Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03389230
Recruitment Status : Recruiting
First Posted : January 3, 2018
Last Update Posted : June 21, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
City of Hope Medical Center

Tracking Information
First Submitted Date  ICMJE December 27, 2017
First Posted Date  ICMJE January 3, 2018
Last Update Posted Date June 21, 2019
Actual Study Start Date  ICMJE June 14, 2018
Estimated Primary Completion Date June 14, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 19, 2019)
  • Incidence of grade 3 adverse events [ Time Frame: Up to 3 years ]
    Tables will be created to summarize all toxicities and side effects by dose, time post treatment, organ, severity and arm.
  • Dose limiting toxicities (DLT) [ Time Frame: Up to 3 years ]
    Rate and associated 90% Clopper and Pearson binomial confidence limits (90% confidence interval [CI]) will be estimated for participants? experiencing DLTs at the recommended phase 2 dose (RP2D) schedule.
  • Incidence of adverse events [ Time Frame: Up to 3 years ]
    Will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Tables will be created to summarize all toxicities and side effects by dose, time post treatment, organ, severity and arm.
Original Primary Outcome Measures  ICMJE
 (submitted: December 27, 2017)
  • Grade 3 adverse events [ Time Frame: Up to 3 years ]
    Tables will be created to summarize all toxicities and side effects by dose, time post treatment, organ, severity and arm.
  • Dose limiting toxicities (DLT) [ Time Frame: Up to 3 years ]
    Rate and associated 90% Clopper and Pearson binomial confidence limits (90% confidence interval [CI]) will be estimated for participants' experiencing DLTs at the recommended phase 2 dose (RP2D) schedule.
  • Incidence of adverse events [ Time Frame: Up to 3 years ]
    Tables will be created to summarize all toxicities and side effects by dose, time post treatment, organ, severity and arm.
Change History Complete list of historical versions of study NCT03389230 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 19, 2019)
  • Chimeric antigen receptor (CAR) T cells detected in tumor cyst fluid, peripheral blood, and cerebrospinal fluid (CSF) [ Time Frame: Up to 3 years ]
    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.
  • Tumor cyst fluid, peripheral blood, and cerebrospinal fluid (CSF) cytokine levels [ Time Frame: Up to 3 years ]
    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.
  • Progression free survival [ Time Frame: At 6 months ]
    Kaplan Meier methods will be used
  • Overall Survival (OS) [ Time Frame: At 6 months ]
    Kaplan Meier methods will be used to estimate median OS and graph the results.
  • Disease response [ Time Frame: Up to 3 years ]
    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.
  • Chimeric antigen receptor (CAR) T cells detected in tumor tissue [ Time Frame: Up to 3 years ]
    T cells numbers, location, and antigen levels will be described.
  • HER2 antigen expression levels in tumor tissue [ Time Frame: Up to 3 years ]
Original Secondary Outcome Measures  ICMJE
 (submitted: December 27, 2017)
  • Chimeric antigen receptor (CAR) T cells detected in tumor cyst fluid, peripheral blood, and cerebrospinal fluid (CSF) [ Time Frame: Up to 3 years ]
    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.
  • Tumor cyst fluid, peripheral blood, and cerebrospinal fluid (CSF) cytokine levels [ Time Frame: Up to 3 years ]
    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.
  • Progression free survival [ Time Frame: At 6 months ]
  • Disease response by Response Assessment in Neuro-Oncology Criteria (RANO) criteria [ Time Frame: Up to 3 years ]
    Will estimate the rate (90% CI) progression free at 6 months and rate (90% CI) with disease response.
  • Chimeric antigen receptor (CAR) T cells detected in tumor tissue [ Time Frame: Up to 3 years ]
    T cells numbers, location, and antigen levels will be described.
  • HER2 antigen expression levels in tumor tissue [ Time Frame: Up to 3 years ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Memory-Enriched T Cells in Treating Patients With Recurrent or Refractory Grade III-IV Glioma
Official Title  ICMJE 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
Brief Summary 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Glioblastoma
  • HER2/Neu Positive
  • Malignant Glioma
  • Recurrent Glioma
  • Refractory Glioma
  • WHO Grade III Glioma
Intervention  ICMJE
  • Biological: CD19CAR-CD28-CD3zeta-EGFRt-expressing Tcm-enriched T-lymphocytes
    Given via catheter
    Other Names:
    • CD19-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 Cells
  • Biological: CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T-lymphocytes
    Given via catheter
    Other Names:
    • CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T Cells
    • CD19R(EQ)28zeta/EGFRt+ Naive and Memory T Cells
    • CD19R(EQ)28zetaEGFRt+ Tn/mem Cells
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Procedure: Leukapheresis
    Undergo leukapheresis
    Other Names:
    • Leukocytopheresis
    • Therapeutic Leukopheresis
Study Arms  ICMJE
  • Experimental: Arm I (intratumoral/intracavitary delivery)
    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.
    Interventions:
    • Biological: CD19CAR-CD28-CD3zeta-EGFRt-expressing Tcm-enriched T-lymphocytes
    • Other: Laboratory Biomarker Analysis
    • Procedure: Leukapheresis
  • Experimental: Arm II (dual delivery Tcm enriched)
    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).
    Interventions:
    • Biological: CD19CAR-CD28-CD3zeta-EGFRt-expressing Tcm-enriched T-lymphocytes
    • Other: Laboratory Biomarker Analysis
    • Procedure: Leukapheresis
  • Experimental: ARM III (dual delivery Tn/mem enriched)
    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).
    Interventions:
    • Biological: CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T-lymphocytes
    • Other: Laboratory Biomarker Analysis
    • Procedure: Leukapheresis
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 19, 2019)
42
Original Estimated Enrollment  ICMJE
 (submitted: December 27, 2017)
81
Estimated Study Completion Date  ICMJE June 14, 2021
Estimated Primary Completion Date June 14, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03389230
Other Study ID Numbers  ICMJE 16064
NCI-2017-01755 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
16064 ( Other Identifier: City of Hope Comprehensive Cancer Center )
P30CA033572 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party City of Hope Medical Center
Study Sponsor  ICMJE City of Hope Medical Center
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Behnam Badie City of Hope Medical Center
PRS Account City of Hope Medical Center
Verification Date June 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP