Clinical Trials /

Memory-Enriched T Cells in Treating Patients With Recurrent or Refractory Grade III-IV Glioma

NCT03389230

Description:

This phase I trial studies the side effects and best dose of memory-enriched T cells in treating patients with grade III-IV glioma that has come back or does not respond to treatment. Memory enriched T cells such as HER2(EQ)BBζ/CD19t+-expressing Tcells may enter and express its genes in immune cells. Immune cells can be engineered to kill glioma cells in the laboratory by inserting a piece of deoxyribonucleic acid (DNA) into the immune cells that allows them to recognize glioma cells. A vector called lentivirus is used to carry the piece of DNA into the immune cell. It is not known whether these immune cells will kill glioma tumor cells when given to patients.

Related Conditions:
  • Malignant Glioma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Memory-Enriched T Cells in Treating Patients With Recurrent or Refractory Grade III-IV Glioma
  • Official Title: Phase I Study of Cellular Immunotherapy Using Memory-Enriched T Cells Lentivirally Transduced to Express a HER2-Specific, Hinge-optimized, 41BB-Costimulatory Chimeric Receptor and a Truncated CD19 for Patients With Recurrent/Refractory Malignant Glioma

Clinical Trial IDs

  • ORG STUDY ID: 16064
  • SECONDARY ID: NCI-2017-01755
  • NCT ID: NCT03389230

Conditions

  • Glioblastoma
  • HER2/Neu Positive
  • Malignant Glioma
  • Recurrent Glioma
  • WHO Grade III/IV Glioma

Interventions

DrugSynonymsArms
HER2(EQ)BBζ/CD19t+ TcmHER2-targeting CAR T cellsSTRATUM I (Intratumoral/Intracavitary delivery)

Purpose

This phase I trial studies the side effects and best dose of memory-enriched T cells in treating patients with grade II-IV glioma that has come back or does not respond to treatment. Memory enriched T cells such as HER2(EQ)BBζ/CD19t+-expressing Tcm may enter and express its genes in immune cells. Immune cells can be engineered to kill glioma cells in the laboratory by inserting a piece of deoxyribonucleic acid (DNA) into the immune cells that allows them to recognize glioma cells. A vector called lentivirus is used to carry the piece of DNA into the immune cell. It is not known whether these immune cells will kill glioma tumor cells when given to patients.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To assess the feasibility and safety of intracavitary/intratumoral (arm 1),
      intraventricular (arm 2), or dual delivery (arm 3: both intracavitary /intratumoral and
      intraventricular) cellular immunotherapy utilizing autologous HER2(EQ)BBζ/CD19t+-expressing
      cells for adult research participants with recurrent/refractory malignant glioma.

      II. To determine maximum tolerated dose schedule (MTD) and a recommended Phase II dosing plan
      (RP2D) for treatment arms 1 (intracavitary/intratumoral) and 3 (dual delivery). An MTD for
      arm 2 will only be sought if arm 3 is found to be too toxic.

      SECONDARY OBJECTIVES:

      I. To describe persistence and expansion of CAR T cells in peripheral blood and cerebral
      spinal fluid (CSF).

      II. To describe cytokine levels (tumor cyst fluid, peripheral blood, and CSF) over the study
      period.

      III. To estimate the six month progression free survival (PFS) rate in research participants
      who receive the full schedule of 3 CAR T cell doses.

      IV. To estimate disease response rates in research participants who receive the full schedule
      of 3 CAR T cell doses.

      V. To estimate median overall survival (OS)in research participants who receive the full
      schedule of 3 CAR T cell doses .

      VI. To evaluate CAR T cell persistence in the tumor tissue and the location of the CAR T
      cells with respect to the injection in research participants who undergo an additional
      resection or autopsy.

      VII. To evaluate HER2 antigen expression levels on tumor tissue pre and post CAR T cell
      therapy in research participants who undergo an additional resection or autopsy.

      OUTLINE: This is a dose-escalation study of HER2(EQBBζ/CD19t+-expressing Tcm.

      Patients undergo leukapheresis over 2-4 hours. Beginning approximately 21 days later,
      patients receive HER2(EQ)BBζ/CD19t+-expressing Tcm via catheter over 5 minutes on days 0, 7,
      and 14. Patients may receive additional doses of HER2(EQ)BBζ/CD19t+-expressing Tcm up to the
      highest cell dose that is deemed safe.

      After completion of study treatment, patients are followed up at 4 weeks, 3, 6, 8, 10 and 12
      months, then annually for at least 15 years.
    

Trial Arms

NameTypeDescriptionInterventions
STRATUM I (Intratumoral/Intracavitary delivery)ExperimentalPatients receive autologous HER2(EQ)BBζ/CD19t+ Tcm cells via intratumoral/intracavitary catheter over 5 minutes weekly for 3 weeks in the absence of disease progression. Beginning as early as 1 week later, patients may receive additional T cell infusions as long as patients remain eligible and there is product available. Patients who progress on intracavitary or intratumoral administration may move to alternative delivery routes for the optional infusions.
    STRATUM II (Intraventricular delivery)ExperimentalPatients receive autologous HER2(EQ)BBζ/CD19t+ Tcm cells via intraventricular catheter over 5 minutes weekly for 3 weeks in the absence of disease progression. Beginning as early as 1 week later, patients may receive additional T cell infusions as long as patients continue to remain eligible and there is product available. Patients who progress on intraventricular administration may move to alternative delivery routes for the optional infusions.
      STRATUM III (Dual delivery)ExperimentalPatients receive autologous HER2(EQ)BBζ/CD19t+ Tcm cells via intratumoral/intracavitary catheter and intraventricular catheter over 5 minutes weekly for 3 weeks in the absence of disease progression. Beginning as early as 1 week later, patients may receive additional T cell infusions as long as patients continue to remain eligible and there is product available. Based on clinical response after the first 3 infusions, the study principal investigator may decide to continue with the optional infusions at either one or both sites (instead of requiring injections at both sites).

        Eligibility Criteria

                Inclusion Criteria:
        
                  -  Participant has a prior histologically-confirmed diagnosis of a grade III or IV
                     glioma, or has a prior histologically-confirmed diagnosis of a grade II glioma and now
                     has radiographic progression consistent with a grade III or IV malignant glioma (MG)
        
                  -  Radiographic evidence of progression/recurrence of the measurable disease more than 12
                     weeks after the end of initial radiation therapy
        
                  -  Karnofsky performance status (KPS) >= 60%
        
                  -  Life expectancy > 4 weeks
        
                  -  Women of child-bearing potential and men must agree to use adequate contraception
                     (hormonal or barrier method of birth control or abstinence) prior to study entry and
                     for six months following duration of study participation; should a woman become
                     pregnant or suspect that she is pregnant while participating on the trial, she should
                     inform her treating physician immediately
        
                  -  City of Hope (COH) Clinical Pathology confirms HER2+ tumor expression by
                     immunohistochemistry (>= 20%, 1+)
        
                  -  All research participants must have the ability to understand and the willingness to
                     sign a written informed consent
        
                ELIGIBILITY TO PROCEED WITH PERIPHERAL BLOOD MONONUCLEAR CELL (PBMC) COLLECTION
        
                  -  Research participant must not require more than 2 mg three times daily (TID) of
                     dexamethasone on the day of PBMC collection
        
                  -  Research participant must have appropriate venous access
        
                  -  At least 2 weeks must have elapsed since the research participant received his/her
                     last dose of prior chemotherapy or radiation
        
                ELIGIBILITY TO PROCEED WITH RICKHAM PLACEMENT
        
                  -  Creatinine < 1.6 mg/dL
        
                  -  White blood cell (WBC) > 2,000/dl (or absolute neutrophil count [ANC] > 1,000)
        
                  -  Platelets >= 100,000/dl
        
                  -  International normalized ratio (INR) < 1.3
        
                  -  Bilirubin < 1.5 mg/dL
        
                  -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2X upper limits
                     of normal
        
                  -  An interval of at least 12 weeks must have elapsed since the completion of initial
                     radiation therapy
        
                  -  Wash-out requirements (standard or investigational):
        
                       -  At least 6 weeks since the completion of a nitrosourea-containing chemotherapy
                          regimen; and
        
                       -  At least 23 days since the completion of temodar and/or 4 weeks for any other
                          non-nitrosourea-containing cytotoxic chemotherapy regimen; if a patient's most
                          recent treatment was with a targeted agent only, and s/he has recovered from any
                          toxicity of this targeted agent, then a waiting period of only 2 weeks is needed
                          from the last dose and the start of study treatment, with the exception of
                          bevacizumab where a wash out period of at least 4 weeks is required before
                          starting study treatment
        
                ELIGIBILITY TO PROCEED WITH CAR T CELL INFUSION
        
                  -  Research participant has a released cryopreserved CAR T cell product
        
                  -  Research participant does not require supplemental oxygen to keep saturation greater
                     than 95% and/or does not have presence of any radiographic abnormalities on chest
                     x-ray that are progressive
        
                  -  Research participant does not require pressor support and/or does not have symptomatic
                     cardiac arrhythmias
        
                  -  Research participant does not have a fever exceeding 38.5 degrees Celsius (C); there
                     is an absence of positive blood cultures for bacteria, fungus, or virus within
                     48-hours prior to T cell infusion and/or there aren't any indications of meningitis
        
                  -  Research participant serum total bilirubin or transaminases does not exceed 2X normal
                     limit
        
                  -  Research participant serum creatinine =<1.8 mg/dL
        
                  -  Research participant does not have uncontrolled seizure activity following surgery
                     prior to starting the first T cell dose
        
                  -  Research participant platelet count must be >= 100,000; however, if platelet level is
                     between 75,000-99,000, then T-cell infusion may proceed after platelet transfusion is
                     given and the post transfusion platelet count is >= 100,000
        
                  -  Research participants must not require more than 2 mg TID of dexamethasone during T
                     cell therapy
        
                Exclusion Criteria:
        
                  -  Research participant requires supplemental oxygen to keep saturation greater than 95%
                     and the situation is not expected to resolve within 2 weeks
        
                  -  Research participant requires pressor support and/or has symptomatic cardiac
                     arrhythmias
        
                  -  Research participant requires dialysis
        
                  -  Research participant has uncontrolled seizure activity and/or clinically evident
                     progressive encephalopathy
        
                  -  Failure of research participant to understand the basic elements of the protocol
                     and/or the risks/benefits of participating in this phase I study; a legal guardian may
                     substitute for the research participant
        
                  -  Research participants with any non-malignant intercurrent illness which is either
                     poorly controlled with currently available treatment, or which is of such severity
                     that the investigators deem it unwise to enter the research participant on protocol
                     shall be ineligible
        
                  -  Research participants with any other active malignancies
        
                  -  Research participants being treated for severe infection or who are recovering from
                     major surgery are ineligible until recovery is deemed complete by the investigator
        
                  -  Research participants with any uncontrolled illness including ongoing or active
                     infection; research participants with known active hepatitis B or C infection;
                     research participants with any signs or symptoms of active infection, positive blood
                     cultures or radiological evidence of infections
        
                  -  Research participants who have confirmed human immunodeficiency virus (HIV) positivity
                     within 4 weeks of enrollment
              
        Maximum Eligible Age:75 Years
        Minimum Eligible Age:18 Years
        Eligible Gender:All
        Healthy Volunteers:No

        Primary Outcome Measures

        Measure:Grade 3 adverse events
        Time Frame:Up to 3 years
        Safety Issue:
        Description: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 cells detected in tumor cyst fluid, peripheral blood, and cerebrospinal fluid (CSF)
        Time Frame:Up to 3 years
        Safety Issue:
        Description:Statistical and graphical methods will be used to describe persistence and expansion of the CAR T cells (tumor cyst fluid, peripheral blood and CSF) over the study period. In study participants that undergo a second resection or following autopsy, T cells numbers, location, and antigen levels will be described.
        Measure:Tumor cyst fluid, peripheral blood, and cerebrospinal fluid (CSF) cytokine levels
        Time Frame:Up to 3 years
        Safety Issue:
        Description:Statistical and graphical methods will be used to describe persistence and expansion of cytokine levels (tumor cyst fluid, peripheral blood, and CSF) over the study period.
        Measure:Progression free survival
        Time Frame:At 6 months
        Safety Issue:
        Description:
        Measure:Disease response by Response Assessment in Neuro-Oncology Criteria (RANO) criteria
        Time Frame:Up to 3 years
        Safety Issue:
        Description:Will estimate the rate (90% CI) progression free at 6 months and rate (90% CI) with disease response.
        Measure:Chimeric antigen receptor (CAR) T cells detected in tumor tissue
        Time Frame:Up to 3 years
        Safety Issue:
        Description:T cells numbers, location, and antigen levels will be described.
        Measure:HER2 antigen expression levels in tumor tissue
        Time Frame:Up to 3 years
        Safety Issue:
        Description:

        Details

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

        Trial Keywords

        • chimeric antigen receptor
        • glioblastoma

        Last Updated

        April 13, 2018