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

  • STATUS
    Recruiting
  • End date
    Dec 15, 2023
  • participants needed
    42
  • sponsor
    City of Hope Medical Center
Updated on 22 August 2021
platelet count
nitrosoureas
measurable disease
karnofsky performance status
x-rays
dexamethasone
cytotoxic chemotherapy
neutrophil count
immunohistochemistry
tumor cells
HER2
blood transfusion
bevacizumab
seizure
malignant glioma
erbb2
cellular therapy
temodar

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 (recurrent) or does not respond to treatment (refractory). Memory enriched T cells such as HER2(EQ)BB/CD19t+ 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.

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. In research participants who receive the full schedule of 3 CAR T cell doses:

IIIa. To estimate median progression free survival (PFS) rate. IIIb. To estimate disease response rates. IIIc. To estimate median overall survival (OS).

IV. In research participants who continue to receive infusions after progressing:

IVa. Estimate disease response. IVb. Describe CAR T cell and endogenous immune populations, as well as cytokine and microenvironment profiles (cerebral spinal fluid [CSF], cyst fluid, peripheral blood) considering post progression therapy(ies), if applicable.

V. For study participants who undergo an additional biopsy/resection or autopsy:

Va. Evaluate CAR T cell persistence in the tumor micro-environment and the location of the CAR T cells with respect to the injection.

Vb. Evaluate HER2 antigen expression levels pre and post CAR T cell therapy.

OUTLINE: This is a dose-escalation study of autologous HER2(EQ)BB/CD19t+ T cells. 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.

Details
Condition Glioma, Glioblastoma Multiforme, High Grade Glioma, Recurrent Glioma, WHO Grade III Glioma, Anaplastic Glioma, Refractory Glioma, Gliomas, HER2/Neu Positive, HER2/Neu Positive, HER2/Neu Positive, malignant glioma, glioblastoma
Treatment laboratory biomarker analysis, leukapheresis, CD19CAR-CD28-CD3zeta-EGFRt-expressing Tcm-enriched T-lymphocytes, CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T-lymphocytes, HER2(EQ)BBzeta/CD19t+Tcm cells, HER2(EQ)BBzeta/CD19t+Tn/mem cells, HER2(EQ)BBζ/CD19t+ T cells
Clinical Study IdentifierNCT03389230
SponsorCity of Hope Medical Center
Last Modified on22 August 2021

Eligibility

Yes No Not Sure

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)
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
Note: For research participants who do not speak English, a short form consent may be used with a COH certified interpreter/translator to proceed with screening and leukapheresis, while the request for a translated full consent is processed; however, the research participant is allowed to proceed with rickham placement and CAR T cell infusion only after the translated full consent form is signed
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 targeted agents, chemotherapy or radiation; at the principal investigator's discretion, exception can be made for investigational agents that are delivered locally into the CSF
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
Note: if the participant had received prior targeted radiation and new lesions have appeared outside of that targeted area, then that may be deemed radiographic evidence of measurable disease even if 12 weeks have not elapsed
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 participant 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
Clear my responses

How to participate?

Step 1 Connect with a study center
What happens next?
  • You can expect the study team to contact you via email or phone in the next few days.
  • Sign up as volunteer to help accelerate the development of new treatments and to get notified about similar trials.

You are contacting

Investigator Avatar

Primary Contact

site

0/250

Additional screening procedures may be conducted by the study team before you can be confirmed eligible to participate.

Learn more

If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.

Learn more

Complete your scheduled study participation activities and then you are done. You may receive summary of study results if provided by the sponsor.

Learn more

Similar trials to consider

Loading...

Browse trials for

Not finding what you're looking for?

Every year hundreds of thousands of volunteers step forward to participate in research. Sign up as a volunteer and receive email notifications when clinical trials are posted in the medical category of interest to you.

Sign up as volunteer

user name

Added by • 

 • 

Private

Reply by • Private
Loading...

Lorem ipsum dolor sit amet consectetur, adipisicing elit. Ipsa vel nobis alias. Quae eveniet velit voluptate quo doloribus maxime et dicta in sequi, corporis quod. Ea, dolor eius? Dolore, vel!

  The passcode will expire in None.
Loading...

No annotations made yet

Add a private note
  • abc Select a piece of text from the left.
  • Add notes visible only to you.
  • Send it to people through a passcode protected link.
Add a private note