Trial Title:
A Phase I Clinical Trial Using Genetically Engineered Autologous T Cells to Express Chimeric Antigen Receptor (CAR) for Treatment of Patients With Refractory or Relapsed CD19-positive B Lymphoid Malignancies
NCT ID:
NCT05705570
Condition:
Acute Lymphoblastic Leukemia, in Relapse
Acute Lymphoblastic Leukemia Refractory
B-cell Lymphoma Recurrent
B-cell Lymphoma Refractory
Chronic Lymphocytic Leukemia Recurrent
Chronic Lymphocytic Leukemia Refractory
Conditions: Official terms:
Lymphoma
Leukemia
Neoplasms
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Lymphoma, B-Cell
Leukemia, Lymphocytic, Chronic, B-Cell
Recurrence
Cyclophosphamide
Fludarabine
Conditions: Keywords:
CAR T cell
CD19+ B-cell Malignancies
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Not yet recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Intervention model description:
A phase I study, with a "3+3" dose escalation design
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Cyclophosphamide
Description:
Cyclophosphamide 60mg/Kg on day -6
Arm group label:
Cyclophosphamide + Fludarabine + Infusion of CAR-T Cells
Intervention type:
Drug
Intervention name:
Fludarabine
Description:
Fludarabine 25mg/m^2 IV on days -5 to -3
Arm group label:
Cyclophosphamide + Fludarabine + Infusion of CAR-T Cells
Intervention type:
Biological
Intervention name:
Chimeric antigen receptor T cells to be implemented in a "3 + 3" design on day 0
Description:
Level -1 (1 x 105 cells/kg)
Level 1 [Starting dose] (5 x 105 cells/kg)
Level 2 (1 x 106 cells/kg)
Level 3 (2 x 106 cells/kg)
Arm group label:
Cyclophosphamide + Fludarabine + Infusion of CAR-T Cells
Summary:
This is a phase l, single arm, prospective open, dose-escalation study in patients with
relapsed or refractory CD19-positive B cell malignancies (ALL, NHL, CLL). The trial will
include adult and pediatric patients. There will be three individual cohorts, defined by
disease biology: pediatric ALL and aggressive pediatric NHL (Cohort 1), adult ALL (Cohort
2) and adult NHL/CLL (Cohort 3).
Detailed description:
We will evaluate the safety of the MB-CART19.1 and determine the recommended dose levels
for the Phase II clinical trial.
Dose evaluation will start in Cohorts 1 and 2 with Dose Level 1 (5x10e5 CAR T cells/Kg)
and in Cohort 3 with Dose Level 2 1x10e6 CAR T cells/Kg) , sparing Dose Level 1 . Each of
the cohorts will evaluate the safety of the CAR-T cells.
In each dose level of each of the three cohorts three 3 + 3 patients will be treated. A
particular dose level will be expanded to 6 patients if one patient out of 3 patients
treated at that particular dose level develops DLT. Once this occurs, further
dose-escalations are halted until the dose has proven to be safe in the expanded cohort.
If 2 or more in a cohort of 6 patients develop DLT no further dose escalation is allowed,
and the next lower dose level will be expanded to 6 patients in total. The highest dose
among the dose levels tested at which no more than one out of six patients experiences
DLT will be considered the MTD. In Dose Level 3, three additional patients will be
treated, if no DLT occurred. Dose Level 0 will be tested only if Dose Level 1 is not
tolerable.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Subjects must have relapsed or refractory ALL, lymphoma or CLL treated with at least
two lines of therapy. Disease must have either progressed after the last regimen or
presented failure to achieve partial or complete remission with the last regimen.
Subjects with Philadelphia Chromosome positive acute lymphoblastic leukemia (Ph+ALL)
subjects are eligible if they progressed, had stable disease or relapsed after two
lines of therapy, including tyrosine kinase inhibitors (TKIs).
Subjects with DLBCL must have progressed, had SD, or recurred after initial
treatment regimens that include an anthracycline and an anti-CD20 monoclonal
antibody.
Subjects with transformed FL, MZL, or CLL/SLL must have progressed, had SD or
recurred with transformed disease after initial treatment for DLBCL.
Subjects who relapse ≥12 months after therapy should have progressed after
autologous transplant or been ineligible for autologous transplant.
2.
2. The patient's disease must be CD19 positive, either by immunohistochemistry or
flow cytometry analysis on the last biopsy available.
3. Age 2 to 70 years.
4. Performance status: Adult Subjects: ECOG ≤ 2 for patients ≥ 16 years; Subjects < 16
years of age: lansky ≥ 50%
5. Normal Organ and Marrow Functioning (supportive treatment is allowed according to
institutional standards, i.e. filgrastim, transfusion)
• Total Bilirubin ≤ 2; AST (SGOT) ≤ 5 times the upper limit of normal; ALT (SGTP) ≤
5 times the upper limit of normal; Serum creatinine ≤ 1.5; Pulse oximetry >91% on
room air; No dyspnea or mild dyspnea (≤ Grade 1); Forced expiratory volume in 1 s
(FEV1) ≥50% or carbon monoxide diffusion test (DLCO) ≥50% of predicted level; Left
ventricular ejection fraction ≥ 45% confirmed by echocardiogram; Subjects must have
the following hematologic function parameters: Neutrophils > 1000/uL; Absolute
Lymphocyte Count > 100/uL; Platelets ≥ 50,000/L Patient should not be excluded if
change of the above parameters due to spinal cord disease infiltration;
6. Prior therapy wash-out - At least 2 weeks or 5 half-lives, whichever is shorter,
must have elapsed since any prior systemic therapy at the time the subject is
planned for leukapheresis, except for systemic inhibitory/stimulatory immune
checkpoint therapy, which requires 5 half-lives, Blinatumomab with 4 months prior
CAR-T infusion.
7. For women of reproductive potential: use a highly effective contraceptive for at
least 1 month prior to screening and agree to use a method during study
participation and for an additional 4 months after CAR T-cell administration has
ended.
8. Subjects must have the ability to understand and the willingness to sign a written
informed consent document.
Exclusion Criteria:
1. Autologous transplant within 6 weeks of planned CAR-T cell infusion;
2. History of allogeneic stem cell transplant 4 months prior CAR T cell infusion.
3. Use of immunosuppression therapy;
• Patients must have completed immunosuppression therapy; Systemic corticosteroid
therapy must be stopped more than 72 hours after infusion; Systemic drugs for
graft-versus-host disease should be withheld at least 4 weeks prior to infusion;
4. Presence of graft-versus-host disease Grade ≥ 2;
5. Receiving CAR T cell treatment outside of this protocol;
6. Active central nervous system or meningeal involvement by tumor. Subjects with
untreated brain metastases/CNS disease will be excluded from this clinical trial
because of their poor prognosis and because they often develop progressive
neurologic dysfunction that would confound the evaluation of neurologic and other
adverse events. Patients with a history of CNS or meningeal involvement must be in a
documented remission by CSF evaluation and contrast-enhanced MRI imaging for at
least 90 days prior to registration.
7. History of active malignancy other than non-melanoma skin cancer, carcinoma in situ
(e.g. cervix, bladder, breast).
8. HIV infection; HTLV
9. Subjects with uncontrolled intercurrent illness including, but not limited to
ongoing or active infection, symptomatic congestive heart failure, unstable angina
pectoris, cardiac arrhythmia, pulmonary abnormalities or psychiatric illness/social
situations that would limit compliance with study requirements.
10. Pregnant or breastfeeding women are excluded from this study because CAR-T cell
therapy may be associated with the potential for teratogenic or abortifacient
effects.
11. Evidence of myelodysplasia or cytogenetic abnormality indicative of myelodysplasia
on any bone marrow biopsy prior to initiation of therapy
12. Serologic status reflecting active hepatitis B or C infection. Patients that are
positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or
hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to
enrollment. (PCR positive patients will be excluded.)
13. Serious and/or potentially fatal medical conditions
14. Patients with history of clinically relevant CNS pathology such as epilepsy, seizure
disorders, paresis, aphasia, uncontrolled cerebrovascular disease, severe brain
injuries, dementia and Parkinson's disease.
15. History of autoimmune disease (i.e. rheumatoid arthritis, systemic lupus
erythematosus) with requirement of immunosuppressive medication within 6 months.
16. Hypersensitivity against any drug or its ingredients/impurities that is scheduled or
likely to be given during trial participation, e.g. as part of the mandatory
lymphodepletion protocol, pre-medication for infusion, rescue medication/salvage
therapies for treatment related toxicities;
Gender:
All
Minimum age:
2 Years
Maximum age:
70 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
Hospital Israelita Albert Einstein
Address:
City:
São Paulo
Zip:
05652-900
Country:
Brazil
Contact:
Last name:
Jose Mauro Kutner, MD, PhD
Phone:
+551121517248
Email:
jose.kutner@einstein.br
Investigator:
Last name:
Lucila Kerbauy, MD, PhH
Email:
Sub-Investigator
Start date:
March 1, 2023
Completion date:
December 1, 2028
Lead sponsor:
Agency:
Hospital Israelita Albert Einstein
Agency class:
Other
Collaborator:
Agency:
Miltenyi Biotec, Inc.
Agency class:
Industry
Source:
Hospital Israelita Albert Einstein
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05705570
