion

CB CAR-NK182 Dose Escalation

Cyclophosphamide DRUG

Part of the lymphodepletion regimen. Administered at 500 mg/m\^2/day on Days -5 to -3 prior to the first CAR-NK cell infusion.

CB CAR-NK182 Dose Escalation

Fludarabine DRUG

Part of the lymphodepletion regimen. Administered at 30 mg/m\^2/day on Days -5 to -3 prior to the first CAR-NK cell infusion.

CB CAR-NK182 Dose Escalation

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female aged 18-75 years (inclusive);
• Understands and voluntarily signs a written informed consent form, and is willing and able to comply with all trial requirements;
• Patients with advanced gastric cancer and advanced pancreatic cancer confirmed by histopathology or cytology, who have failed standard treatment or cannot tolerate standard treatment, including but not limited to: pancreatic cancer and gastric cancer;
• Immunohistochemical (IHC) detection of CLDN18.2, the positive expression of CLDN18.2 in tumors must be ≥ 10%;
• At least 1 measurable lesion according to RECIST 1.1;
• ECOG score is 0-1;
• All toxic reactions caused by previous antineoplastic therapy were resolved to grade 0-1 (according to NCI CTCAE 5.0 edition); Expected survival ≥ 12 weeks;
• In addition to the primary disease, no serious hematology, heart and lung, liver and kidney disease, laboratory tests meet the following requirements:
• Peripheral blood neutrophil absolute value ≥ 2000/mm3, platelet ≥ 50000/mm3 Serum creatinine ≤ 1.5mg/dL;ALT (alanine aminotransferase)/AST (aspartate aminotransferase) below 2.5 times the upper limit of normal; Total bilirubin ≤ 1.5mg/dL; Cardiac ejection fraction (EF)≥ 50%; International standard ratio (INR) or prothrombin time (PT) below 1.5 times the upper limit of normal; Activated partial coagulation time (aPTT) below 1.5 times the upper limit of normal; 10. Women of childbearing potential must have a negative serum pregnancy test and agree to effective birth control during the treatment phase and within 12 months after injection of CAR-NK cells; Male patients must agree to use effective birth control during the study and for 12 months after injection of CAR-NK cells.

You may not qualify if:

• History of other tumors;
• Patients who have received CAR-T,CAR-NK,TCR-T and other cell therapy targeting Claudin18.2 within 3 months before study treatment;
• Patients with hypersensitivity to cell therapy or any related drugs;
• Active autoimmune diseases;
• Active infections that cannot be controlled;
• HIV infection, uncontrolled HBV, HCV and syphilis infections;
• Have metastatic disease of the central nervous system (CNS), leptomeningeal disease or spinal cord compression;
• Patients with severe heart disease;
• Patients with unstable/active ulcers or bleeding from the digestive system;
• Patients with a history of bleeding or bleeding tendency in the digestive system;
• Pregnant or lactating women;
• There are other factors that the researcher believes are not suitable for participating in the trial.

Sponsors & Collaborators

• Zhejiang Provincial People's Hospital: lead
• Hangzhou RongGu Biotechnology Limited Company: collaborator
• Zhejiang University: collaborator

Study Sites (1)

Zhejiang Provincial People's Hospital

Hangzhou, Zhejiang, China

Location

Related Publications (10)

• Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020 Jan;70(1):7-30. doi: 10.3322/caac.21590. Epub 2020 Jan 8.

  PMID: 31912902 BACKGROUND

• Fanotto V, Cordio S, Pasquini G, Fontanella C, Rimassa L, Leone F, Rosati G, Santini D, Giampieri R, Di Donato S, Tomasello G, Silvestris N, Pietrantonio F, Battaglin F, Avallone A, Scartozzi M, Lutrino ES, Melisi D, Antonuzzo L, Pellegrino A, Torri V, Aprile G. Prognostic factors in 868 advanced gastric cancer patients treated with second-line chemotherapy in the real world. Gastric Cancer. 2017 Sep;20(5):825-833. doi: 10.1007/s10120-016-0681-6. Epub 2016 Dec 27.

  PMID: 28028664 BACKGROUND

• Tabernero J, Hoff PM, Shen L, Ohtsu A, Shah MA, Cheng K, Song C, Wu H, Eng-Wong J, Kim K, Kang YK. Pertuzumab plus trastuzumab and chemotherapy for HER2-positive metastatic gastric or gastro-oesophageal junction cancer (JACOB): final analysis of a double-blind, randomised, placebo-controlled phase 3 study. Lancet Oncol. 2018 Oct;19(10):1372-1384. doi: 10.1016/S1470-2045(18)30481-9. Epub 2018 Sep 11.

  PMID: 30217672 BACKGROUND

• Thuss-Patience PC, Shah MA, Ohtsu A, Van Cutsem E, Ajani JA, Castro H, Mansoor W, Chung HC, Bodoky G, Shitara K, Phillips GDL, van der Horst T, Harle-Yge ML, Althaus BL, Kang YK. Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): an international randomised, open-label, adaptive, phase 2/3 study. Lancet Oncol. 2017 May;18(5):640-653. doi: 10.1016/S1470-2045(17)30111-0. Epub 2017 Mar 23.

  PMID: 28343975 BACKGROUND

• Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Ruschoff J, Kang YK; ToGA Trial Investigators. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010 Aug 28;376(9742):687-97. doi: 10.1016/S0140-6736(10)61121-X. Epub 2010 Aug 19.

  PMID: 20728210 BACKGROUND

• Heinemann V, Ebert MP, Laubender RP, Bevan P, Mala C, Boeck S. Phase II randomised proof-of-concept study of the urokinase inhibitor upamostat (WX-671) in combination with gemcitabine compared with gemcitabine alone in patients with non-resectable, locally advanced pancreatic cancer. Br J Cancer. 2013 Mar 5;108(4):766-70. doi: 10.1038/bjc.2013.62. Epub 2013 Feb 14.

  PMID: 23412098 BACKGROUND

• Cappell KM, Kochenderfer JN. Long-term outcomes following CAR T cell therapy: what we know so far. Nat Rev Clin Oncol. 2023 Jun;20(6):359-371. doi: 10.1038/s41571-023-00754-1. Epub 2023 Apr 13.

  PMID: 37055515 BACKGROUND

• Khawar MB, Gao G, Rafiq M, Shehzadi A, Afzal A, Abbasi MH, Sheikh N, Afzal N, Ashraf MA, Hamid SE, Shahzaman S, Kawish N, Sun H. Breaking down barriers: The potential of smarter CAR-engineered NK cells against solid tumors. J Cell Biochem. 2023 Aug;124(8):1082-1104. doi: 10.1002/jcb.30460. Epub 2023 Aug 11.

  PMID: 37566723 BACKGROUND

• Gowrikumar S, Singh AB, Dhawan P. Role of Claudin Proteins in Regulating Cancer Stem Cells and Chemoresistance-Potential Implication in Disease Prognosis and Therapy. Int J Mol Sci. 2019 Dec 20;21(1):53. doi: 10.3390/ijms21010053.

  PMID: 31861759 BACKGROUND

• Kyuno D, Takasawa A, Takasawa K, Ono Y, Aoyama T, Magara K, Nakamori Y, Takemasa I, Osanai M. Claudin-18.2 as a therapeutic target in cancers: cumulative findings from basic research and clinical trials. Tissue Barriers. 2022 Jan 2;10(1):1967080. doi: 10.1080/21688370.2021.1967080. Epub 2021 Sep 5.

  PMID: 34486479 BACKGROUND

MeSH Terms

Conditions

Stomach Neoplasms

Interventions

Cyclophosphamide; fludarabine

Condition Hierarchy (Ancestors)

Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Stomach Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Study Officials

• Yang Liu, M.D.

  Zhejiang Provincial People's Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD

Study Record Dates

• First Submitted: June 13, 2024
• First Posted: June 18, 2024
• Study Start: July 3, 2024
• Primary Completion: October 10, 2025
• Study Completion: December 30, 2025
• Last Updated: April 16, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)