Trial Title:
Intracerebroventricular Administration of CD19-CAR T Cells (CD19CAR-CD28-CD3zeta-EGFRt-expressing Tcm-enriched T-lymphocytes) for the Treatment of Primary Central Nervous System Lymphoma
NCT ID:
NCT05625594
Condition:
Central Nervous System Lymphoma
Conditions: Official terms:
Lymphoma
Cyclophosphamide
Fludarabine
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Procedure
Intervention name:
Aspiration
Description:
Undergo CSF aspiration
Arm group label:
Treatment (leukapheresis, CD19-CAR T cells)
Intervention type:
Procedure
Intervention name:
Biospecimen Collection
Description:
Undergo blood sample collection
Arm group label:
Treatment (leukapheresis, CD19-CAR T cells)
Other name:
Biological Sample Collection
Other name:
Biospecimen Collected
Other name:
Specimen Collection
Intervention type:
Procedure
Intervention name:
Catheterization
Description:
Undergo catheterization
Arm group label:
Treatment (leukapheresis, CD19-CAR T cells)
Other name:
Catheter Insertion
Intervention type:
Biological
Intervention name:
CD19CAR-CD28-CD3zeta-EGFRt-expressing Tcm-enriched T-lymphocytes
Description:
Given ICV
Arm group label:
Treatment (leukapheresis, CD19-CAR T cells)
Other name:
CD19-CAR-specific/truncated EGFR Lentiviral Vector-transduced T Cells
Other name:
CD19CAR-CD28-CD3zeta-EGFRt-expressing Tcm-enriched T Cells
Other name:
CD19R(EQ)28zeta/EGFRt+ TCM
Other name:
CD19R(EQ)28zeta/truncated Human EGFR+ Central Memory T Cells
Other name:
CD19R:CD28:lentiviral/EGFRt+ T Cells
Intervention type:
Procedure
Intervention name:
Computed Tomography
Description:
Undergo CT
Arm group label:
Treatment (leukapheresis, CD19-CAR T cells)
Other name:
CAT
Other name:
CAT Scan
Other name:
Computed Axial Tomography
Other name:
Computerized Axial Tomography
Other name:
Computerized Tomography
Other name:
CT
Other name:
CT Scan
Other name:
tomography
Intervention type:
Drug
Intervention name:
Cyclophosphamide
Description:
Given IV
Arm group label:
Treatment (leukapheresis, CD19-CAR T cells)
Other name:
(-)-Cyclophosphamide
Other name:
2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
Other name:
Carloxan
Other name:
Ciclofosfamida
Other name:
Ciclofosfamide
Other name:
Cicloxal
Other name:
Clafen
Other name:
Claphene
Other name:
CP monohydrate
Other name:
CTX
Other name:
CYCLO-cell
Other name:
Cycloblastin
Other name:
Cycloblastine
Other name:
Cyclophospham
Other name:
Cyclophosphamid monohydrate
Other name:
Cyclophosphamide Monohydrate
Other name:
Cyclophosphamidum
Other name:
Cyclophosphan
Other name:
Cyclophosphane
Other name:
Cyclophosphanum
Other name:
Cyclostin
Other name:
Cyclostine
Other name:
Cytophosphan
Other name:
Cytophosphane
Other name:
Cytoxan
Other name:
Fosfaseron
Other name:
Genoxal
Other name:
Genuxal
Other name:
Ledoxina
Other name:
Mitoxan
Other name:
Neosar
Other name:
Revimmune
Other name:
Syklofosfamid
Other name:
WR- 138719
Intervention type:
Drug
Intervention name:
Fludarabine
Description:
Given IV
Arm group label:
Treatment (leukapheresis, CD19-CAR T cells)
Other name:
Fluradosa
Intervention type:
Procedure
Intervention name:
Leukapheresis
Description:
Undergo leukapheresis
Arm group label:
Treatment (leukapheresis, CD19-CAR T cells)
Other name:
Leukocytopheresis
Other name:
Therapeutic Leukopheresis
Intervention type:
Procedure
Intervention name:
Lumbar Puncture
Description:
Undergo lumbar puncture
Arm group label:
Treatment (leukapheresis, CD19-CAR T cells)
Other name:
LP
Other name:
Spinal Tap
Intervention type:
Procedure
Intervention name:
Magnetic Resonance Imaging
Description:
Undergo MRI
Arm group label:
Treatment (leukapheresis, CD19-CAR T cells)
Other name:
Magnetic Resonance
Other name:
Magnetic Resonance Imaging Scan
Other name:
Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
Other name:
MR
Other name:
MR Imaging
Other name:
MRI
Other name:
MRI Scan
Other name:
NMR Imaging
Other name:
NMRI
Other name:
Nuclear Magnetic Resonance Imaging
Intervention type:
Procedure
Intervention name:
Positron Emission Tomography
Description:
Undergo PET
Arm group label:
Treatment (leukapheresis, CD19-CAR T cells)
Other name:
Medical Imaging, Positron Emission Tomography
Other name:
PET
Other name:
PET Scan
Other name:
Positron Emission Tomography Scan
Other name:
Positron-Emission Tomography
Other name:
proton magnetic resonance spectroscopic imaging
Other name:
PT
Summary:
This phase I trial tests the safety, side effects, and best dose of
intracerebroventricularly (ICV) administered CD19-chimeric antigen receptor (CAR) T cells
in treating patients with primary central nervous system (CNS) lymphoma. CAR T cell
therapy is a type of treatment in which a patient's T cells (a type of immune system
cell) are changed in the laboratory so they will attack cancer cells. T cells are taken
from a patient's blood. Then the gene for a special receptor that binds to a certain
protein, CD19, on the patient's cancer cells is added to the T cells in the laboratory.
The special receptor is called a chimeric antigen receptor (CAR). Large numbers of the
CAR T cells are grown in the laboratory and given to the patient by infusion for
treatment of certain cancers. ICV is an injection technique that delivers the CD19-CAR T
cells directly into the cerebrospinal fluid (which flows in and around the hollow spaces
of the brain and spinal cord, and the thin layers of tissue that cover and protect the
brain and spinal cord) in the brain, through a surgically placed catheter. Giving
CD19-CAR T cells ICV may be more effective at treating patients with primary CNS lymphoma
than giving them via other methods.
Detailed description:
PRIMARY OBJECTIVES:
I. Examine and describe the safety and feasibility of ICV delivery of
CD19CAR-CD28-CD3zeta-EGFRt-expressing Tcm-enriched T-lymphocytes (CD19-CAR T cells) and
determine the recommended phase 2 dose (RP2D) in participants with primary CNS lymphoma
(PCNSL).
II. Determine the activity of ICV-delivered CD19-CAR T cells based on disease response at
the maximum tolerated dose (MTD).
SECONDAY OBJECTIVES:
I. Describe persistence, expansion and phenotype of endogenous and CD19-CAR T cells in
peripheral blood (PB), and cerebral spinal fluid (CSF), when available.
II. Describe cytokine levels (PB, CSF) over study period. III. Quantify B-cell aplasia
over the treatment period as a surrogate for targeted cytotoxicity in the periphery.
IV. Assess prolonged cytopenia based on prolonged grade 4 continuous or intermittent
anemia, neutropenia, thrombocytopenia, and hypogammaglobulinemia > 60 days or deemed
medically significant.
V. Estimate rates of disease response. VI Estimate rate of 6-month progression free
survival (PFS6mon). VII. Estimate median overall survival (OS).
EXPLORATORY OBJECTIVES:
I. Characterize changes in potential molecular and gene-analysis based indicators of
neurotoxicity in CSF and PB.
II. Describe the tumor phenotype pre- and post-therapy. III. Characterize functional and
phenotypic metabolic profile of CAR T cells pre- and post-infusion.
IV. Assess the presence and magnitude of human anti-mouse antibody (HAMA).
OUTLINE: This is a dose-escalation study followed by a dose-expansion study.
Patients may undergo catheterization, undergo leukapheresis, may receive fludarabine
intravenously (IV) and cyclophosphamide IV, and receive CD19-CAR T cells ICV on study.
Patients also undergo magnetic resonance imaging (MRI), positron emission tomography
(PET), computed tomography (CT), collection of blood samples, and CSF aspiration
throughout the trial, and lumbar puncture as clinically indicated.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Participant 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 City of Hope (COH) certified interpreter/translator to
proceed with screening and leukapheresis, while the request for a translated
full consent is processed. However, the research participant can proceed with
lymphodepletion (if applicable) and CAR T cell infusion only after the
translated full consent form is signed
- Agreement to allow the use of archival tissue from diagnostic tumor biopsies. If
unavailable exceptions may be granted with study principal investigator (PI)
approval
- Age >= 18 years
- Eastern Cooperative Oncology Group (ECOG) performance status 0 - 2
- Documented primary CNS lymphoma. Progression must be determined radiographically.
Participant must have measurable disease which could be a measurable lymphomatous
mass or, in the case of leptomeningeal only disease, measurable lymphoma cells in
CSF by flow cytometry
- Documented current CD19+ tumor expression if prior CD19 directed therapy was used
- Participant must have received and failed or have been intolerant to CNS directed
therapy like high dose methotrexate or high dose cytarabine based regimens.
Participants are not required to have failed all of these agents if, in the
investigator's opinion, they would benefit from treatment on the current protocol
- No known contraindications to leukapheresis, steroids or tocilizumab
- Participant of reproductive potential must agree to use acceptable birth control
methods throughout study therapy and for 3 months after final dose of study
treatment
- Total serum bilirubin =< 2.0 mg/dL (within 14 days of signing the screening and
leukapheresis consent)
- Patients with Gilbert syndrome may be included if their total bilirubin is =<
3.0 x upper limit of normal (ULN) and direct bilirubin =< 1.5 x ULN
- Aspartate aminotransferase (AST) =< 2.5 x ULN (within 14 days of signing the
screening and leukapheresis consent)
- Alanine aminotransferase (ALT) =< 2.5 x ULN (within 14 days of signing the screening
and leukapheresis consent)
- Creatinine clearance of >= 50 mL/min per the Cockcroft-Gault formula (within 14 days
of signing the screening and leukapheresis consent)
- Cardiac function (12 lead-electrocardiogram [ECG]) without acute abnormalities
requiring investigation or intervention (within 14 days of signing the screening and
leukapheresis consent)
- Absolute neutrophil count >= 750/uL (within 14 days of signing the screening and
leukapheresis consent)
- Hemoglobin (Hb) >= 8 g/dl (within 14 days of signing the screening and leukapheresis
consent)
- Platelet count >= 50,000/uL (within 14 days of signing the screening and
leukapheresis consent)
- Ejection fraction measured by echocardiogram or multigated acquisition scan (MUGA) >
40% (evaluation within 6 weeks of screening does not need to be repeated) (within 14
days of signing the screening and leukapheresis consent)
- Oxygen (O2) saturation > 92% not requiring oxygen supplementation (within 14 days of
signing the screening and leukapheresis consent)
- Women of childbearing potential (WOCBP): negative urine or serum pregnancy test
(within 14 days of signing the screening and leukapheresis consent)
- If the urine test is positive or cannot be confirmed as negative, a serum
pregnancy test will be required
Exclusion Criteria:
- Participants who received prior CAR T cell therapy
- Participant has not yet recovered from toxicities of prior therapy
- Participant with clinically significant arrhythmia or arrhythmias not stable on
medical management within two weeks of signing the screening and leukapheresis
consent
- Participant with known history or prior diagnosis of optic neuritis or other
immunologic or inflammatory disease affecting the central nervous system, including
seizure disorder
- Active autoimmune disease requiring systemic immunosuppressive therapy
- Needing dexamethasone more than 4mg/day (or equivalent) within 72 hours prior to
leukapheresis or CAR T cell infusion
- History of allergic reactions attributed to compounds of similar chemical or
biologic composition or other agents used in this study
- Known bleeding disorders (e.g., von Willebrand's disease) or hemophilia
- History of stroke or intracranial hemorrhage within 6 months prior to signing the
screening and leukapheresis consent
- History of other malignancies, except for malignancy surgically resected (or treated
with other modalities) with curative intent with no known active disease present for
>= 3 years, basal cell carcinoma of the skin or localized squamous cell carcinoma of
the skin
- Uncontrolled active infection
- Active hepatitis B or hepatitis C infection: subjects who are hepatitis B core
antibody (anti-HBc) positive and who are surface antigen negative will need to have
a negative polymerase chain reaction (PCR) result. Those who are hepatitis B surface
antigen (HbsAg) positive or hepatitis B PCR positive will be excluded
- Subjects who are hepatitis B core antibody positive (or have a known history of
hepatitis B virus [HBV] infection) should be monitored quarterly with a
quantitative PCR test for HBV deoxyribonucleic acid (DNA). HBV monitoring
should last until 12 months after last dose of study drug. Any subject with a
rising viral load (above lower limit of detection) should discontinue study
drug and have antiviral therapy instituted and a consultation with a physician
with expertise in managing hepatitis B. Subjects who are core antibody (Ab)
positive at study enrollment are strongly recommended to start Entecavir before
start and until completion of study treatment
- Subjects who are hepatitis C antibody positive will need to have a negative PCR
result. Those who are hepatitis C PCR positive will be excluded
- Subjects who are hepatitis C antibody positive will need to have a negative PCR
result. Those who are hepatitis C PCR positive will be excluded
- Human immunodeficiency virus (HIV) infection
- Active significant bacterial, fungal or viral (other than those listed) infections
- Any other condition that would, in the investigator's judgment, contraindicate the
subject's participation in the clinical study due to safety concerns with clinical
study procedures
- Prospective participants who, in the opinion of the investigator, may not be able to
comply with all study procedures (including compliance issues related to
feasibility/logistics)
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
City of Hope Medical Center
Address:
City:
Duarte
Zip:
91010
Country:
United States
Status:
Recruiting
Contact:
Last name:
Tanya Siddiqi
Phone:
626-803-3458
Email:
tsiddiqi@coh.org
Investigator:
Last name:
Tanya Siddiqi
Email:
Principal Investigator
Start date:
June 29, 2023
Completion date:
May 21, 2026
Lead sponsor:
Agency:
City of Hope Medical Center
Agency class:
Other
Collaborator:
Agency:
National Cancer Institute (NCI)
Agency class:
NIH
Source:
City of Hope Medical Center
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05625594
