B7-H3 CAR-T for Recurrent or Refractory Glioblastoma

• ClinicalTrials.gov Identifier: NCT04077866
• Recruitment Status: Not yet recruiting
• First Posted: September 4, 2019
• Last Update Posted: September 4, 2019
• Sponsor: Second Affiliated Hospital, School of Medicine, Zhejiang University
• 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

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Recurrent Glioblastoma; Refractory Glioblastoma	Drug: Temozolomide; Biological: B7-H3 CAR-T; Other: Placebo	Phase 1; Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 100 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Participant)
• Primary Purpose: Treatment
• Official Title: B7-H3-Targeted Chimeric Antigen Receptor (CAR) T Cells in Treating Patients With Recurrent or Refractory Glioblastoma
• Estimated Study Start Date: March 1, 2020
• Estimated Primary Completion Date: May 1, 2024
• Estimated Study Completion Date: May 1, 2024

Arms and Interventions

Arm	Intervention/treatment
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	Drug: Temozolomide; Temozolomide is an FDA-approved drug that is given to patients; Other Name: TMZ; 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
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	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

Outcome Measures

Primary Outcome Measures :

1. Overall survival (OS) [ Time Frame: up to 15 years ]
   Kaplan Meier methods will be used to estimate median OS
2. 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

Secondary Outcome Measures :

1. 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
2. Maximum tolerated dose (MTD) [ Time Frame: 12 weeks ]
   The highest dose of B7-H3 CAR-T that does not cause targeted dose-limiting toxicity
3. 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)
4. 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)
5. 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.

Other Outcome Measures:

1. 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
2. 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

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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)

Contacts and Locations

Contacts

Contact: Jianmin Zhang, MD; +86-13805722695; 2307010@zju.edu.cn

Locations

China, Zhejiang

the Second Affiliated Hospital of Zhejiang University School of Medicine

Hangzhou, Zhejiang, China, 310009

Huzhou Central Hospital; Not yet recruiting

Huzhou, Zhejiang, China, 313003

Contact: Zhongzhou Su, MD

Ningbo Yinzhou People's Hospital; Not yet recruiting

Ningbo, Zhejiang, China, 315040

Contact: Feng Gao, MD

Sponsors and Collaborators

Second Affiliated Hospital, School of Medicine, Zhejiang University

Ningbo Yinzhou People's Hospital

Huzhou Central Hospital

BoYuan RunSheng Pharma (Hangzhou) Co., Ltd.

More Information

• Responsible Party: Second Affiliated Hospital, School of Medicine, Zhejiang University
• ClinicalTrials.gov Identifier: NCT04077866 History of Changes
• Other Study ID Numbers: SAHZJUBP102
• First Posted: September 4, 2019
• Last Update Posted: September 4, 2019
• Last Verified: September 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Glioblastoma; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Temozolomide; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents