Pan-T Booster Co-expressing MSLN CAR T Cell Therapy in Advanced/Metastatic Solid Tumors

Trial Title: Pan-T Booster Co-expressing MSLN CAR T Cell Therapy in Advanced/Metastatic Solid Tumors

NCT ID: NCT05693844

Condition: Advanced or Metastatic Solid Tumors

Conditions: Official terms:
Neoplasms
Paclitaxel
Cyclophosphamide
Fludarabine
Albumin-Bound Paclitaxel

Study type: Interventional

Study phase: Phase 1/Phase 2

Overall status: Recruiting

Study design:

Allocation: N/A

Intervention model: Single Group Assignment

Primary purpose: Treatment

Masking: None (Open Label)

Intervention:

Intervention type: Biological
Intervention name: Pan-T booster co-expressing MSLN CAR T cell
Description: Starting Dose: 1×10^6 cells/kg
Arm group label: Pan-T booster co-expressing MSLN CAR T cell

Intervention type: Drug
Intervention name: Albumin-bound paclitaxel
Description: Administered intravenously at dose of 100-200mg/m2 on day -5
Arm group label: Pan-T booster co-expressing MSLN CAR T cell

Intervention type: Drug
Intervention name: Cyclophosphamide
Description: Administered intravenously at a total dose of 15-30mg/kg on day -3 and day -2
Arm group label: Pan-T booster co-expressing MSLN CAR T cell

Intervention type: Drug
Intervention name: Fludarabine
Description: Administered intravenously at dose of 30mg/m2/d on day -3 and day -2
Arm group label: Pan-T booster co-expressing MSLN CAR T cell

Summary: In preclinical study, investigators have demonstrated that the newly developed pan-T booster (harbouring CD40 agonist and one T cell costimulator agonist) co-expressing MSLN CAR T cell possess more powerful antitumor activity than previously reported MSLN-CAR T cells. In this clinical trial, enrolled patients receive an initial dose of pan-T booster co-expressing MSLN CAR T cells at 1×10^6 cells/kg based on the basic principle of dose escalation design, in order to evaluate the safety, feasibility, pharmacokinetics/pharmacodynamics, and efficacy of pan-T booster co-expressing MSLN CAR T cell in vivo.

Detailed description: In this study, investigators have developed a novel CAR T cell system targeting mesothelin (MSLN) antigen, termed as Pan-T booster (harbouring CD40 agonist and one T cell costimulator agonist) co-expressing MSLN CAR T cell. Preclinical study demonstrated that this novel pan-T booster co-expressing MSLN CAR T cell possess more powerful antitumor activity than previously reported MSLN-CAR T cells. In this clinical trial, enrolled patients receive an initial dose of pan-T booster co-expressing MSLN CAR T cells at 1×10^6 cells/kg based on the basic principle of dose escalation design, in order to evaluate the safety, feasibility, pharmacokinetics/pharmacodynamics, and efficacy of pan-T booster co-expressing MSLN CAR T cell in vivo. The level of CAR-T cell expansion and the duration of expansion are important determining factors for subsequent dose escalation infusions (3×10^6 cells/kg and 6×10^6 cells/kg). Repeated infusion, immune checkpoint inhibitor (such as anti-PD1/PD-L1) or local therapy (radiotherapy) are allowed when patients achieve clinical benefit and the level of CAR-T cell expansion declines to low level. In the 3 patients receiving the first dose treatment, we observed high levels of expansion of both total T cells and CAR T cells in the PB after CAR T cell infusion (CAR T > 300 per microliter, total T cells reaching 10 times the number of CAR T cells), one patient experienced a grade 2 pulmonary toxicity and transient liver dysfunction during the CAR T cell expansion period (infusion 14 days later), transient marked enlargement of the spleen, and required to be treated with glucocorticoids and ruxolitinib to control T cell toxicity. Efficacy monitoring showed that some target lesion clearance or reduction could be achieved within 2-4 weeks after CAR T infusion. Based on these observations, it was concluded that low-dose CAR T infusion (CAR+T cells 1×10^6 cells/kg) could achieve the sufficient level of CAR T cell expansion, and the initially planned CAR T dose escalation was dispensable. Subsequent patients after May 10th, 2024, will all be treated using 1×10^6 cells/kg dose.

Criteria for eligibility:
Criteria:
Inclusion Criteria: - 1. Age from 18 to 75 years with estimated life expectancy >3 months. - 2. Histopathological confirmed advanced or metastatic solid tumors failed to at least first-line treatment or initially diagnosed advanced/metastatic solid tumors that have no NCCN guideline recommended standard first-line therapy. Mesothelin antigen expression percentage >＝10%. - 3. Have at least one measurable target lesion. - 4. 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 rebiopsy in the process of this study. - 5. 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. - 6. Have an Eastern Cooperative Oncology Group performance status (ECOG) of 0 or 2 at the time of enrollment. - 7. Have adequate organ function, which should be confirmed within 2 weeks prior to the first dose of study drugs. - 8. Previous treatment with anti-PD-1/PD-L1 antibodies are allowed. - 9. Ability to understand and sign a written informed consent document. - 10. 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. Exclusion Criteria: - 1. Active, known or suspected autoimmune diseases. - 2. 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. - 3. Subjects are being treated with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of enrollment. - 4. History of severe hypersensitive reactions to other monoclonal antibodies. - 5. History of allergy or intolerance to study drug components. - 6. Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results. - 7. History or concurrent condition of interstitial lung disease of any grade or severely impaired pulmonary function. - 8. 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. - 9. History of human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS). - 10. 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. - 11. 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)]. - 12. Vaccination within 30 days of study enrollment. - 13. Active bleeding or known hemorrhagic tendency. - 14. Subjects with unhealed surgical wounds for more than 30 days. - 15. Being participating any other trials or withdraw within 4 weeks.

Gender: All

Minimum age: 18 Years

Maximum age: 75 Years

Healthy volunteers: No

Locations:

Facility:
Name: Kaichao Feng

Address:
City: Beijing
Zip: 100853
Country: China

Status: Recruiting

Contact:
Last name: Kaichao Feng, MD

Phone: +861066937231
Email: timothyfkc@126.com

Investigator:
Last name: Weidong Han, PhD
Email: Principal Investigator

Start date: January 20, 2023

Completion date: December 31, 2026

Lead sponsor:
Agency: Chinese PLA General Hospital
Agency class: Other

Collaborator:
Agency: UTC Therapeutics Inc.
Agency class: Industry

Source: Chinese PLA General Hospital

Record processing date: ClinicalTrials.gov processed this data on November 12, 2024

Source: ClinicalTrials.gov page: https://clinicaltrials.gov/ct2/show/NCT05693844