B7-H3 CAR-T for Recurrent or Refractory Glioblastoma

  • STATUS
    Recruiting
  • End date
    Jul 1, 2024
  • participants needed
    40
  • sponsor
    Second Affiliated Hospital, School of Medicine, Zhejiang University
Updated on 25 January 2021
serum pregnancy test
international normalized ratio
neutrophil count
immunohistochemistry
bevacizumab
aptt
recurrent disease
glioblastoma multiforme
temozolomide

Summary

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.

Description

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.

Details
Condition Recurrent Glioblastoma, Refractory Glioblastoma
Treatment Temozolomide, B7-H3 CAR-T
Clinical Study IdentifierNCT04077866
SponsorSecond Affiliated Hospital, School of Medicine, Zhejiang University
Last Modified on25 January 2021

Eligibility

Yes No Not Sure

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
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/LNeutrophil count >= 1500/LPlatelets >= 100 x 103/LHemoglobin >= 9.0 g/dL
Serum Creatinine <= 1.5ULN or Creatinine Clearance Rate (Cockcroft and Gault) > 30 mL/min/1.73 m2
Alanine Transaminase (ALT) <= 5ULN 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)
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