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

Official title

Phase I/II Study of Pan-T Booster Co-expressing MSLN CAR T Cell Therapy in Advanced/Metastatic Solid Tumors

Overview

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.

Interventions

• Biological Pan-T booster co-expressing MSLN CAR T cell
  Starting Dose: 1×10\^6 cells/kg
• Drug Albumin-bound paclitaxel
  Administered intravenously at dose of 100-200mg/m2 on day -5
• Drug Cyclophosphamide
  Administered intravenously at a total dose of 15-30mg/kg on day -3 and day -2
• Drug Fludarabine
  Administered intravenously at dose of 30mg/m2/d on day -3 and day -2

Primary outcome measures

• Incidence of treatment related adverse events [Time frame: Up to 12 months since the initiation of MSLN targeted CAR T cell therapy]
• Incidence of dose limiting toxicities (DLTs) [Time frame: Up to 28 days since the initiation of MSLN targeted CAR T cell therapy]

Secondary outcome measures (6)

• Number and copy number of MSLN targeted CAR T cell [Time frame: Up to 3 years]
• Objective response rate (ORR) [Time frame: Up to 3 years]
• Progression Free Survival (PFS) [Time frame: Up to 3 years]
• Time to response (TTR) [Time frame: Up to 3 years]
• Duration of response (DOR) [Time frame: Up to 3 years]
• Overall Survival (OS) [Time frame: Up to 3 years]

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Kaichao Feng — Beijing

Identifiers

NCT: NCT05693844 · CHN-PLAGH-BT-077

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗