Recurrent Glioblastoma, Refractory Glioblastoma
Conditions
Keywords
Chimeric Antigen Receptor (CAR)-T, Glioblastoma
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.
Interventions
DRUGB7-H3 CAR-T
The B7-H3 CAR-T will be administrated via intratumoral or Intracerebroventricular injection through an Ommaya catheter in between Temozolomide cycles. Temozolomide will be stopped during the infusion of B7-H3 CAR-T
DRUGTemozolomide
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.
Sponsors
BoYuan RunSheng Pharma (Hangzhou) Co., Ltd.
Second Affiliated Hospital, School of Medicine, Zhejiang University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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, 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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| Maximum tolerated dose (MTD) | 12 weeks | The highest dose of B7-H3 CAR-T that does not cause targeted dose limiting toxicity |
| 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 |
| Overall survival (OS) | 2 years, up to 15 years if necessary | Kaplan Meier methods will be used to estimate median OS |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The pharmacokinetics (PK) of B7-H3 CAR-T | 12 weeks | Peak Concentration (Cmax) of B7-H3 CAR-T in peripheral blood (PB) and cerebral spinal fluid (CSF) |
| 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Cytokine levels in PB and CSF | 12 weeks | The concentration of cytokines (IL-1, IL-2, IL-6, IL-10, TNF-α, IFN-γ) in PB and CSF |
| T cell phenotype | 12 weeks | The chimeric antigen receptor positive (CAR+) T cell and memory/effector T cell percentages and cell counts detected in peripheral blood (PB), and cerebral spinal fluid (CSF). Statistical and graphical methods will be used to describe persistence and expansion |
Countries
China
Contacts
Primary ContactJianmin Zhang, MD
Outcome results
None listed