B7-H3 CAR-T for Recurrent or Refractory Glioblastoma

Study Overview
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Brief Summary
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This is a randomized, parallel-arm, phase I/II study to evaluate the safety and efficacy of B7-H3 CAR-T in between Temozolomide cycles comparing to Temozolomide alone in treating patients with glioblastoma that has come back or does not respond to the standard treatment. The antigen B7-H3 is highly expressed in glioblastoma of a subset of patients. B7-H3 CAR-T, made from isolated patient peripheral blood mononuclear cells, can specifically attack patient glioblastoma cells that expressing B7-H3.

Detailed Description
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Background B7-H3 is expressed in 70% of patients with glioblastoma B7-H3 is not expressed in normal tissues especially not in central nervous system. Therefore, it is an attractive GBM target for CAR-T therapy The investigators constructed a retroviral vector encoding a chimeric antigen receptor (CAR) targeting B7-H3, which can mediate CAR transfer into patient T cells with high efficiency. Objectives To evaluate the safety and tolerability intratumoral/intracerebroventricular injection of B7-H3 CAR-T when used in between Temozolomide cycles To compare the overall survival (OS) and progression-free survival (PFS) of R/R GBM patients treated with B7-H3 CAR-T in between Temozolomide cycles vs Temozolomide alone To access the pharmacokinetics and pharmacodynamics of B7-H3 CAR-T in between Temozolomide cycles Design Experimental group: Patients autologous T cells are activated and transduced with retrovirus containing B7-H3 CAR. CAR-T cells are expanded ex vivo and infused back to patients via intratumoral or intracerebroventricular injection through an Ommaya catheter. 3 injections of CAR-T are planned at two different doses with 1-2 weeks intervals. The CAR-T injections occur in between Temozolomide (TMZ) cycles. Temozolomide treatment during the cycles of CAR-T injections will be stopped and resumed next cycle. Patients may receive additional CAR-T cycles at the discretion of the principal investigator and oncologist. Control group: Patients will receive regular cycles of Temozolomide treatment with 5 days of treatment and 23 days of interval.

Official Title
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B7-H3-Targeted Chimeric Antigen Receptor (CAR) T Cells in Treating Patients With Recurrent or Refractory Glioblastoma

Conditions
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Recurrent Glioblastoma, Refractory Glioblastoma

Intervention / Treatment
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* Drug: Temozolomide
* Biological: B7-H3 CAR-T


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented informed consent of the participant and/or legally authorized representative. Histologically confirmed diagnosis of World Health Organization (WHO) classification grade IV glioblastoma (GBM). Clinical Pathology confirms B7-H3 positive tumor expression by immunohistochemistry (IHC) at the initial tumor presentation or recurrent disease (H-score >= 50). Relapsed/refractory disease confirmed by radiographic evidence after standard therapy. Suitable for the surgery of the placement of the Ommaya catheter. Eastern Cooperative Oncology Group (ECOG) =0 or 1 (need to be confirmed before intratumoral or intracerebroventricular injection) >= 8 weeks after completion of front-line radiation therapy >= 6 weeks after completion of nitrourea chemotherapy >= 14 days after completion of Temozolomide or other chemotherapy 2 weeks of wash-out time after completion of targeted therapy with related adverse events (AE) on baseline (4 weeks for Bevacizumab). Patients with other chronic AEs are in the investigator's judgement Blood cell count： White blood count (WBC) >= 2000/μL；Neutrophil count >= 1500/μL；Platelets >= 100 x 103/μL；Hemoglobin >= 9.0 g/dL Serum Creatinine <= 1.5×ULN or Creatinine Clearance Rate (Cockcroft and Gault) > 30 mL/min/1.73 m2 Alanine Transaminase (ALT) <= 5×ULN and total bilirubin < 2.0mg/dL Lung function: Oxygen (O2) saturation >= 92% on room air and < CTCAE grade 1 dyspnea Heart function: Left ventricular ejection fraction (LVEF) >= 40% by multigated acquisition (MUGA) scan or echocardiogram Normal coagulation function: prothrombin time (PT)，activated partial thromboplastin time (APTT) and international normalized ratio (INR) Good blood vessel condition for leukapheresis Women of childbearing potential (WOCBP): negative urine or serum pregnancy test Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity within one year after B7-H3 CAR-T infusion Exclusion Criteria: Other active malignancy in the past 2 years except non-melanoma skin cancer, completely surgical removed low grade tumor, post-therapeutic limited-stage prostate cancer, biopsy confirmed in situ cervical carcinoma, PAP test confirmed squamous intraepithelial lesions Participant is undergoing or planning to take other anti-tumor therapies Participant is systematic steroid-dependent, or is expecting to be treated with systematic steroid Active immunodeficiency virus (HIV) or hepatitis B or hepatitis C virus infection Active infection from fungi, bacteria and/or viruses Known history of the following cardiac diseases in the past 6 months: New York Heart Association (NYHA) defined grade III or IV heart failure, cardiac angioplasty, myocardial infarction, unstable angina and other clinically significant heart diseases Known history and/or clinically evident central nerve system diseases: seizure, epileptic seizure, aphasia, paralysis, stroke, severe brain damage, dementia, Parkinson's Disease, cerebellar diseases, organic brain syndrome and psychiatric disorders Autoimmune diseases Pregnant or breastfeeding females Therapeutic doses of corticosteroid within 7 days before leukapheresis or 72 hours before B7-H3 CAR-T infusion Cytotoxic chemotherapy without lymphocytotoxicity within 1 week before leukapheresis except that the treatment has been stopped for more than 3 half-lives of the drug Lymphocytotoxic chemotherapy (cyclophosphamide, Ifosfamide and bendamustine) within 2 weeks before leukapheresis Other clinical trials drugs within 4 weeks before leukapheresis except that the drug has no effect or the disease has progressed, and the treatment has been stopped for more than 3 half-lives of the drug Radiotherapy within 6 weeks before leukapheresis Prior trials of CAR-T or other cell therapy Any other condition that would, in the investigator's judgment, contraindicate the subject's participation in the clinical study due to safety concerns with clinical study procedures Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Temozolomide alone<br>Temozolomide will be given to patients orally every 5 days with 23 days interval. The initial dose is 150 mg/m2 on the first day and 200 mg/m2 for the rest if no toxicity is seen. If 200 mg/m2 is toxic, the drug will return to 150 mg/m2 or will be stopped. | Drug: Temozolomide<br>* Temozolomide is an FDA-approved drug that is given to patients<br>* Other names: TMZ;|
| Experimental: Temozolomide + B7-H3 CAR-T<br>Temozolomide will be given to patients orally every 5 days with 23 days interval. The initial dose is 150 mg/m2 on the first day and 200 mg/m2 for the rest if no toxicity is seen. If 200 mg/m2 is toxic, the drug will return to 150 mg/m2 or will be stopped. The B7-H3 CAR-T will be administrated via intratumoral or Intracerebroventricular injection through an Ommaya catheter in between Temozolomide cycles. Temozolomide treatment in the cycles of B7-H3 CAR-T treatment will be stopped. | Drug: Temozolomide<br>* Temozolomide is an FDA-approved drug that is given to patients<br>* Other names: TMZ;Biological: B7-H3 CAR-T<br>* B7-H3-targeting CAR-T cells derived from patient own peripheral blood mononuclear cells will be given to patients via intracerebral injection though an Ommaya catheter<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | Kaplan Meier methods will be used to estimate median OS | 2 years, up to 15 years if necessary | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and type of adverse events | Number of Participants With Treatment-Related Adverse Events and Types of adverse events as Assessed by CTCAE v4.0 | 12 weeks | 
| Maximum tolerated dose (MTD) | The highest dose of B7-H3 CAR-T that does not cause targeted dose-limiting toxicity | 12 weeks | 
| Progression-free survival (PFS) | Kaplan Meier methods will be used to estimate median PFS. Progression is defined by Response Assessment in Neuro-Oncology (RANO) criteria | 2 years, up to 15 years if necessary | 
| Peak Concentration (Cmax) of B7-H3 CAR-T | Peak Concentration (Cmax) of B7-H3 CAR-T in peripheral blood (PB) and cerebral spinal fluid (CSF) | 12 weeks | 
| Area under the concentration versus time curve (AUC) of B7-H3 CAR-T | Area under the concentration versus time curve (AUC) of B7-H3 CAR-T in peripheral blood (PB) and cerebral spinal fluid (CSF) | 12 weeks | 
| Disease response (ORR, CR, PR, DOR) | Objective Response Rate (ORR) will be assessed by comparison with baseline magnetic resonance imaging by RANO. Complete Response (CR) is disappearance of all measurable and non-measurable disease for at least 4 weeks. Partial Response (PR) is >/= 50% decrease in lesions for at least 4 weeks. Duration of Response (DOR) is the time between the initial response to the treatment and subsequent disease progression. | 2 years, up to 15 years if necessary |