Chimeric Antigen Receptor (CAR) T Cells With a Chlorotoxin Tumor-Targeting Domain for the Treatment of MPP2+ Recurrent or Progressive Glioblastoma

STATUS

Recruiting
participants needed

36
sponsor

City of Hope Medical Center

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Updated on 19 February 2024

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HIV Infection

absolute neutrophil count

serum pregnancy test

measurable disease

neutrophil count

karnofsky performance status

tumor cells

immunohistochemistry

leukapheresis

recurrent disease

malignant glioma

glioblastoma multiforme

mpp2

expression by immunohistochemistry

glioma

Summary

This phase I trial studies the side effects and best dose of chimeric antigen receptor (CAR) T cells with a chlorotoxin tumor-targeting domain in treating patients with MPP2+ glioblastoma that has come back (recurrent) or that is growing, spreading, or getting worse (progressive). Vaccines made from a gene-modified virus may help the body build an effective immune response to kill tumor cells.

Description

PRIMARY OBJECTIVES:

I. Assess the feasibility and safety of dual delivery of chlorotoxin (EQ)-CD28-CD3zeta-CD19t-expressing CAR T-lymphocytes NCI SYs (chlorotoxin [CLTX]-CAR T cells) for participants with MMP2+ recurrent or progressive glioblastoma.

II. Determine the maximum tolerated dose schedule (MTD) and a recommended phase 2 dosing plan (RP2D) for dual delivery of CLTX-CAR T cells for participants with MMP2+ recurrent or progressive glioblastoma.

SECONDARY OBJECTIVES:

I. Describe persistence, expansion, and phenotype of endogenous and CLTX-CAR CAR T cells in tumor cyst fluid (TCF), peripheral blood (PB), and cerebrospinal fluid (CSF).

II. Describe cytokine levels in PB, TCF, and CSF over the study period.

III. In research participants who receive the full schedule of 3 cycles of CLTX-CAR T cells:

IIIa. Estimate the six month progression free survival (PFS) rate. IIIb. Estimate the nine month overall survival (OS) rate. IIIc. Estimate disease response rates. IIId. Estimate median overall survival (OS).

IV. In study participants who undergo an additional biopsy/resection or autopsy:

IVa. Evaluate CAR T cell persistence in the tumor tissue and the location of the CAR T cells with respect to the injection site.

IVb. Evaluate CLTX-targeted antigen expression levels on tumor tissue pre and post CAR T cell therapy.

V. Use mathematical modeling of tumor growth to evaluate benefit of treatment.

OUTLINE: This is a dose-escalation study.

Patients receive chlorotoxin (EQ)-CD28-CD3zeta-CD19t-expressing CAR T-lymphocytes NCI SYs via dual delivery starting on day 0 for 3 weekly cycles over 28 days. Each treatment cycle begins with one or two CAR T cell infusions (one at each catheter site) and lasts for 1 week. Beginning 1 week after cycle 3, patients may continue with CAR T treatment per principal investigator and patient discretion. Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, 3, 6, 9, and 12 months, and then yearly for up to 15 years.

Details

Condition	Recurrent Glioblastoma, Recurrent Malignant Glioma, Recurrent WHO Grade II Glioma, Recurrent WHO Grade III Glioma
Age	18years - 100years
Treatment	Chlorotoxin (EQ)-CD28-CD3zeta-CD19t-expressing CAR T-lymphocytes
Clinical Study Identifier	NCT04214392
Sponsor	City of Hope Medical Center
Last Modified on	19 February 2024

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Eligibility		Yes	No	Not Sure
Inclusion Criteria
	Documented informed consent of the participant and/or legally authorized representative. Assent, when appropriate, will be obtained per institutional guidelines
	Agreement to allow the use of archival tissue from diagnostic tumor biopsies. If unavailable, exceptions may be granted with study principal investigator (PI) approval
	Karnofsky performance status (KPS) >= 60%
	Eastern Cooperative Oncology Group (ECOG) =< 2
	Life expectancy >= 4 weeks
	Participant has a prior histologically-confirmed diagnosis of a grade IV glioblastoma, or has a prior histologically-confirmed diagnosis of a grade II or III malignant glioma and now has radiographic progression consistent with a grade IV glioblastoma
	Relapsed disease: radiographic evidence of recurrence/progression of measurable disease after standard therapy, and >= 12 weeks after completion of front-line radiation therapy
	City of Hope (COH) Clinical Pathology confirms matrix metalloproteinase (MMP)2+ tumor expression by immunohistochemistry (>= 20% moderate/high MMP2 [2+/3+])
	White blood cell (WBC) > 2000 /dl (or absolute neutrophil count [ANC] >= 1,000/mm^3) (to be performed within 14 days prior to leukapheresis unless otherwise stated)
	Platelets >= 75,000/mm^3 (to be performed within 14 days prior to leukapheresis unless otherwise stated)
	Hemoglobin >= 8 g/dl (to be performed within 14 days prior to leukapheresis unless otherwise stated)
	Total bilirubin =< 1.5 upper limit of normal (ULN) (to be performed within 14 days prior to leukapheresis unless otherwise stated)
	Aspartate aminotransferase (AST) =< 2.5 x ULN (to be performed within 14 days prior to leukapheresis unless otherwise stated)
	Alanine aminotransferase (ALT) =< 2.5 x ULN (to be performed within 14 days prior to leukapheresis unless otherwise stated)
	Serum creatinine =< 1.6 mg/dL (to be performed within 14 days prior to leukapheresis unless otherwise stated)
	Oxygen (O2) saturation >= 95% on room air (to be performed within 14 days prior to leukapheresis unless otherwise stated)
	Seronegative for human immunodeficiency virus (HIV) antigen (Ag)/antibody (Ab) combo (to be performed within 14 days prior to leukapheresis unless otherwise stated)
	Women of childbearing potential (WOCBP): negative urine or serum pregnancy test (to be performed within 14 days prior to leukapheresis unless otherwise stated)
	If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
	Agreement by females and males 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 CAR T cells
	Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only)
Exclusion Criteria
	Owing to higher frequency of wound-related complications, participants who have had prior bevacizumab therapy are excluded
	Participant has 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
	Active diarrhea
	Clinically significant uncontrolled illness
	Active infection requiring antibiotics
	Known history of immunodeficiency virus (HIV) or hepatitis B or hepatitis C infection
	Other active malignancy
	Females 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 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)

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Chimeric Antigen Receptor (CAR) T Cells With a Chlorotoxin Tumor-Targeting Domain for the Treatment of MPP2+ Recurrent or Progressive Glioblastoma