TGFβR-KO CAR-EGFR T Cells in Previously Treated Advanced EGFR-positive Solid Tumors

NCT04976218 | Unknown Phase 1 DMC

• 1 other identifier: CHN-PLAGH-BT-067
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

Chimeric antigen receptor modified T (CART) cell therapy has been identified as a breakthrough therapy in hematologic malignancies. However, CART cell therapy yielded no satisfactory efficacy data in the study of solid tumors. One of major challenges is the complicated immunosuppressive tumor microenvironment (TME) in solid tumors. It has been reported that transforming growth factor-β (TGF-β) is one of the major regulatory factors in the TME. In this study, we construct CAR-EGFR-TGFβR-KO T cell by knocking out TGF-β receptor Ⅱ through CRISPR/Cas9 in order to study the anti-tumor activities and safety profiles of CAR-EGFR-TGFβR-KO T cell in previously treated advanced EGFR positive solid tumors.

Conditions

Solid Tumor, Adult; EGFR Overexpression

Outcome Measures

Primary Outcomes (1)

• Number of subjects occuring treatment related adverse events

  Determining the safety profile following the initiation of treatment and grading these toxicities by CTCAE v5.0

  Up to 24 weeks following the infusion of TGFβR-KO CAR-EGFR T cells.

Secondary Outcomes (2)

• The percentage of enrolled patients that respond to TGFβR-KO CAR-EGFR T cell therapy.

  Up to 24 weeks following the infusion of TGFβR-KO CAR-EGFR T cells.

• The percentage of enrolled patients alive and without progression at 6 months

  6 months

Study Arms (1)

Experimental arm

EXPERIMENTAL

Enrolled patients in this arm will be administered TGFβR-KO CAR-EGFR T Cells in 3+3 based escalation manner.

Biological: TGFβR-KO CAR-EGFR T Cells

Interventions

TGFβR-KO CAR-EGFR T Cells BIOLOGICAL

Enrolled patients will be administered TGFβR-KO CAR-EGFR T Cells in 3+3 based escalation manner. The infused CAR+ T cell dose in phase IA will be started initially at 1-2×10\^5/kg, dose 2 will be 1×10\^6/kg，and dose 3 will be 1×10\^7/kg, if DLT occurs in dose level 3, the following dose will return to 5×10\^6/kg. In expansion period, the dose of infused CAR+ T cells will be determined by the recommended cell dose from phase IA.

Experimental arm

Eligibility Criteria

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

You may qualify if:

• Age from 18 to 75 years with estimated life expectancy \>3 months.
• Histopathological confirmed advanced solid tumors failed to at least first-line standard treatment. EGFR antigen expression level ≥ 50%.
• Have at least one measurable target lesion.
• Fresh solid tumor samples or formalin-fixed paraffin embedded tumor archival samples within 6 months are necessary; Fresh tumor samples are preferred. Subjects are willing to accept tumor re-biopsy in the process of this study.
• Previous treatment must be completed for more than 4 weeks prior to the enrollment of this study, and subjects have recovered to \<= grade 1 toxicity.
• Have an Eastern Cooperative Oncology Group performance status (ECOG) of 0 or 2 at the time of enrollment.
• Have adequate organ function, which should be confirmed within 2 weeks prior to the first dose of study drugs.
• Previous treatment with anti-PD-1/PD-L1 antibodies are allowed.
• Ability to understand and sign a written informed consent document.
• Women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, and up to 90 days after the last dose of the drug.

You may not qualify if:

• Active, known or suspected autoimmune diseases.
• Known brain metastases or active central nervous system (CNS). Subjects with CNS metastases who were treated with radiotherapy for at least 3 months prior to enrollment, have no central nervous symptoms and are off corticosteroids, are eligible for enrollment, but require a brain MRI screening.
• Subjects are being treated with either corticosteroids (\>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of enrollment.
• History of severe hypersensitive reactions to other monoclonal antibodies.
• History of allergy or intolerance to study drug components.
• Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results.
• History or concurrent condition of interstitial lung disease of any grade or severely impaired pulmonary function.
• Uncontrolled intercurrent illness, including ongoing or active systemic infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia (excluding insignificant sinus bradycardia and sinus tachycardia) or psychiatric illness/social situations and any other illness that would limit compliance with study requirements and jeopardize the safety of the patient.
• History of human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS).
• Pregnant or breast-feeding. Women of childbearing potential must have a pregnancy test performed within 7 days before the enrollment, and a negative result must be documented.
• Previous or concurrent cancer within 3 years prior to treatment start EXCEPT for curatively treated cervical cancer in situ, non-melanoma skin cancer, superficial bladder tumors \[Ta (non-invasive tumor), Tis (carcinoma in situ) and T1 (tumor invades lamina propria)\].
• Vaccination within 30 days of study enrollment.
• Active bleeding or known hemorrhagic tendency.
• Subjects with unhealed surgical wounds for more than 30 days.
• Being participating any other trials or withdraw within 4 weeks.

Sponsors & Collaborators

• Chinese PLA General Hospital: lead

Study Sites (1)

Chinese PLA General Hospital

Beijing, Beijing Municipality, 100853, China

RECRUITING

Study Officials

• Weidong Han, PhD

  Biotherapeutic Department, Chinese PLA General Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Weidong Han, PhD

CONTACT

+86-10-66937463; hanwdrsw69@yahoo.com

Kaichao Feng, MD

CONTACT

+86-10-66937231; timothyfkc@126.com

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: Director of Bio-therapeutic Department

Model Details: TGFβR-KO CAR-EGFR T Cells will be administered to eligible patients in a 3+3 dose escalation manner.

Study Record Dates

• First Submitted: July 19, 2021
• First Posted: July 26, 2021
• Study Start: March 15, 2022
• Primary Completion: December 20, 2023
• Study Completion: December 31, 2024
• Last Updated: November 16, 2022

Record last verified: 2022-11

Locations

CN (1)