Pilot Study of B7-H3 CAR-T in Treating Patients With Recurrent and Refractory Glioblastoma
- Conditions
- Refractory GlioblastomaRecurrent Glioblastoma
- Interventions
- Registration Number
- NCT04385173
- Lead Sponsor
- Second Affiliated Hospital, School of Medicine, Zhejiang University
- Brief Summary
This is a pilot phase I study to evaluate the safety and efficacy on B7-H3 CAR-T in between Temozolomide cycles 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
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 to the historical Temozolomide data
* To access the pharmacokinetics and pharmacodynamics of B7-H3 CAR-T in between Temozolomide cycles
Design
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 in the cycle 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 12
- 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
- Other active malignancy in the past 2 years except non-melanoma skin cancer, completely surgical removed low grade tumor, posttherapeutic 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)
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description B7-H3 CAR-T B7-H3 CAR-T Patients will received regular cycles of Temozolomide treatment with 5 days of treatment and 23 days of interval. 3 infusions of B7-H3 CAR-T with 1-2 weeks of interval will be used in between cycles of Temozolomide treatment. Temozolomide treatment during B7-H3 CAR-T infusions will be stopped and resumed after CAR-T infusion. B7-H3 CAR-T Temozolomide Patients will received regular cycles of Temozolomide treatment with 5 days of treatment and 23 days of interval. 3 infusions of B7-H3 CAR-T with 1-2 weeks of interval will be used in between cycles of Temozolomide treatment. Temozolomide treatment during B7-H3 CAR-T infusions will be stopped and resumed after CAR-T infusion.
- Primary Outcome Measures
Name Time Method Overall survival (OS) 2 years, up to 15 years if necessary Kaplan Meier methods will be used to estimate median OS
Incidence and type of adverse events 12 weeks Number of Participants With Treatment-Related Adverse Events and Types of adverse events as Assessed by CTCAE v4.0
Maximum tolerated dose (MTD) 12 weeks The highest dose of B7-H3 CAR-T that does not cause targeted dose limiting toxicity
Progression-free survival (PFS) 2 years, up to 15 years if necessary Kaplan Meier methods will be used to estimate median PFS. Progression is defined by Response Assessment in Neuro-Oncology (RANO) criteria
- Secondary Outcome Measures
Name Time Method Disease response (ORR, CR, PR, DOR) 2 years, up to 15 years if necessary 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.
The pharmacokinetics (PK) of B7-H3 CAR-T 12 weeks Area under the concentration versus time curve (AUC) of B7-H3 CAR-T in peripheral blood (PB) and cerebral spinal fluid (CSF)
Trial Locations
- Locations (1)
the Second Affiliated Hospital of Zhejiang University School of Medicine
🇨🇳Hangzhou, Zhejiang, China