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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
Temozolomide is an FDA-approved drug that is given to patients
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
the Second Affiliated Hospital of Zhejiang University School of Medicine
Hangzhou, Zhejiang, China
RECRUITINGHuzhou Central Hospital
Huzhou, Zhejiang, China
NOT_YET_RECRUITINGNingbo Yinzhou People's Hospital
Ningbo, Zhejiang, China
NOT_YET_RECRUITINGOverall survival (OS)
Kaplan Meier methods will be used to estimate median OS
Time frame: 2 years, up to 15 years if necessary
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
Time frame: 12 weeks
Maximum tolerated dose (MTD)
The highest dose of B7-H3 CAR-T that does not cause targeted dose-limiting toxicity
Time frame: 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
Time frame: 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)
Time frame: 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)
Time frame: 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.
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NONE
Enrollment
40
Time frame: 2 years, up to 15 years if necessary