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 II-IV glioma that has come back (recurrent) or does not respond to treatment (refractory). Memory enriched T cells such as CD19CAR-CD28-CD3zeta-EGFRt-expressing T cells 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:
  • Low Grade Glioma
  • 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
  • SECONDARY ID: 16064
  • SECONDARY ID: P30CA033572
  • NCT ID: NCT03389230

Conditions

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

Interventions

DrugSynonymsArms
CD19CAR-CD28-CD3zeta-EGFRt-expressing Tcm-enriched T-lymphocytesCD19-CAR-specific/truncated EGFR Lentiviral Vector-transduced T Cells, CD19CAR-CD28-CD3zeta-EGFRt-expressing Tcm-enriched T Cells, CD19R(EQ)28zeta/EGFRt+ TCM, CD19R(EQ)28zeta/truncated Human EGFR+ Central Memory T Cells, CD19R:CD28:lentiviral/EGFRt+ T CellsArm I (intratumoral/intracavitary delivery)
CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T-lymphocytesCD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T Cells, CD19R(EQ)28zeta/EGFRt+ Naive and Memory T Cells, CD19R(EQ)28zetaEGFRt+ Tn/mem CellsARM III (dual delivery Tn/mem enriched)

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 CD19CAR-CD28-CD3zeta-EGFRt-expressing T cells 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 cellular immunotherapy utilizing ex vivo expanded
      autologous memory-enriched T cells that are genetically modified using a self-inactivating
      (SIN) lentiviral vector to express a HER2-specific, hinge-optimized, 41BB-costimulatory
      chimeric antigen receptor (CAR), as well as a truncated human CD19 (HER2[EQ]BBzeta/CD19t+)
      for participants with recurrent/refractory malignant glioma in one of the following ways: Arm
      1 (intracavitary/intratumoral HER2(EQ)BBzeta/CD19+ T CM), Arm 2 (dual delivery [both
      intracavitary/intratumoral and intraventricular] of HER2(EQ)BBzeta/CD19+ T CM), or Arm 3
      (dual delivery [both intracavitary/intratumoral and intraventricular] of HER2(EQ)BBzeta/CD19+
      T N/MEM).

      II. To determine maximum tolerated dose schedule (MTD) and a recommended Phase II dosing plan
      (RP2D) for arm 3 (dual delivery).

      SECONDARY OBJECTIVES:

      I. To describe persistence and expansion of CAR T cells in tumor cyst fluid, 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 median progression free survival (PFS) rate. IV. To estimate disease
      response rates. V. To estimate median overall survival (OS). VI. Evaluate CAR T cell
      persistence in the tumor micro-environment and the location of the CAR T cells with respect
      to the injection in research participants who undergo an additional biopsy/resection or
      autopsy.

      VII. Evaluate HER2 antigen expression levels pre and post CAR T cell therapy in research
      participants who undergo an additional biopsy/resection or autopsy.

      OUTLINE: This is a dose-escalation study of autologous CD19CAR-CD28-CD3zeta-EGFRt-expressing
      Tcm. Participants are assigned to 1 of 3 arms.

      ARM I: Patients receive autologous HER2(EQ)BBzeta/CD19t+ Tcm cells via
      intratumoral/intracavitary catheter over 5 minutes weekly for 3 weeks. 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.

      ARM II: Patients receive autologous HER2(EQ)BBzeta/CD19t+ Tcm cells via
      intratumoral/intracavitary catheter and intraventricular catheter over 5 minutes weekly for 3
      weeks. 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).

      ARM III: Patients receive autologous HER2(EQ)BBzeta/CD19t+ Tn/mem cells via
      intratumoral/intracavitary catheter and intraventricular catheter over 5 minutes weekly for 3
      weeks. 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).

      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
Arm I (intratumoral/intracavitary delivery)ExperimentalPatients receive autologous HER2(EQ)BBzeta/CD19t+ Tcm cells via intratumoral/intracavitary catheter over 5 minutes weekly for 3 weeks. 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.
  • CD19CAR-CD28-CD3zeta-EGFRt-expressing Tcm-enriched T-lymphocytes
Arm II (dual delivery Tcm enriched)ExperimentalPatients receive autologous HER2(EQ)BBzeta/CD19t+ Tcm cells via intratumoral/intracavitary catheter and intraventricular catheter over 5 minutes weekly for 3 weeks. 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).
  • CD19CAR-CD28-CD3zeta-EGFRt-expressing Tcm-enriched T-lymphocytes
ARM III (dual delivery Tn/mem enriched)ExperimentalPatients receive autologous HER2(EQ)BBzeta/CD19t+ Tn/mem cells via intratumoral/intracavitary catheter and intraventricular catheter over 5 minutes weekly for 3 weeks. 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).
  • CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T-lymphocytes

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

          -  The effects of HER2(EQBBzeta/CD19t+ T cells on the developing fetus are unknown. For
             this reason, 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

               -  Once research participants meet eligibility to proceed with Rickham placement,
                  they will be deemed accrued on to the study

          -  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) < 2.5 x upper
             limits of normal

          -  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 participants does NOT have any known history of congestive heart failure
             (CHF) or cardiac symptoms consistent with NYHA classification III-IV within 6 months
             prior to Day 1 of protocol treatment, cardiomyopathy, myocarditis, myocardial
             infarction (MI), exposure to cardiotoxic medications or with clinical history
             suggestive of the above must have an EKG and echocardiogram (ECHO) performed within 42
             days prior to registration and as clinical indicated while on treatment

          -  If the research participants has new symptoms of CHF, cardiomyopathy, myocarditis, MI,
             or exposure to cardiotoxic medications they already had a cardiac consultation,
             creatinine phosphokinase (CPK), and troponin testing at pre study deeming them fit for
             study participation

          -  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 2 x 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 CAR 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 CAR
             T cell 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 must have passed since the completion of Temodar and/or 4 weeks
                  for any other non-nitrosourea-containing cytotoxic chemotherapy regimen; if a
                  participant?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 CAR T cell infusion with
                  the exception of bevacizumab where a wash out period of at least 4 weeks is
                  required before starting CAR 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 participants with a known history of congestive heart failure (CHF) or
             cardiac symptoms consistent with New York Heart Association (NYHA) classification
             III-IV within 6 months prior to Day 1 of protocol treatment, cardiomyopathy,
             myocarditis, myocardial infarction (MI), exposure to cardiotoxic medications or with
             clinical history suggestive of the above must have an electrocardiogram (EKG) and
             echocardiogram (ECHO) performed within 42 days prior to registration and as clinically
             indicated while on treatment

          -  Research participants with new symptoms of CHF, cardiomyopathy, myocarditis, MI, or
             exposure to cardiotoxic medications must have a cardiac consultation, creatinine
             phosphokinase (CPK), and troponin testing at pre -study and as clinically indicated

          -  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:Incidence of 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 biopsy 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:Kaplan Meier methods will be used
Measure:Overall Survival (OS)
Time Frame:At 6 months
Safety Issue:
Description:Kaplan Meier methods will be used to estimate median OS and graph the results.
Measure:Disease response
Time Frame:Up to 3 years
Safety Issue:
Description:Will be measured by Response Assessment in Neuro-Oncology Criteria (RANO) criteria. 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:Recruiting
Lead Sponsor:City of Hope Medical Center

Last Updated

June 19, 2019