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

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ClinicalTrials.gov Identifier: NCT04214392
Recruitment Status : Recruiting
First Posted : January 2, 2020
Last Update Posted : March 31, 2020
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
City of Hope Medical Center

Brief 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 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.

Condition or disease Intervention/treatment Phase
Recurrent Glioblastoma Recurrent Malignant Glioma Recurrent WHO Grade II Glioma Recurrent WHO Grade III Glioma Biological: Chlorotoxin (EQ)-CD28-CD3zeta-CD19t-expressing CAR T-lymphocytes NCI SYs Phase 1

Detailed 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 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 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 21 days. Each treatment cycle begins with one or two CAR T cell infusions (one at each catheter site) and lasts for 1 week. Begin 1 week after 3 cycles, patients my continue with CAR T treatment per principal investigator and participant 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1 Study to Evaluate Chimeric Antigen Receptor (CAR) T Cells With a Chlorotoxin Tumor-Targeting Domain for Patients With Recurrent or Progressive Glioblastoma
Estimated Study Start Date : May 1, 2020
Estimated Primary Completion Date : February 6, 2023
Estimated Study Completion Date : February 6, 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Treatment (CAR T cell therapy)
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 21 days. Each treatment cycle begins with one or two CAR T cell infusions (one at each catheter site) and lasts for 1 week. Begin 1 week after 3 cycles, patients my continue with CAR T treatment per principal investigator and participant discretion. Treatment continues in the absence of disease progression or unacceptable toxicity.
Biological: Chlorotoxin (EQ)-CD28-CD3zeta-CD19t-expressing CAR T-lymphocytes NCI SYs
Given via dual delivery




Primary Outcome Measures :
  1. Dose limiting toxicity (DLT) [ Time Frame: 21 days ]
    Will be assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE version 5.0). Rate and associated 90% Clopper and Pearson binomial confidence limits (90% confidence interval) will be estimated for participants experiencing DLTs at the recommended phase 2 dose schedule. Tables will be created to summarize all toxicities and side effects by dose, time post treatment, organ, severity, and arm.


Secondary Outcome Measures :
  1. Chimeric antigen receptor (CAR) T cell [ Time Frame: 15 years ]
    Will assess its levels and phenotype detected in tumor cyst fluid (TCF), peripheral blood (PB), and cerebrospinal fluid (CSF) (absolute number per ul by flowcytometry). Statistical and graphical methods will be used.

  2. Endogenous T cell [ Time Frame: 15 years ]
    Will assess its level and phenotype detected in TCF, PB, and CSF (absolute number per ul by flowcytometry). Statistical and graphical methods will be used.

  3. Cytokine levels in TCF, PB and CSF [ Time Frame: 15 years ]
  4. Progression free survival time [ Time Frame: At 6 months ]
  5. Disease response [ Time Frame: At 6 months ]
    Will be assessed by modified Response Assessment in Neuro-Oncology Criteria (RANO) criteria with the need for bevacizumab as an additional indicator of progression.

  6. Overall survival (OS) [ Time Frame: At 9 months ]
    Kaplan Meier methods will be used to estimate median OS and graph the results.

  7. CAR T cells detected in tumor tissue [ Time Frame: 15 years ]
    Will be assessed by immunohistochemistry.

  8. Chlorotoxin-targeted antigen expression levels in tumor tissue [ Time Frame: 15 years ]
    Will assess the pathology H score.

  9. Biomathematical modeling of tumor growth [ Time Frame: 15 years ]
    Will assess growth parameters based on serial brain magnetic resonance imaging (MRI)s.

  10. Biomathematical modeling of Perfusion [ Time Frame: 15 years ]
    Will assess perfusion parameters based on serial brain magnetic resonance imaging (MRI)s.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (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. 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 (> 15% high MMP2 (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)
  • 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:

  • Participant has received prior bevacizumab therapy
  • 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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04214392


Locations
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United States, California
City of Hope Medical Center Recruiting
Duarte, California, United States, 91010
Contact: Behnam Badie    626-218-7293    bbadie@coh.org   
Principal Investigator: Behnam Badie         
Sponsors and Collaborators
City of Hope Medical Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Behnam Badie City of Hope Medical Center

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Responsible Party: City of Hope Medical Center
ClinicalTrials.gov Identifier: NCT04214392    
Other Study ID Numbers: 19309
NCI-2019-08393 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
19309 ( Other Identifier: City of Hope Comprehensive Cancer Center )
First Posted: January 2, 2020    Key Record Dates
Last Update Posted: March 31, 2020
Last Verified: February 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Glioblastoma
Glioma
Astrocytoma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue