Trial Title:
Humanized CD19-Specific CAR T Cells for the Treatment of Patients With Positive Relapsed or Refractory CD19 Positive B-Cell Acute Lymphoblastic Leukemia
NCT ID:
NCT06447987
Condition:
Recurrent Acute Lymphoblastic Leukemia
Refractory Acute Lymphoblastic Leukemia
Conditions: Official terms:
Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Cyclophosphamide
Fludarabine
Cetuximab
Antineoplastic Agents, Immunological
Antibodies
Immunoglobulins
Antibodies, Monoclonal
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Sequential Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Procedure
Intervention name:
Allogeneic Hematopoietic Stem Cell Transplantation
Description:
Undergo alloHCT
Arm group label:
Treatment (huCD19-CAR T)
Other name:
Allogeneic
Other name:
Allogeneic Hematopoietic Cell Transplantation
Other name:
Allogeneic Stem Cell Transplantation
Other name:
HSC
Other name:
HSCT
Other name:
Stem Cell Transplantation, Allogeneic
Intervention type:
Procedure
Intervention name:
Biospecimen Collection
Description:
Undergo blood sample collection
Arm group label:
Treatment (huCD19-CAR T)
Other name:
Biological Sample Collection
Other name:
Biospecimen Collected
Other name:
Specimen Collection
Intervention type:
Procedure
Intervention name:
Bone Marrow Aspiration
Description:
Undergo bone marrow biopsy and aspiration
Arm group label:
Treatment (huCD19-CAR T)
Intervention type:
Procedure
Intervention name:
Bone Marrow Biopsy
Description:
Undergo bone marrow biopsy and aspiration
Arm group label:
Treatment (huCD19-CAR T)
Other name:
Biopsy of Bone Marrow
Other name:
Biopsy, Bone Marrow
Intervention type:
Biological
Intervention name:
CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T-lymphocytes
Description:
Given IV
Arm group label:
Treatment (huCD19-CAR T)
Other name:
CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T Cells
Other name:
CD19R(EQ)28zeta/EGFRt+ Naive and Memory T Cells
Other name:
CD19R(EQ)28zetaEGFRt+ Tn/mem Cells
Intervention type:
Biological
Intervention name:
Cetuximab
Description:
Given IV
Arm group label:
Treatment (huCD19-CAR T)
Other name:
C225
Other name:
Cetuximab Biosimilar CDP-1
Other name:
Cetuximab Biosimilar CMAB009
Other name:
Cetuximab Biosimilar KL 140
Other name:
Chimeric Anti-EGFR Monoclonal Antibody
Other name:
Chimeric MoAb C225
Other name:
Chimeric Monoclonal Antibody C225
Other name:
Erbitux
Other name:
IMC-C225
Intervention type:
Procedure
Intervention name:
Computed Tomography
Description:
Undergo CT and PET
Arm group label:
Treatment (huCD19-CAR T)
Other name:
CAT
Other name:
CAT Scan
Other name:
Computed Axial Tomography
Other name:
Computerized Axial Tomography
Other name:
Computerized axial tomography (procedure)
Other name:
Computerized Tomography
Other name:
Computerized Tomography (CT) scan
Other name:
CT
Other name:
CT Scan
Other name:
tomography
Intervention type:
Drug
Intervention name:
Cyclophosphamide
Description:
Given IV
Arm group label:
Treatment (huCD19-CAR T)
Other name:
(-)-Cyclophosphamide
Other name:
2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
Other name:
Asta B 518
Other name:
B-518
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
Other name:
WR-138719
Intervention type:
Procedure
Intervention name:
Echocardiography
Description:
Undergo ECHO
Arm group label:
Treatment (huCD19-CAR T)
Other name:
EC
Intervention type:
Drug
Intervention name:
Fludarabine
Description:
Given IV
Arm group label:
Treatment (huCD19-CAR T)
Other name:
Fluradosa
Intervention type:
Procedure
Intervention name:
Leukapheresis
Description:
Undergo leukapheresis
Arm group label:
Treatment (huCD19-CAR T)
Other name:
Leukocytopheresis
Other name:
Therapeutic Leukopheresis
Intervention type:
Procedure
Intervention name:
Magnetic Resonance Imaging
Description:
Undergo MRI
Arm group label:
Treatment (huCD19-CAR T)
Other name:
Magnetic Resonance
Other name:
Magnetic Resonance Imaging (MRI)
Other name:
Magnetic resonance imaging (procedure)
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:
MRIs
Other name:
NMR Imaging
Other name:
NMRI
Other name:
Nuclear Magnetic Resonance Imaging
Other name:
sMRI
Other name:
Structural MRI
Intervention type:
Procedure
Intervention name:
Multigated Acquisition Scan
Description:
Undergo MUGA
Arm group label:
Treatment (huCD19-CAR T)
Other name:
Blood Pool Scan
Other name:
Equilibrium Radionuclide Angiography
Other name:
Gated Blood Pool Imaging
Other name:
Gated Heart Pool Scan
Other name:
MUGA
Other name:
MUGA Scan
Other name:
Multi-Gated Acquisition Scan
Other name:
Radionuclide Ventriculogram Scan
Other name:
Radionuclide Ventriculography
Other name:
RNVG
Other name:
SYMA Scanning
Other name:
Synchronized Multigated Acquisition Scanning
Intervention type:
Procedure
Intervention name:
Positron Emission Tomography
Description:
Undergo PET/CT
Arm group label:
Treatment (huCD19-CAR T)
Other name:
Medical Imaging, Positron Emission Tomography
Other name:
PET
Other name:
PET Scan
Other name:
Positron emission tomography (procedure)
Other name:
Positron Emission Tomography Scan
Other name:
Positron-Emission Tomography
Other name:
proton magnetic resonance spectroscopic imaging
Other name:
PT
Summary:
This phase Ib trial tests the safety, side effects, and effectiveness of humanized
(hu)CD19-chimeric antigen receptor (CAR) T cell therapy in treating patients with CD19
positive B-cell acute lymphoblastic leukemia (ALL) that has come back after a period of
improvement (relapsed) or that has not responded to previous treatment (refractory). CAR
T-cell therapy is a 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,
such as 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
huCD19 positive CAR T cells are grown in the laboratory and given to the patient by
infusion for treatment of certain cancers. Chemotherapy drugs, such as fludarabine and
cyclophosphamide, work in different ways to stop the growth of cancer cells, either by
killing the cells, by stopping them from dividing, or by stopping them from spreading.
huCD19-CAR T cell therapy may be safe, tolerable and effective in treating patients with
relapsed or refractory CD19 positive ALL.
Detailed description:
PRIMARY OBJECTIVES:
I. Assess the safety and tolerability of Tn/mem-enriched
huCD19(VH4VK1)(dCH2)BBzeta/EGFRt+ T cells (huCD19 CAR T) as single-dose monotherapy by
evaluation of toxicities including type, frequency, severity, attribution, time course
and duration.
II. Determine the maximum feasible dose (MFD)/recommended phase 2 dose(s) schedule (RP2D)
of huCD19 CAR T as single-dose monotherapy on relapsed/refractory (r/r) ALL patients.
SECONDARY OBJECTIVES:
I. Obtain preliminary estimates of complete remission (complete remission [CR] /complete
response with incomplete bone marrow recovery [CRi]) rate(s).
II. Overall response rate (CR, CRi): best response. III. Duration of response (CR, CRi).
IV. Minimal residual disease (MRD)- negative CR/CRi. V. The number and rate of bridging
to transplant. VI. Estimate the progression free survival (PFS) and overall survival (OS)
rate, at 6-months and 1-year post (first) huCD19 CAR T cell infusion.
EXPLORATORY OBJECTIVES:
I. Access the expansion and persistence of T cell via flow cytometry in blood, bone
marrow (BM) and cerebrospinal fluid (CSF).
II. Assess the phenotype and activation status of CAR T via flow cytometry, polymerase
chain reaction (PCR), and cytokine analysis.
III. Assess CAR T cell clonal expansion and repertoires of endogenous T cells. IV. Assess
immunophenotyping and functional analyses of CAR T cell products. V. Determine the role
of the immunologic milieu. VI. Evaluation of B cell aplasia. VII. Serum cytokine
measurement. VIII. Tumor antigen analysis. XIV. Evaluation of Immunogenicity by
enzyme-linked immunosorbent assay (ELISA). X. For subjects who receive cetuximab for CAR
T cell ablation, assess the activity of infusional cetuximab to eliminate transferred
huCD19-CAR T cells.
OUTLINE: This is a dose-escalation study of huCD19-CAR T, followed by a dose-expansion
study.
Patients undergo leukapheresis then receive lymphodepletion chemotherapy with fludarabine
ntravenously (IV) and cyclophosphamide IV on days -5, -4 and -3 and huCD19-CAR T IV cells
over 10-15 minutes on day 0. Patients may optionally receive cetuximab IV over 60-120
minutes at least 28 days post T cell infusion and undergo allogeneic hematopoietic cell
transplantation (alloHCT). Additionally, patients undergo echocardiography (ECHO) or
multigated acquisition scan ((MUGA), computed tomography (CT) or positron emission
tomography (PET)/CT and optional magnetic resonance imaging (MRI) on study and bone
marrow biopsy and aspiration and blood sample collection throughout the study.
After completion of study treatment, patients are followed up monthly for 1 year then
yearly for up to 15 years.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Documented informed consent of the participant
- Agreement to allow the use of archival tissue from diagnostic tumor biopsies.
- If unavailable, exceptions may be granted with study principal investigator
(PI) approval
- 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 is allowed to
proceed with lymphodepletion and T cell infusion only after the translated full
consent form is signed
- Age: ≥ 18 years
- Eastern Cooperative Oncology Group (ECOG) 0-2 / Karnofsky performance status (KPS) ≥
70
- Histologically confirmed CD19+ relapsed/refractory ALL with at least 2 prior lines
of therapy
- Prior alloHCT > 100 days prior to enrollment may be considered a prior line of
therapy
- Research participants with confirmed 1st or higher relapse of disease by morphology,
cytogenetics or molecular, or research participants with refractory or residual
disease
- Participants with central nervous system (CNS) involvement by leukemia (CNS2
and CNS3) may be considered eligible after discussions with the study team
- Patients with only MRD+ disease may be eligible
- Patients with isolated extramedullary disease may also be eligible
- Total bilirubin ≤ 2.0 X upper limit of normal (ULN) (unless has Gilbert's disease or
related to leukemia involving the liver)
- Aspartate aminotransferase (AST) ≤ 2.5 x ULN (unless related to leukemia involving
the liver)
- Alanine aminotransferase (ALT) ≤ 2.5 x ULN (unless related to leukemia involving the
liver)
- Creatinine clearance of ≥ 50 mL/min per 24-hour urine test or the Cockcroft-Gault
formula
- Left ventricular ejection fraction (LVEF) ≥ 45%
- Note: To be performed within 28 days prior to start of protocol therapy
- Cardiac function (12 lead-electrocardiogram [ECG]): Corrected QT interval (QTc) must
be ≤ 480 msec
- Oxygen (O2) saturation > 92% on room air
- Note To be performed within 28 days prior to start of protocol therapy
- Seronegative for HIV quantitative polymerase chain reaction (qPCR), hepatitis C
virus (HCV), active hepatitis B virus (HBV) (surface antigen negative), and syphilis
(rapid plasma reagin [RPR])
- If positive, hepatitis C ribonucleic acid (RNA) quantitation must be performed.
OR
- If seropositive for HIV, HCV or HBV, nucleic acid quantitation must be
performed. The viral load must be undetectable
- Meets other institutional and federal requirements for infectious disease titer
requirements
- Note Infectious disease testing to be performed within 28 days prior to start
of protocol therapy
- Women of childbearing potential (WOCBP): negative urine or serum pregnancy test. If
the urine test is positive or cannot be confirmed as negative, a serum pregnancy
test will be required
- Agreement by females and males of childbearing potential to use an effective method
of birth control or abstain from heterosexual activity for the course of the study
through at least 6 months after the last dose of protocol therapy
- Childbearing potential defined as not being surgically sterilized (men and
women) or have not been free from menses for > 1 year (women only)
- ELIGIBILITY TO PROCEED WITH PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMC) COLLECTION FOR
CAR T CELL MANUFACTURING
- Research participant has signed the 'screening and leukapheresis' informed consent
- Research participant must have appropriate venous access, have a central line or be
willing to undergo central or temporary line placement
- The last dose of systemic chemotherapy must be at least 2 weeks before the
leukapheresis procedure with the following exceptions:
- Steroids and vincristine are allowed up to 7 days prior to leukapheresis.
- Intrathecal chemotherapy is allowed up to 3 days prior to leukapheresis.
- Tyrosine kinase inhibitors are allowed up to 48 hours prior to leukapheresis.
- Hydrea is allowed up to 48 hours prior to leukapheresis.
- The research participant cannot be on ≥ 7.5 mg prednisone or equivalent doses
of other corticosteroids at the time of leukapheresis. Note: Topical and
inhaled corticosteroids in standard doses and physiologic replacement for
subjects with adrenal insufficiency are allowed
- The last dose of prior targeted agents, immunotherapy or radiation must be at least
2 weeks before the leukapheresis procedure
- If the research participant has undergone prior alloHCT, 100 days must have elapsed
since allogeneic stem cell transplant to undergo PBMC collection for CAR T cell
manufacturing
- ELIGIBILITY TO UNDERGO LYMPHODEPLETION
- Research participant's absolute leukemic blast count does not exceed 10,000 cells/uL
- The last dose of chemotherapy, maintenance therapy, radiation therapy, biological
therapy, and/or immunotherapy must have been 7 days prior to start of
lymphodepletion
- The following washout periods must be met:
- Corticosteroids 3 days
- Biologic agents 3 half lives
- Oral chemotherapeutic agents 3 half lives
- Intrathecal chemotherapy 3 days
- Chemo and/or immunotherapy 2 weeks
- Local radiation to sites 7 days
- Non myeloablative agents 7 days
- Investigational agents 2 weeks, or at least 3 half lives
- Hydroxyurea no washout period
- Research participant has a released cryopreserved CAR T cell product for CAR T cell
infusion on approximately day 0 (performed no more than 7 days prior to start of
lymphodepletion)
- ECOG < 2 / KPS ≥ 70 (performed no more than 7 days prior to start of
lymphodepletion)
- No ongoing post treatment ≥ grade 3 non-heme toxicities (with exception of grade 3
glucose intolerance, cholesterol, triglyceride, peripheral neuropathy, and
hyperglycemia) (performed no more than 7 days prior to start of lymphodepletion)
- Research participant does not require supplemental oxygen to keep saturation greater
than or equal to 92% and/or does not have any radiographic abnormalities on chest
x-ray that are progressive (performed no more than 7 days prior to start of
lymphodepletion)
- Research participant does not require pressor support and/or does not have
symptomatic cardiac arrhythmias (performed no more than 7 days prior to start of
lymphodepletion)
- Research participant does not have a fever exceeding 38.5 degree Celsius (C); there
is an absence of positive blood cultures for bacteria, fungus, or virus within
48-hours prior to lymphodepletion and/or there aren't any indications of meningitis
(performed no more than 7 days prior to start of lymphodepletion)
- Research participant serum total bilirubin does not exceed 2.5X normal limit or
transaminases do not exceed 3X normal limit unless related to underlying leukemia
(to be discussed at the discretion of the PI/study team) (performed no more than 7
days prior to start of lymphodepletion)
- Note: in the event a participant has elevated levels of liver enzymes possibly
related to underlying disease/disease progression, the participant will still
be considered eligible
- Research participant serum creatinine ≤ 2 mg/dL (performed no more than 7 days prior
to start of lymphodepletion)
- Research participant does not have uncontrolled seizure activity (performed no more
than 7 days prior to start of lymphodepletion)
- ELIGIBILITY TO PROCEED WITH CAR T CELL INFUSION
- No ongoing post treatment ≥ grade 3 non-heme toxicities (with exception of grade 3
glucose intolerance, cholesterol, triglyceride, peripheral neuropathy, and
hyperglycemia)
- Prednisone (or prednisone equivalent) dose of ≤ 7.5 mg/kg/day is allowed
- Prohibited medications have not been administered
- KPS ≥ 70
- No untreated or active systemic infection
- No Class III/IV cardiovascular disability according to the NYHA Classification
- Research participant does not require supplemental oxygen to keep saturation greater
than or equal to 92% and/or does not have 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 degree 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 does not exceed 2.5X normal limit or
transaminases do not exceed 3X normal limit unless related to underlying leukemia
(to be discussed at the discretion of the PI/study team)
- Research participant serum creatinine ≤ 2 mg/dL
- Research participant does not have uncontrolled seizure activity
- ELIGIBILITY TO PROCEED WITH OPTIONAL CAR T CELL ABLATION
- Research participant has > 1% CAR T cells in the peripheral blood
- No known hypersensitivity to cetuximab
- Not requiring supplemental oxygen or mechanical ventilation, oxygen saturation 92%
or higher on room air
- Not requiring pressor support, no symptomatic cardiac arrhythmias, no acute coronary
syndrome, or uncontrolled hypertension
- Serum creatinine did NOT increase by more than 2.5 fold from base line (at time of
screening )
- Adequate liver function defined as total bilirubin < 3.0 mg/dl, AST < 5 x ULN; ALT <
5 x ULN
- Research participant without clinically significant encephalopathy/new focal
deficits
- No clinical evidence of uncontrolled active infectious process
Exclusion Criteria:
- Allogeneic stem cell transplant within 100 days at the time of enrollment
- Received prior CAR T therapy within 90 days of enrollment
- EXCEPTION: Participants who have previously received B-cell-activating factor
receptor (BAFFR)-CAR T cells will be excluded from this study
- Failure of research participant to understand the basic elements of the protocol
and/or the risks/benefits of participating in this phase I study
- History of allergic reactions attributed to compounds of similar chemical or
biologic composition to study agent(s)
- History or presence of clinically relevant CNS pathology such as uncontrolled
seizure disorder, recent stroke, severe brain injuries, dementia, cerebellar disease
or psychosis
- Autoimmune disease or active graft versus host disease (GVHD) requiring systemic
immunosuppressant therapy
- Class III/IV cardiovascular disability according to the New York Heart Association
(NYHA) Classification
- History of other malignancies, except for malignancy surgically resected (or treated
with other modalities) with curative intent, basal cell carcinoma of the skin or
localized squamous cell carcinoma of the skin; non-muscle invasive bladder cancer;
malignancy treated with curative intent with no known active disease present for ≥ 2
years
- Clinically significant uncontrolled illness
- Active systemic uncontrolled infection requiring antibiotics
- Known history of immunodeficiency virus (HIV) or 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 HBV infection) should be monitored quarterly with a
quantitative PCR test for HBV deoxyribonucleic acid (DNA). HBV monitoring
should last until 12 months after the 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
- Females only: Pregnant or breastfeeding
- Concurrent use of systemic steroids or chronic use of immunosuppressant medications.
Recent or current use of topical or inhaled steroids is not exclusionary.
Physiologic replacement of steroids (prednisone ≤ 7.5 mg /day or equivalent) is
allowed
- Any other condition that would, in the investigator's judgment, contraindicate the
patient'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:
Ibrahim Aldoss
Phone:
626-218-2405
Email:
ialdoss@coh.org
Investigator:
Last name:
Ibrahim Aldoss
Email:
Principal Investigator
Start date:
December 15, 2024
Completion date:
December 5, 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/NCT06447987
