TIL Therapy Combined With Pembrolizumab for Advanced or Metastatic Refractory Stomach and Esophageal Cancer

NCT ID: NCT06532799

Last Updated: 2024-11-12

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 75 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-09-10
• Study Completion Date: 2026-12-28

Brief Summary

This Phase I/II study evaluates the safety and efficacy of autologous tumor-infiltrating lymphocytes (TIL) therapy combined with Pembrolizumab (Keytruda) immunotherapy in patients with advanced or metastatic refractory stomach and esophageal cancer. Lifileucel (Amtagvi), the first FDA-approved TIL therapy, has shown significant promise in treating unresectable or metastatic melanoma by leveraging the patient's own immune cells to target and destroy cancer cells. This study aims to apply a similar approach to stomach and esophageal cancers. TILs will be harvested from patients' tumors, expanded in vitro, and infused back into the patients following a non-myeloablative lymphodepletion regimen. Pembrolizumab, a monoclonal antibody that targets the PD-1 receptor on T cells, will be administered to enhance the immune response. The primary endpoint is to determine the objective response rate (ORR) of this combined therapy. Secondary endpoints include disease control rate (DCR), progression-free survival (PFS), overall survival (OS), duration of response (DOR), and quality of life (QoL). This trial aims to provide a novel, personalized treatment option for patients with limited therapeutic alternatives.

Detailed Description

Tumor-infiltrating lymphocytes (TILs) therapy is an advanced form of adoptive cell therapy that harnesses the patient's immune cells to fight cancer. Lifileucel (Amtagvi), the first FDA-approved TIL therapy, has demonstrated substantial efficacy in treating unresectable or metastatic melanoma. By extracting lymphocytes from the patient's tumor, expanding them ex vivo, and reinfusing them, Lifileucel has shown to significantly enhance the immune system's ability to target and destroy cancer cells. This promising approach serves as the foundation for the current study, aiming to apply a similar methodology to advanced or metastatic refractory stomach and esophageal cancers, which typically have poor prognoses and limited treatment options.

This trial involves a multi-step treatment process. First, tumor samples are collected from patients for TIL extraction. Following this, a lymphodepletion regimen using cyclophosphamide and fludarabine is administered to prepare the body for the infusion of expanded autologous TILs. After the TIL infusion, Aldesleukin (IL-2) is given to stimulate the TILs' activity. Pembrolizumab (Keytruda), an immunotherapy that targets the PD-1 receptor on T cells, is also administered to further enhance the immune response against the tumor.

The primary goal of this trial is to determine the objective response rate (ORR) of this combined therapy. Secondary endpoints include the disease control rate (DCR), progression-free survival (PFS), overall survival (OS), duration of response (DOR), and changes in the quality of life (QoL) of patients.

Patients will be closely monitored for side effects and reactions during their hospital stay and throughout the follow-up period. Safety will be assessed based on the incidence and severity of adverse events, while efficacy will be evaluated using RECIST v1.1 criteria. By leveraging the patient's own immune cells and combining them with advanced immunotherapies, this trial aims to provide a novel, personalized treatment option for patients with advanced or metastatic refractory stomach and esophageal cancer, building on the success observed with Lifileucel (Amtagvi) in melanoma treatment.

Conditions

Stomach Cancer; Stomach Cancer Recurrent; Stomach Cancer, Adenocarcinoma; Esophageal Cancer; Esophageal Cancer Metastatic to Bone; Esophageal Cancer Metastatic to Lung; Esophageal Cancer Metastatic to Liver

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Biological Tumor Infiltrating Lymphocytes (TIL) Therapy with Immunotherapy

Patients receive pembrolizumab IV on day -14, cyclophosphamide IV QD on days -7 to -6, fludarabine IV over 30 minutes QD on days -5 to -1, and TILs IV infusion on day 0. Patients also receive pembrolizumab IV on day 28 and 70, and undergo surgery on day 80.

MAINTENANCE: Patients receive pembrolizumab IV every 6 weeks for up to 1 year in the absence of disease progression or unacceptable toxicity.

Group Type: EXPERIMENTAL

Tumor Infiltrating Lymphocytes (TIL)

Intervention Type: BIOLOGICAL

Tumor Infiltrating Lymphocytes (TIL) IV

Cyclophosphamid

Intervention Type: DRUG

Cyclophosphamide will be administered as an intravenous (IV) infusion for two days.

Fludarabine

Intervention Type: DRUG

Fludarabine will be administered as an intravenous (IV) infusion for five days.

Interleukin-2

Intervention Type: DRUG

After TIL infusion, IL-2 will be started as a bolus administration every eight hours, for a maximum of eight doses.

Pembrolizumab

Intervention Type: DRUG

Intravenous (IV) infusion

Interventions

Tumor Infiltrating Lymphocytes (TIL)

Tumor Infiltrating Lymphocytes (TIL) IV

Intervention Type: BIOLOGICAL

Cyclophosphamid

Cyclophosphamide will be administered as an intravenous (IV) infusion for two days.

Intervention Type: DRUG

Fludarabine

Fludarabine will be administered as an intravenous (IV) infusion for five days.

Intervention Type: DRUG

Interleukin-2

After TIL infusion, IL-2 will be started as a bolus administration every eight hours, for a maximum of eight doses.

Intervention Type: DRUG

Pembrolizumab

Intravenous (IV) infusion

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Age: 16 years to 90 years
• Histologically diagnosed as primary/relapsed/metastasized Cancer
• Expected life span more than 3 months
• Karnofsky≥60% or ECOG score 0-2
• Test subjects have failed standard treatment regimens, or there are no standard treatment regimens available.
• Test subjects must have tumor regions eligible for biopsy or resection, or malignant body fluid where TILs can be isolated
• At least 1 evaluable tumor lesion
• Hematology and Chemistry（within 7 days prior to enrollment）:
• Absolute count of white blood cells≥2.5×10^9/L
• Absolute count of neutropils≥1.5×10^9/L
• Absolute count of lymphocytes ≥0.7×109/L
• Platelet count≥100×10^9
• hemoglobin≥90 g/L
• Activated partial thromboplastin time (APTT) ≤1.5xULN (Unless received anticoagulant therapy within the previous 3 days)
• International normalized ratio (INR) ≤1.5xULN (Unless received anticoagulant therapy within the previous 3 days)
• Serum creatinine ≤1.5mg/dL(or ≤132.6μmol/L), or clearance rate≥50mL/min
• Serum ALT/AST ≤3×ULN(subjects with liver metastasis ≤3×ULN)
• Totol bilirubin≤1.5×ULN
• No absolute or relative contraindications to operation or biopsy
• Test subjects with child-bearing potential must be willing to practice approved highly effective methods of contraception at the time of informed consent and continue within 1 year after the completion of lymphodepletion
• Any malignant tumor-targeting therapies, including radiotherapy, chemotherapy, and biologics must cease 28 days before obtaining TILs
• Be able to understand and sign the informed consent document;
• Be able to stick to the follow-up visit plan and other requirements in the agreement.

Exclusion Criteria

• Need glucocorticoid treatment, and daily dose of Prednisone greater than 15mg (or equivalent doses of hormones) or outoimmune diseases requiring immunomodulatory treatment
• Forced expiratory volume in one second (FEV1) less than 2L, diffusing capacity of the lung for carbon monoxide (DLCO) (calibrated) less than 40%
• Significant cardiovascular anomalies according to any of the following definitions:
• New York Heart Association (NYHA) Grade III or IV congestive heart failure, clinically significant
• Low blood pressure, uncontrollable symptomatic coronary artery diseases, or ejection fraction less than 35%; Severe cardiac rhythm and conduction anomaly, such as ventricular arrhythmia requiring clinical intervention, second-third degree atrioventricular conductive block, etc.
• Human immunodeficiency virus (HIV) infection or anti-HIV antibody positive, active HBV or HCV infection (HBsAg positive and/or anti-HCV positive), syphilis infection or Treponema pallidum antibody positive.
• Severe physical or mental diseases;
• Have a systemic active infection requiring treatment, or have positive blood cultures(or imaging evidence of infection).
• Having been treated within a month or being treated now with other medicines, or other biologic therapy, chemo-or radiotherapy.
• History of allergy to chemical compounds consisting of chemical and biological substances resembling cell therapy.
• Having received immunotherapy and developed an irAE level greater than Level 3.
• Previous anti-tumor treatment AE did not return to CTCAE5.0 version grade 1 or below (toxicity considered by the investigator as non-safety concerns like alopecia excluded).
• Females in pregnancy or lactation. History of organ transplantation, allogeneic stem cell transplantation, and renal replacement therapy.
• Researchers consider the test subject as having a history of other severe systemic diseases, or other reasons inappropriate for the clinical study.

• Minimum Eligible Age: 16 Years
• Maximum Eligible Age: 90 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Essen Biotech

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

District One Hospital

Beijing, Beijing Municipality, China

Site Status: RECRUITING

Countries

China

Central Contacts

Rhoda M Smith, Phd

Role: CONTACT

clinical-trials@essen-biotech.com

+12077706670

Facility Contacts

SAMI XI, dr

Role: primary

SFM@districtonehospital.com

+14012275001

Other Identifiers

ESBI202471

Identifier Type: -

Identifier Source: org_study_id