Clinical Trials /

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

NCT04214392

Description:

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.

Related Conditions:
  • Glioblastoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: 19309
  • SECONDARY ID: NCI-2019-08393
  • SECONDARY ID: 19309
  • NCT ID: NCT04214392

Conditions

  • Recurrent Glioblastoma
  • Recurrent Malignant Glioma
  • Recurrent WHO Grade II Glioma
  • Recurrent WHO Grade III Glioma

Interventions

DrugSynonymsArms
Chlorotoxin (EQ)-CD28-CD3zeta-CD19t-expressing CAR T-lymphocytes NCI SYsTreatment (CAR T cell therapy)

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (CAR T cell therapy)ExperimentalPatients 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.
  • Chlorotoxin (EQ)-CD28-CD3zeta-CD19t-expressing CAR T-lymphocytes NCI SYs

Eligibility 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)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose limiting toxicity (DLT)
Time Frame:21 days
Safety Issue:
Description: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

Measure:Chimeric antigen receptor (CAR) T cell
Time Frame:15 years
Safety Issue:
Description: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.
Measure:Endogenous T cell
Time Frame:15 years
Safety Issue:
Description: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.
Measure:Cytokine levels in TCF, PB and CSF
Time Frame:15 years
Safety Issue:
Description:
Measure:Progression free survival time
Time Frame:At 6 months
Safety Issue:
Description:
Measure:Disease response
Time Frame:At 6 months
Safety Issue:
Description:Will be assessed by modified Response Assessment in Neuro-Oncology Criteria (RANO) criteria with the need for bevacizumab as an additional indicator of progression.
Measure:Overall survival (OS)
Time Frame:At 9 months
Safety Issue:
Description:Kaplan Meier methods will be used to estimate median OS and graph the results.
Measure:CAR T cells detected in tumor tissue
Time Frame:15 years
Safety Issue:
Description:Will be assessed by immunohistochemistry.
Measure:Chlorotoxin-targeted antigen expression levels in tumor tissue
Time Frame:15 years
Safety Issue:
Description:Will assess the pathology H score.
Measure:Biomathematical modeling of tumor growth
Time Frame:15 years
Safety Issue:
Description:Will assess perfusion and growth parameters based on serial brain magnetic resonance imaging (MRI)s.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:City of Hope Medical Center

Last Updated

December 27, 2019