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B7-H3 CAR-T for Recurrent or Refractory Glioblastoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04077866
Recruitment Status : Not yet recruiting
First Posted : September 4, 2019
Last Update Posted : September 4, 2019
Sponsor:
Collaborators:
Ningbo Yinzhou People's Hospital
Huzhou Central Hospital
BoYuan RunSheng Pharma (Hangzhou) Co., Ltd.
Information provided by (Responsible Party):
Second Affiliated Hospital, School of Medicine, Zhejiang University

Tracking Information
First Submitted Date  ICMJE August 26, 2019
First Posted Date  ICMJE September 4, 2019
Last Update Posted Date September 4, 2019
Estimated Study Start Date  ICMJE March 1, 2020
Estimated Primary Completion Date May 1, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 3, 2019)
  • Overall survival (OS) [ Time Frame: up to 15 years ]
    Kaplan Meier methods will be used to estimate median OS
  • Progression-free survival (PFS) [ Time Frame: up to 15 years ]
    Kaplan Meier methods will be used to estimate median PFS. Progression is defined by Response Assessment in Neuro-Oncology (RANO) criteria
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: September 3, 2019)
  • Incidence and type of adverse events [ Time Frame: 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) [ Time Frame: 12 weeks ]
    The highest dose of B7-H3 CAR-T that does not cause targeted dose-limiting toxicity
  • Peak Concentration (Cmax) of B7-H3 CAR-T [ Time Frame: 12 weeks ]
    Peak Concentration (Cmax) of B7-H3 CAR-T in peripheral blood (PB) and cerebral spinal fluid (CSF)
  • Area under the concentration versus time curve (AUC) of B7-H3 CAR-T [ Time Frame: 12 weeks ]
    Area under the concentration versus time curve (AUC) of B7-H3 CAR-T in peripheral blood (PB) and cerebral spinal fluid (CSF)
  • Disease response (ORR, CR, PR, DOR) [ Time Frame: up to 15 years ]
    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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: September 3, 2019)
  • Cytokine levels in PB and CSF [ Time Frame: 12 weeks ]
    The concentration of cytokines (IL-1, IL-2, IL-6, IL-10, TNF-α, IFN-γ) in PB and CSF
  • T cell levels and phenotype [ Time Frame: 12 weeks ]
    The chimeric antigen receptor (CAR) T and endogenous T cell levels and memory/effector phenotype detected in peripheral blood (PB), and cerebral spinal fluid (CSF) (absolute number per ul). Statistical and graphical methods will be used to describe persistence and expansion
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE B7-H3 CAR-T for Recurrent or Refractory Glioblastoma
Official Title  ICMJE B7-H3-Targeted Chimeric Antigen Receptor (CAR) T Cells in Treating Patients With Recurrent or Refractory Glioblastoma
Brief Summary This is a randomized, parallel-arm, phase I study to evaluate the safety and efficacy on B7-H3 CAR-T in combination with Temozolomide 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 combination with Temozolomide
  • To determine the overall response rate (ORR) of B7-H3 CAR-T in combination with Temozolomide
  • To access the pharmacokinetics and pharmacodynamics of B7-H3 CAR-T in combination with pharmacodynamics

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 cell diluent is used as placebo and the injections occur in between post radiotherapy Temozolomide (TMZ) cycles. Patients may receive additional CAR-T cycles at the discretion of the principal investigator and oncologist.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
Condition  ICMJE
  • Recurrent Glioblastoma
  • Refractory Glioblastoma
Intervention  ICMJE
  • Drug: Temozolomide
    Temozolomide is an FDA-approved drug that is given to patients
    Other Name: TMZ
  • Biological: B7-H3 CAR-T
    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
  • Other: Placebo
    Placebo is 2% human serum albumin in pharmaceutical preservative-free normal saline and will be given to patients via intracerebral injection though an Ommaya catheter
Study Arms  ICMJE
  • Active Comparator: Temozolomide + Placebo

    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 placebo will be administrated via intratumoral or Intracerebroventricular injection through an Ommaya catheter in between Temozolomide cycles

    Interventions:
    • Drug: Temozolomide
    • Other: Placebo
  • Experimental: Temozolomide + B7-H3 CAR-T

    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

    Interventions:
    • Drug: Temozolomide
    • Biological: B7-H3 CAR-T
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: September 3, 2019)
100
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 1, 2024
Estimated Primary Completion Date May 1, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Jianmin Zhang, MD +86-13805722695 2307010@zju.edu.cn
Listed Location Countries  ICMJE China
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04077866
Other Study ID Numbers  ICMJE SAHZJUBP102
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Second Affiliated Hospital, School of Medicine, Zhejiang University
Study Sponsor  ICMJE Second Affiliated Hospital, School of Medicine, Zhejiang University
Collaborators  ICMJE
  • Ningbo Yinzhou People's Hospital
  • Huzhou Central Hospital
  • BoYuan RunSheng Pharma (Hangzhou) Co., Ltd.
Investigators  ICMJE Not Provided
PRS Account Second Affiliated Hospital, School of Medicine, Zhejiang University
Verification Date September 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP