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

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ClinicalTrials.gov Identifier: NCT03389230
Recruitment Status : Not yet recruiting
First Posted : January 3, 2018
Last Update Posted : January 3, 2018
Sponsor:
Collaborator:
Information provided by (Responsible Party):

Study Description
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 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.

Condition or disease Intervention/treatment Phase
Glioblastoma HER2/Neu Positive Malignant Glioma Recurrent Glioma WHO Grade III/IV Glioma Procedure: Leukapheresis Biological: HER2(EQ)BBζ/CD19t+ Tcm Other: Laboratory Biomarker Analysis Phase 1

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.


Study Design

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 81 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Anticipated Study Start Date : February 2018
Estimated Primary Completion Date : February 2021
Estimated Study Completion Date : February 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Memory
U.S. FDA Resources

Arms and Interventions

Arm Intervention/treatment
Experimental: STRATUM I (Intratumoral/Intracavitary delivery)
Patients 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.
Procedure: Leukapheresis
Undergo leukapheresis
Other Names:
  • Leukocytopheresis
  • Therapeutic Leukopheresis
Biological: HER2(EQ)BBζ/CD19t+ Tcm
Given via catheter
Other Name: HER2-targeting CAR T cells
Other: Laboratory Biomarker Analysis
Correlative studies
Experimental: STRATUM II (Intraventricular delivery)
Patients 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.
Procedure: Leukapheresis
Undergo leukapheresis
Other Names:
  • Leukocytopheresis
  • Therapeutic Leukopheresis
Biological: HER2(EQ)BBζ/CD19t+ Tcm
Given via catheter
Other Name: HER2-targeting CAR T cells
Other: Laboratory Biomarker Analysis
Correlative studies
Experimental: STRATUM III (Dual delivery)
Patients 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).
Procedure: Leukapheresis
Undergo leukapheresis
Other Names:
  • Leukocytopheresis
  • Therapeutic Leukopheresis
Biological: HER2(EQ)BBζ/CD19t+ Tcm
Given via catheter
Other Name: HER2-targeting CAR T cells
Other: Laboratory Biomarker Analysis
Correlative studies


Outcome Measures

Primary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. Progression free survival [ Time Frame: At 6 months ]
  4. 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.

  5. 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.

  6. HER2 antigen expression levels in tumor tissue [ Time Frame: Up to 3 years ]

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations

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): NCT03389230


Locations
United States, California
City of Hope Medical Center Not yet recruiting
Duarte, California, United States, 91010
Contact: Behnam Badie, MD    626-256-4673    bbadie@coh.org   
Principal Investigator: Behnam Badie, MD         
Sponsors and Collaborators
City of Hope Medical Center
Mustang Bio, Inc.
Investigators
Principal Investigator: Behnam Badie, MD City of Hope Medical Center
More Information

Responsible Party: City of Hope Medical Center
ClinicalTrials.gov Identifier: NCT03389230     History of Changes
Other Study ID Numbers: 16064
NCI-2017-01755 ( Registry Identifier: NCI CTRP )
First Posted: January 3, 2018    Key Record Dates
Last Update Posted: January 3, 2018
Last Verified: December 2017

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

Additional relevant MeSH terms:
Glioblastoma
Glioma
Astrocytoma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue