Safety and Efficacy Study of Anti-B7-H3 CAR-T Cell Therapy for Recurrent Glioblastoma

Study Overview
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Brief Summary
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This is an open, single-arm, dose-escalation and multiple-dose study to evaluate the safety, tolerability and preliminary effectiveness of B7-H3-targeting Chimeric Antigen Receptor-T (CAR-T) cell therapy on patients with recurrent glioblastomas. The study also plan to explore the Maximum Tolerated Dose (MTD) and determine the Recommended Phase II Dose (RP2D) of the CAR-T cell therapy.

Official Title
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An Open, Single-arm, Phase 1 Study to Evaluate the Safety/Preliminary Effectiveness and Determine the Maximal Tolerated Dose of B7-H3-targeting CAR-T Cell Therapy in Treating Recurrent Glioblastomas

Conditions
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Glioblastoma

Intervention / Treatment
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* Biological: B7-H3-targeting CAR-T cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, aged 18-75 years (including 18 and 75 years old)； Patients with relapsed glioblastoma, as confirmed by positron emission tomography (PET) or histologic pathology； A >= 30% staining extent of B7-H3 in his/her primary/recurrent tumor tissue by the immunochemical method; Karnofsky scale score>=50 Availability in collecting peripheral blood mononuclear cells (PBMCs) ； Adequate laboratory values and adequate organ function; Patients with childbearing/fathering potential must agree to use highly effective contraception； Exclusion Criteria: Pregnant or breastfeeding females； Contraindication to bevacizumab； Within 5 days before the CAR-T cell infusion, subjects receiving systemic administration of steroids with dosage more than 10mg/d prednisone or the equivalent doses of other steroids ( not including inhaled corticosteroid)； Comorbid with Other uncontrolled malignancy； Active immunodeficiency virus (HIV) or hepatitis B virus or hepatitis C virus or tuberculosis infection; Subjects receiving the placement of a carmustine slow-release wafer within 6 months before the enrollment; Autoimmune diseases; Receiving long-term immunosuppressive treatment after organ transplantation; Severe or uncontrolled psychiatric diseases or condition that could increase adverse events or interfere the evaluation of outcomes; Not recovered from the toxicities or side effects by previous treatment; Subjects who have participated the other interventional trial within one month before the enrollment, or have received other CAR-T cell therapies or gene-modified cell therapy before enrollment. Subjects with medical conditions that affect signing the written informed consent or complying with the research procedures, the medical conditions including, but not limited to cardio-cerebral vascular diseases, renal dysfunction/failure, pulmonary embolism, coagulation disorders, active systemic infection, uncontrolled infection et. al; or patients who are unwilling or unable to comply with the research procedures; these Subjects with other conditions that would interfere trial participation at the investigator's discretion.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional Model Description: a 3+3 design is used to determine Maximum Tolerated Dose (MTD) and the recommended phase 2 dose (RP2D)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CAR-T cell therapy<br>Dose-escalation phase: A 3+3 dose-escalation design is used to determine MTD & R2PD. Anti-B7-H3 autologous CAR-T cells were given biweekly to patients at the following doses for each cycle, and 4 cycles as one course. Dose1: 3 patients at a dose of 20 million cells for each cycle. Dose 2: 3 patients at a dose of 60 million cells for each cycle. Dose 3: 3 patients at a dose of 150 million cells for each cycle. Dose 4: 3 patients at a dose of 450 million cells for each cycle. Dose 5: 3 patients at a dose of 900 million cells for each cycle. R2PD confirmation phase: Determine the R2PD based on the results from the previous dose-escalation study; Treat another 12 patients with anti-B7-H3 autologous CAR-T cells biweekly at the R2PD to further confirm the safety of R2PD. At each dose phase, if the patients show tolerate and response to the treatment, these patients would receive several courses of treatment at PI's discretion. | Biological: B7-H3-targeting CAR-T cells<br>* Patients will be treated with anti-B7-H3 autologous CAR-T cells that are delivered into the intracranial tumor resection cavity or ventricular system using an Ommaya device.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Dose Limiting Toxicity (DLT) | To evaluate the DLT incidence occurred within three months after B7-H3 CAR-T cells infusion | three months post CAR-T cells infusion | 
| Safety：Incidence and severity of adverse events | To evaluate the possible adverse events occurred within three months after B7-H3 CAR-T cell infusion, including the incidence and severity of symptoms such as cytokine release syndrome and neurotoxicity | three months post CAR-T cells infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy：Overall survival rate at 12 months | The proportion of subjects who have survived for more than 12 months since the diagnosis of recurrent glioblastoma | 12 months post CAR-T cells infusion | 
| Efficacy：objective remission rate | The proportion of subjects reaching complete remission / partial remission in optimal remission | 1, 2, 3, 4, 5, 6 months post CAR-T cells infusion | 
| pharmacokinetics：Cmax | observed maximum plasma concentration (Cmax) | Samples collected pre-injection, and 1, 2, 3, 5, 7, 9, 11,13 days post the first injection; Samples collected pre-injection, and 2, 7, 13 days post re-injections | 
| pharmacokinetics：Tmax | time to reach maximum plasma concentration (tmax) | Samples collected pre-injection, and 1, 2, 3, 5, 7, 9, 11,13 days post the first injection; Samples collected pre-injection, and 2, 7, 13 days post re-injections | 
| pharmacokinetics：AUC | area under the plasma concentration-time curve from time zero to 28 days after dosing (AUC(0-28)) | Sample taken pre-injection, and 1, 2, 3, 5, 7, 9, 11,13 days post the first injection; Sample taken pre-injection, and 2,7,13 days post re-injections |