Trial Title:
CD19-directed CAR-T Cell Therapy for R/R Acute Leukemia and Lymphoma
NCT ID:
NCT06101381
Condition:
Leukemia, Acute Lymphoblastic
Lymphoma, Non-Hodgkin
Conditions: Official terms:
Lymphoma
Leukemia
Lymphoma, Non-Hodgkin
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Conditions: Keywords:
Cell therapy
Chimeric antigen receptor T cell
CAR-T cell
CD19
Lymphoma
Acute Leukemia
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Biological
Intervention name:
CART-19
Description:
The academic CART-19 consists of autologous T lymphocytes transduced with a lentiviral
vector to express a second-generation chimeric antigen receptor with a single chain
variable fragment (scFv) targeting the CD19 antigen conjugated with 4-1BB co-stimulatory
and CD3z signaling domains.
Arm group label:
CD19-directed CAR-T cell
Summary:
The goal of this prospective, multicentric, single-arm, phase I/II clinical trial is to
evaluate the safety and efficacy of a novel CD19-directed CAR-T cell locally produced in
an academic institution in Brazil in patients with refractory or relapsed acute
lymphoblastic leukemia or non-Hodgkin lymphoma.
Participants will receive a single intravenous infusion of an autologous academic
anti-CD19 CAR-T cell and will be followed for 5 years.
Detailed description:
Eighty-one patients with refractory/relapsed (R/R) B acute lymphoblastic leukemia (B-ALL)
or non-Hodgkin lymphoma (B-NHL) will be included in this multicentric, phase I/II
clinical trial to evaluate the safety and efficacy of a novel academic CD19-directed
CAR-T cell developed in Brazil.
After the inclusion of the patient, lymphocyte apheresis will be performed for lymphocyte
collection, followed by activation, transduction with a lentiviral vector, and expansion
of produced CAR-T cells.
The patient will be hospitalized and receive lymphodepleting chemotherapy started five
days before CAR-T cells infusion, with cyclophosphamide (300 mg/m2/day) and fludarabine
(30 mg/m2/day) for three days. On Day 0, CAR-T cells will be intravenously administered
over 20-30 minutes. The optimal CAR-T cell dose will be 1,7 to 5,4 x106 cells/kg, for ALL
patients, and 0,6 to 6,0 x 108 cells (total dose) for NHL patients, but any dose higher
than 0,2 x 106 cells/kg (for patients < 50 Kg) or 0,14 x 106 cells/kg and 0,1 x 108 cells
(total dose) (for patients ≥ 50Kg), and lower than the maximal 2,6 x 108 cells (total
dose) will be infused, depending on the obtained cellular product. During and after
infusion, the patient will be monitored for signs and symptoms of toxicity and will
remain hospitalized for at least two weeks. All patients will receive anti-viral and
anti-pneumocystis prophylaxis. They will be monitored to evaluate treatment efficacy, and
acute and late toxicities for five years after infusion.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
For non-Hodgkin Lymphomas (B-NHL):
- Provision of signed Informed Consent form;
- Age between 18 and 70 years;
- Performance status according to the Eastern Cooperative Oncology Group < 2;
- Relapsed or refractory B-NHL of the following types (confirmed by biopsy):
- Diffuse large B-cell lymphoma (DLBCL, NOS);
- High-grade B-cell lymphoma (HGBCL);
- Diffuse large B-cell lymphoma/high-grade B-cell lymphoma with MYC and BCL-2
rearrangement;
- Follicular lymphoma (FL) grade 3B; or
- Transformed follicular lymphoma (tFL)
- Refractory or relapsed to two or more lines of systemic therapy, with at least one
scheme containing an anti-CD20 monoclonal antibody and anthracycline, as defined
below:
- Refractoriness: partial response (PR), stable disease (SD), or progressive
disease (PD) as the best response to the last treatment, assessed by PET-CT,
according to the Lugano criteria and confirmed by a new biopsy.
- Relapsed disease: disease reappearance after obtaining a complete response to
the last treatment, assessed by PET-CT, according to the Lugano criteria and
confirmed by a new biopsy.
- Have performed, or be ineligible for, autologous hematopoietic progenitor cell
transplantation (ASCT). Ineligibility is defined by:
- Lack of at least partial response after salvage chemotherapy; or
- Failure to mobilize and/or collect hematopoietic progenitor cells (HPC), as
defined by the investigator.
- Measurable disease, defined as:
- Nodal lesions >15 mm in the long axis, regardless of the length of the short
axis, and/or
- Extranodal lesions (outside lymph node or nodal mass, but including liver and
spleen) >10 mm in long axis, regardless of the length of the short axis.
- Adequate organ function:
Renal function defined as:
- estimated glomerular filtration rate (eGFR) ≥ 40 mL/min/1.73 m2
Hepatic function defined as:
- Alanine Transaminase (ALT) and Aspartate Transaminase (AST) ≤ 2.5 × ULN; and
- Total bilirubin ≤ 1.5 × ULN, except for patients with Gilbert syndrome.
Hematologic Function (regardless of transfusions for 14 days) defined as:
- Absolute neutrophil count (ANC) >500/uL
- Platelets ≥ 50,000/uL
- Hemoglobin >7.0 g/dl
- In women of childbearing potential, willingness to use effective means of birth
control for 1 year after CAR-T cell infusion.
- In male participants, willingness to use a barrier birth control method for 1
year after CAR-T cell infusion
- Able to comply with inpatient treatment, outpatient treatment, laboratory
monitoring, and required clinic visits for the duration of study participation.
For Acute Lymphoblastic Leukemia (B-ALL):
- Provision of signed Informed Consent form;
- Age ≥ 3 and < 25 years;
- Performance status < 2, according to the Eastern Cooperative Oncology Group for
patients ≥ 16 years old, or ≥ 50%, according to the Lansky performance status for
patients younger than 16 years old;
- Relapsed or refractory CD19 positive B-ALL, with documentation of CD19 disease
expression within 3 months of screening visit.
- Relapsed or refractory disease as defined below;
- Failure to obtain hematologic complete remission (bone marrow with < 5%
lymphoblasts by morphologic assessment) after 2 distinct chemotherapy lines; or
- Relapsed or refractoriness after at least 1 previous chemotherapy regimen and
ineligibility for allogeneic hematopoietic progenitor cell transplantation
(HSCT) due to lack of available donor (including alternative donors),
comorbidity, have previously undergone or refused HSCT; or
- Relapsed disease ≥ 6 months after HSCT; or
- Relapsed or refractoriness after ≥ TKi for Philadelphia-positive B-ALL.
- Bone marrow with ≥ 5% lymphoblasts by morphologic assessment within 30 days from
screening
- Adequate organ function:
Renal function defined as:
- Estimated glomerular filtration rate (eGFR) ≥ 40 mL/min/1.73 m2
Hepatic function defined as:
- Alanine Transaminase (ALT) and Aspartate Transaminase (AST) ≤ 5 × ULN; and
- Total bilirubin ≤ 2 × ULN, except for patients with Gilbert syndrome.
- In women of childbearing potential, willingness to use effective means of birth
control for 1 year after CAR-T cell infusion.
- In male participants, willingness to use a barrier birth control method for 1
year after CAR-T cell infusion
- Able to comply with outpatient treatment, laboratory monitoring, and required
clinic visits for the duration of study participation. duration of the parent
study and the long-term follow-up observational study
Exclusion Criteria:
For non-Hodgkin Lymphomas (B-NHL):
- Previous or concurrent cancer distinct from B-NHL within 2 years before screening,
except for the following:
- Curatively treated nonmelanomatous skin cancer;
- Curatively treated cervical carcinoma in situ;
- Localized breast cancer treated with curative intent with no evidence of active
disease; or
- Localized prostate cancer undergoing active surveillance or anti-androgenic
therapy, without evidence of metastatic disease.
- Syndromes and/or genetic diseases with impact on the hematopoietic system, including
Down's syndrome, Fanconi anemia, telomeropathies, Li Fraumeni, Blackfan-Diamond
anemia, or congenital immunodeficiencies;
- History of previous CAR-T therapy;
- History of previous solid organ transplantation;
- Active central nervous system (CNS) involvement by disease, detected by image or
cytology/immunophenotyping of cerebrospinal fluid (CSF);
- Primary central nervous system lymphoma (PCNSL);
- Primary mediastinal large B cell lymphoma (PMBCL);
- Evidence of uncontrolled systemic infection (viral, bacterial, or fungal) which
requires IV antibiotics, within 2 weeks before the screening visit;
- Known HIV infection;
- Known HTLV I and II infection;
- History of previous tuberculosis;
- Positive Chagas disease serology;
- Hepatitis B or hepatitis C testing indicating active/ongoing infection, as defined
as:
- HBV: Patients with positive HBsAg are excluded. Patients with positive anti-HBc
and negative HBsAg require hepatitis B PCR evaluation before randomization.
Patients who are hepatitis B PCR-positive will be excluded.
- HCV: Patients with positive hepatitis C antibody may be enrolled with a
negative result for hepatitis C RNA before study inclusion. Patients who are
hepatitis C RNA-positive will be excluded.
- History of a symptomatic CNS disease (or which required treatment within the past
year), such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease;
- Significant cardiovascular disease defined as ≥ grade 3 New York Heart Association
functional classification system of heart failure, history of myocardial infarction,
uncontrolled or symptomatic arrhythmias, or unstable angina within the past 6 months
before the screening;
- Chronic lung disease, with hypoxemia (Oxygen saturation measured by pulse oximetry >
93% on room air), or uncontrolled within 4 weeks before the screening visit
- History of an autoimmune disease (including, but not limited to, myasthenia gravis,
myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,
inflammatory bowel disease, vascular thrombosis associated with antiphospholipid
syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome,
multiple sclerosis, vasculitis, or glomerulonephritis) with end-organ damage or
requiring systemic immunosuppression/systemic disease-modifying agents in the 2
years preceding the screening visit;
- Participants with hypothyroidism receiving a stable dose of thyroid replacement
hormone may be eligible.
- Participants with controlled type 1 diabetes mellitus who are on an insulin
regimen are eligible for the study.
- History of deep vein thrombosis or pulmonary embolism within 6 months before the
screening visit, or need to use systemic anticoagulation at the time of screening
for any other reason;
- Major surgery within 4 weeks of the screening visit;
- History or suspicion of hemophagocytic lymphohistiocytosis (HLH);
- Vaccination with a live or attenuated virus vaccine within one month before the
screening visit;
- Patients with known hypersensitivity, including anaphylaxis, to any component of the
investigational treatment;
- Pregnancy, lactation, or plan to get pregnant during the study or within 12 months
after CAR-T cell infusion;
- In women of childbearing potential a negative serologic pregnancy test must be
obtained 7 days before CAR-T cell infusion;
- Women of childbearing potential, and all male participants, must be willing to
observe barrier and highly effective birth control methods (outlined in the study
protocol) for 12 months following CAR-T cell infusion;
- Presence of any other medical condition that in the investigator's opinion may
interfere with the safety or effectiveness evaluation of the study;
- Life expectancy less than 12 weeks, by investigator assessment.
For Acute Lymphoblastic Leukemia (B-ALL)::
- Previous or concurrent cancer distinct from B-NHL within 2 years before screening,
except for the following:
- Curatively treated nonmelanomatous skin cancer;
- Curatively treated cervical carcinoma in situ;
- Localized breast cancer treated with curative intent with no evidence of active
disease; or
- Localized prostate cancer undergoing active surveillance or anti-androgenic
therapy, without evidence of metastatic disease.
- Syndromes and/or genetic diseases with impact on the hematopoietic system, including
Down's syndrome, Fanconi anemia, telomeropathies, Li Fraumeni, Blackfan-Diamond
anemia, or congenital immunodeficiencies;
- Isolated extramedullary disease;
- Active central nervous system (CNS) involvement by disease (CNS-3 according to NCCN
guideline), detected by cytology/immunophenotyping of cerebrospinal fluid (CSF)
within 30 days from screening visit.
- Patients with CNS-1 and CNS-2 within 30 days from screening visit may be
enrolled;
- Burkitt's Leukemia/Lymphoma
- Active acute or chronic graft-versus-host disease (GvHD), or controlled with
immunosuppressants in the previous 12 weeks before the screening visit;
- Failure to obtain hematologic complete remission (bone marrow with < 5% lymphoblasts
by morphologic assessment) after an anti-CD19 antibody-containing treatment (e.g.
Blinatumomab);
- History of previous CAR-T therapy;
- History of previous solid organ transplantation;
- Evidence of uncontrolled systemic infection (viral, bacterial, or fungal) which
requires IV antibiotics, within 2 weeks before the screening visit;
- Known HIV infection;
- Known HTLV I and II infection;
- History of previous tuberculosis;
- Positive Chagas' disease serology;
- Hepatitis B or hepatitis C testing indicating active/ongoing infection, as defined
as:
- HBV: Patients with positive HBsAg are excluded. Patients with positive anti-HBc
and negative HBsAg require hepatitis B PCR evaluation before randomization.
Patients who are hepatitis B PCR-positive will be excluded.
- HCV: Patients with positive hepatitis C antibody may be enrolled with a
negative result for hepatitis C RNA before study inclusion. Patients who are
hepatitis C RNA-positive will be excluded.
- History of a symptomatic CNS disease (or which required treatment within the past
year), such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease;
- Significant cardiovascular disease defined as ≥ grade 3 New York Heart Association
functional classification system of heart failure, history of myocardial infarction,
uncontrolled or symptomatic arrhythmias, or unstable angina within the past 6 months
before the screening;
- Chronic lung disease, with hypoxemia (Oxygen saturation measured by pulse oximetry >
93% on room air), or uncontrolled within 4 weeks before the screening visit
- History of an autoimmune disease (including, but not limited to, myasthenia gravis,
myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,
inflammatory bowel disease, vascular thrombosis associated with antiphospholipid
syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome,
multiple sclerosis, vasculitis, or glomerulonephritis) with end-organ damage or
requiring systemic immunosuppression/systemic disease-modifying agents in the 2
years preceding the screening visit;
- Participants with hypothyroidism receiving a stable dose of thyroid replacement
hormone may be eligible.
- Participants with controlled type 1 diabetes mellitus who are on an insulin
regimen are eligible for the study.
- History of deep vein thrombosis or pulmonary embolism within 6 months before the
screening visit, or need to use systemic anticoagulation at the time of screening
for any other reason;
- Major surgery within 4 weeks of the screening visit;
- History or suspicion of hemophagocytic lymphohistiocytosis (HLH);
- Vaccination with a live or attenuated virus vaccine within one month before the
screening visit;
- Patients with known hypersensitivity, including anaphylaxis, to any component of the
investigational treatment;
- Pregnancy, lactation, or plan to get pregnant during the study or within 12 months
after CAR-T cell infusion;
- In women of childbearing potential a negative serologic pregnancy test must be
obtained 7 days before CAR-T cell infusion;
- Women of childbearing potential, and all male participants, must be willing to
observe barrier and highly effective birth control methods (outlined in the study
protocol) for 12 months following CAR-T cell infusion;
- Presence of any other medical condition that in the investigator's opinion may
interfere with the safety or effectiveness evaluation of the study;
- Life expectancy less than 12 weeks, by investigator assessment.
Gender:
All
Minimum age:
3 Years
Maximum age:
70 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
Ribeirao Preto School of Medicine, University of Sao Paulo
Address:
City:
Ribeirao Preto
Zip:
14048-900
Country:
Brazil
Contact:
Last name:
Diego V Cle, MD, PhD, MBA
Phone:
+551621019300
Email:
terapia@hemocentro.fmrp.usp.br
Contact backup:
Last name:
Camila D Donadel, MS
Phone:
+551621019300
Email:
terapia@hemocentro.fmrp.usp.br
Start date:
October 2023
Completion date:
October 2028
Lead sponsor:
Agency:
University of Sao Paulo
Agency class:
Other
Collaborator:
Agency:
Blood Center of Ribeirao Preto
Agency class:
Other
Collaborator:
Agency:
Hospital das Clínicas de Ribeirão Preto
Agency class:
Other
Source:
University of Sao Paulo
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06101381
