Trial Title:
TCR Reserved and Power3 Gene Knock-out Allogeneic CD19-targeting CAR-T Cell Therapy in r/r B-ALL
NCT ID:
NCT06481735
Condition:
Acute Lymphocytic Leukemia
Conditions: Official terms:
Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Cyclophosphamide
Fludarabine
Fludarabine phosphate
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Biological
Intervention name:
TCR reserved and Power3 Gene Knock-out Allogeneic CD19-targeting CAR-T cell
Description:
Phase 1 dose escalation (3+3) : dose 1 (1 × 10^6 cells/kg) , dose 2 (3 × 10^6 cells/kg),
dose 3 (6 × 10^6 cells/kg); Phase 2 : dose of RP2D.
Arm group label:
Patients with refractory or relapsed B-ALL
Other name:
Allogeneic Power3 knock-out CD19 CAR-T
Intervention type:
Drug
Intervention name:
Fludarabine
Description:
Intravenous fludarabine 25~30 mg/m^2/day on days -5, -4, and -3.
Arm group label:
Patients with refractory or relapsed B-ALL
Other name:
Fludarabine Phosphate for Injection
Intervention type:
Drug
Intervention name:
Cyclophosphamide
Description:
Intravenous cyclophosphamide 250~500 mg/m^2/day on days -5, -4, and -3.
Arm group label:
Patients with refractory or relapsed B-ALL
Other name:
Cyclophosphamide for Injection
Summary:
The safety and efficacy of the chimeric antigen receptor (CAR)-T, a CD19-targeting, TRAC
and Power3 double gene deleted allogeneic CAR-T cell product, are undergoing rigorous
evaluation in NHL subjects from the ATHENA trial (NCT06014073). Unexpectedly, expansion
of the initial residual CD3-positive CAR T from products were measured in patients'
peripheral blood (PB) without exception. Accompanying with host immune reconstitution and
appearance of the detectable B cells, the CD3-positive allogenic CAR T cells exhibited a
compelling amplification advantage over CD3-negative CAR T cells. The amplification of
CD3-positive CAR T cell population dynamically suppressed host B cell recovery, and
presumably surveilled the recurrence or progression of tumors, but did not induce typical
Graft-versus-host-disease (GvHD). Additionally, a series of in vitro experiments
illustrated that the HLA-mismatched fratricide between host T cells and TCR-reserved
Power3-deleted allogenic CAR T cells was markedly slashed, which in combination with
investigators' observed clinical safety date supported the notion that only genomic
deletion of Power3 gene in allo-CAR T cells is sufficient to overcome GvHD and host T
cell-mediated rejection response.
In this study, investigators will disable the Power3 gene of T cells from healthy donors
to prepare CAR T cells. This approach harnesses the tonic signaling of CAR T cells,
resulting in enhanced persistence and improved response to treatment. The purpose of this
study is to evaluate the safety and efficacy of allogeneic Power3 knock-out CD19 CAR-T in
B-cell acute lymphoblastic leukaemia (B-ALL).
Detailed description:
Phase 1 (dose escalation)
In phase 1, 6-18 subjects will be enrolled. Subjects will receive 3 doses of allogeneic
Power3 knock-out CD19 CAR-T cell therapy ( 1 × 10^6 cells/kg、3 × 10^6 cells/kg、6 × 10^6
cells/kg) increases from low dose to high dose according to the "3 + 3" principle:
Three (3) subjects are enrolled in a cohort corresponding to a dose level. If 1 subject
in a cohort of 3 subjects experiences a dose-limiting toxicity (DLT), 3 additional
subjects will be enrolled at the current dose level. For safety purposes, the
administration of allogeneic Power3 knock-out CD19 CAR-T will be staggered by 28 days
between the first two subjects in each cohort. And for each of the remaining cohorts, the
administration of allogeneic Power3 knock-out CD19 CAR-T will be staggered by 28 days
before enter into the next cohort.
Phase 2 (expansion cohort)
In phase 2, 10 to 12 subjects will be enrolled and receive cell infusion at dose of
recommended phase 2 dose (RP2D), which will be determined based on the maximum tolerated
dose (MTD), occurrence of DLT, the obtained efficacy results,
pharmacokinetics/pharmacodynamics and other data according to the phase 1.
Objectives
The primary objectives of the phase 1 were to evaluate the tolerability and safety of
allogeneic Power3 knock-out CD19 CAR-T in patients with refractory/relapsed (r/r) B-ALL,
and determine RP2D. The primary purpose of the phase 2 study was to evaluate the efficacy
of allogeneic Power3 knock-out CD19 CAR-T in the above population.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Age 16-70 (inclusive).
2. Patient with r/r CD19+ B-ALL, as per guidelines (NCCN, 2019)
- morphologically confirmed with ≥ 5% leukaemic blasts in the bonemarrow;
- or presenting a quantifiable MRD load of 1x10^-3 , assessed by multiparameter
flow cytometry and/or quantitative polymerase chain reaction, at the end of the
last induction treatment.
Relapsed disease is defined as:
- second or subsequent bone marrow relapse or,
- any bone marrow relapse after allo-HSCT.
Refractory disease is defined by not achieving an initial CR after 2 cycles of a
standard chemotherapy regimen (primary refractory). Subjects who were refractory to
subsequent chemotherapy regimens after an initial remission were considered
chemorefractory.
3. Toxicities due to prior therapy must be stable and recovered to ≤ Grade 1 (except
for hematological toxicities and clinically non-significant toxicities such as
alopecia).
4. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
5. Adequate renal, hepatic, pulmonary and cardiac function defined as:
- Serum creatinine≤1.5 upper limit of normal (ULN) or creatinine clearance (as
estimated by Cockcroft Gault) ≥ 60 mL/min.
- Serum alanine aminotransferase / aspartate aminotransferase (ALT/AST) ≤ 3 upper
limit of normal (ULN); Total bilirubin ≤ 1.5 ULN, except in subjects with 3)
Gilbert's syndrome.
- Cardiac ejection fraction ≥ 50%, no evidence of pericardial effusion as
determined by an echocardiogram (ECHO), and no clinically significant
electrocardiogram (ECG) findings.
- Coagulation Function: International Normalized Ratio (INR) ≤ 1.5 times the
upper limit of normal (ULN), and Activated Partial Thromboplastin Time (APTT) ≤
1.5 times ULN.
- Baseline oxygen saturation >91% on room air.
6. Subjects of both genders who are willing to practice birth control from the time of
consent through 6 months after the completion of conditioning chemotherapy. Females
of childbearing potential must have a negative serum or urine pregnancy test
(females who have undergone surgical sterilization or who have been postmenopausal
for at least 2 years are not considered to be of childbearing potential).
7. Voluntarily participate in this clinical trial and sign an informed consent form.
Exclusion Criteria:
1. Expected survival time < 3 months per Principal Investigator's opinion.
2. History of malignancy other than nonmelanoma skin cancer or carcinoma in situ (e.g.
cervix, bladder, breast) unless disease free for at least 3 years.
3. History of allogeneic stem cell transplantation.
4. Prior CD19 targeted therapy.
5. Prior CAR-T therapy or other genetically modified T cell therapy.
6. Active central nervous system (CNS) leukaemia (CNS-3).
7. Burkitt cell (L3 ALL) or mixed lineage acute leukaemia.
8. Clinically active significant CNS dysfunction.
9. Known history of irreversible severe neurological toxicity related to previous
antileukaemic treatment leading to organic central nervous system lesions.
10. B-ALL with clinically suspected extra-medullary involvement.
11. Use of previous anti-leukemic therapy within 5 half-lives prior to allogeneic Power3
knock-out CD19 CAR-T administration; participation in non-interventional registries
or epidemiological studies is allowed.
12. Radioimmunotherapy, radiotherapy, within 8 weeks (except prophylaxis of CNS
involvement) before Inclusion.
13. History of severe, immediate hypersensitivity reaction attributed to lymphodepletion
drugs or any component of allogeneic Power3 knock-out CD19 CAR-T.
14. Presence or suspicion of fungal, bacterial, viral, or other infection that is
uncontrolled or requiring intravenous (IV) antimicrobials for management.
15. Uncontrolled or active infectious diseases, such as human immunodeficiency virus
(HIV) infection, acute or chronic active hepatitis B or C, epstein-barr virus (EBV),
and cytomegalovirus (CMV) infection.
16. History or presence of CNS disorder such as seizure disorder, cerebrovascular
ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with
CNS involvement.
17. Subjects with cardiac atrial or cardiac ventricular lymphoma involvement.
18. History of myocardial infarction, cardiac angioplasty or stenting, unstable angina,
or other clinically significant cardiac disease within 12 months of enrollment.
19. Expected or possible requirement for urgent therapy within 6 weeks due to ongoing or
impending oncologic emergency (eg, tumor mass effect, tumor lysis syndrome).
20. Primary immunodeficiency.
21. History of autoimmune disease (e.g. Crohn's, rheumatoid arthritis, systemic lupus)
resulting in end organ injury or requiring systemic immunosuppression/systemic
disease modifying agents within the last 2 years.
22. History of symptomatic deep vein thrombosis or pulmonary embolism requiring systemic
anticoagulation within 6 months of enrollment.
23. Any medical condition likely to interfere with assessment of safety or efficacy of
study treatment.
24. History of severe immediate hypersensitivity reaction to any of the agents used in
this study.
25. Vaccine ≤ 6 weeks prior to planned start of conditioning regimen.
26. In the investigator's judgment, the subject is unlikely to complete all
protocol-required study visits or procedures, including follow-up visits, or comply
with the study requirements for participation.
Gender:
All
Minimum age:
16 Years
Maximum age:
70 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
Biotherapeutic Department of Chinese PLA General Hospital
Address:
City:
Beijing
Zip:
100853
Country:
China
Status:
Recruiting
Contact:
Last name:
Weidong Han, M.D
Phone:
+86-010-66937463
Email:
hanwdrsw@sina.com
Investigator:
Last name:
Qingming Yang, M.D
Email:
Sub-Investigator
Investigator:
Last name:
Yang Liu, M.D
Email:
Sub-Investigator
Investigator:
Last name:
Jinhong Shi, M.S
Email:
Sub-Investigator
Investigator:
Last name:
Chunmeng Wang, M.S
Email:
Sub-Investigator
Start date:
July 1, 2024
Completion date:
July 1, 2027
Lead sponsor:
Agency:
Chinese PLA General Hospital
Agency class:
Other
Collaborator:
Agency:
Peking University
Agency class:
Other
Collaborator:
Agency:
EdiGene Inc.
Agency class:
Industry
Source:
Chinese PLA General Hospital
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06481735
