A Phase 1b Study to Evaluate CHM-1101, a CAR T-Cell Therapy With a Chlorotoxin Tumor-Targeting Domain for Patients With Matrix Metallopeptidase 2 Positive (MMP2+) Recurrent or Progressive Glioblastoma Multiforme
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- 入组人数
- 1
- 试验地点
- 2
- 主要终点
- Cytokine Release Syndrome (CRS)
研究概览
简要总结
This is a phase 1b study to evaluate the safety of chimeric antigen receptor (CAR) T cells with a chlorotoxin tumor-targeting domain (ie, CHM-1101, the study treatment) to determine the best dose of CHM-1101, and to assess the effectiveness of CHM-1101 in treating MMP2+ glioblastoma that has come back (recurrent) or that is growing, spreading, or getting worse (progressive).
详细描述
This is a phase 1b, multicenter, feasibility/safety study of the dual delivery (administered through both intracavitary/intratumoral [ICT] and intraventricular [ICV] catheters) of CHM-1101, an autologous chlorotoxin-chimeric antigen receptor (CLTX-CAR) cell product, in participants with recurrent or progressive GBM. The investigational product is identified as CHM-1101 (CLTX(EQ)28ζ/CD19t+ CAR T cells).
PRIMARY OBJECTIVE
• To determine the recommended phase 2 dose (RP2D) for dual ICT and ICV delivery of CHM-1101 in participants with MMP2+ recurrent or progressive GBM.
SECONDARY OBJECTIVES
- To assess the feasibility and safety of dual delivery of CHM-1101.
- To describe the persistence, expansion, immunogenicity, and phenotype of CHM-1101 and endogenous cells tumor cyst fluid (TCF), peripheral blood (PB), and cerebrospinal fluid (CSF).
- In participants who receive at least 2 of the 3 planned doses of CHM-1101 in Cycle 1:
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Documented informed consent of the subject and/or legally authorized representative.
- •Agreement to allow the use of archival tissue from diagnostic tumor biopsies.
- •Age 18 years and older.
- •ECOG status of 0 or
- •Life expectancy ≥12 weeks.
- •Subject has a prior histologically confirmed diagnosis of a grade 4 glioblastoma multiforme (GBM) or a prior histologically confirmed diagnosis of a grade 2 or 3 malignant glioma and now has radiographic progression consistent with a grade 4 GBM (IDH wild type), grade 4 diffuse astrocytoma (IDH mutant), or has a unifocal relapse of GBM.
- •Relapsed disease: radiographic evidence of recurrence/progression of measurable disease after standard therapy and ≥ 12 weeks after completion of front-line radiation therapy.
- •Confirmed MMP2+ tumor expression by IHC (≥20% moderate/high MMP2 score [2+ or 3+]).
- •Adequate venous access to perform leukapheresis.
- •No known contraindications to leukapheresis or steroids.
- •In-range baseline laboratory values for WBC (>2000/dL [or ANC ≥1000/mm^3]), platelets (≥75000/mm^3), total bilirubin (≤1.5xULN), AST (≤2.5xULN), ALT (≤2.5xULN), serum creatinine (≤1.5xmg/dL), and oxygen saturation (≥95% on room air)
- •Seronegative for human immunodeficiency virus (HIV) by antigen/antibody (Ag/Ab) testing.
- •Seronegative for hepatitis B and/or hepatitis C virus.
- •Women of childbearing potential must have a negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test is required.
- •Agreement by women AND men of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 3 months after the last dose of CHM-
- •(Childbearing potential is defined as not being surgically sterilized (women and men) or, for women, having not been free from menses for > 1 year.)
排除标准
- •Within 3 months of having received prior bevacizumab therapy at the time of enrollment.
- •Not yet recovered from toxicities of prior therapy.
- •Uncontrolled seizure activity and/or clinically evident progressive encephalopathy.
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent.
- •Clinically significant uncontrolled illness.
- •Active infection requiring antibiotics.
- •Known history of HIV or hepatitis B or hepatitis C infection.
- •Other active malignancy.
- •Women only-pregnant or breastfeeding.
- •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 subjects who, in the opinion of the Investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics).
研究组 & 干预措施
Treatment (CAR T cell therapy) 2
Arm 2 participants will undergo resection of their tumor. Participants receive half the CHM-1101 dose via Rickham catheters into the tumor cavity and half into the lateral ventricle.
Cycle 1 (28 days) CHM 1101 total dose will be divided across 3 once-weekly administrations.
After Cycle 1, additional cycles may be initiated in the absence of disease progression or unacceptable toxicity provided that the principal investigator and participant agree to continue and if adequate autologous CAR-T doses remain.
干预措施: CHM-1101 CAR-T cells (Biological)
Treatment (CAR T cell therapy) 1
Arm 1 participants will undergo resection of their tumor. Participants receive half the CHM-1101 dose via Rickham catheters into the tumor cavity and half into the lateral ventricle.
Cycle 1 (28 days) CHM 1101 total dose will be divided across 3 once-weekly administrations.
After Cycle 1, additional cycles may be initiated in the absence of disease progression or unacceptable toxicity provided that the principal investigator and participant agree to continue and if adequate autologous CAR-T doses remain.
干预措施: CHM-1101 CAR-T cells (Biological)
结局指标
主要结局
Cytokine Release Syndrome (CRS)
时间窗: up tp 15 years
Assessed per American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading guideline, evaluating levels and phenotype detected in tumor cyst fluid (TCF), peripheral blood (PB), and cerebrospinal fluid (CSF) (absolute number per µL by flowcytometry).
All other adverse events and toxicities
时间窗: up to 15 years
Assessed per NCI CTCAE v5.0.
Dose-limiting toxicity (DLT)
时间窗: 28 days
Assessed according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0.
次要结局
- Disease response(12 months)
- Chimeric antigen receptor (CAR) T cell(up to 15 years)
- Human anti-CAR antibody (HACA)(up to 15 years)
- Progression free survival (PFS) time(12 months)
- Overall survival (OS)(up to 15 years)
- Clinical benefit rate(12 months)
- Endogenous T cell(up to15 years)