Gene Knock-out CAR-T Cell Therapy for Acute Lymphocytic Leukemia

A Phase 1/2 Multicenter Study Evaluating the Safety and Efficacy of TCR Reserved and Power3 (SPPL3) Gene Knock-out Allogeneic CD19-targeting CAR-T Cell Therapy in Adults With Refractory/Relapsed B-cell Acute Lymphoblastic Leukaemia

This study is testing a new type of CAR-T cell therapy to see if it can help people with hard-to-treat B-cell acute lymphoblastic leukemia feel better and fight their cancer.

Quick facts

• Phase: PHASE1; PHASE2
• Study type: Interventional
• Enrollment: 30 (estimated)
• Ages: 16 Years to 70 Years
• Sex: All
• Sponsor: Chinese PLA General Hospital (other)
• Drugs / interventions: CAR-T, chemotherapy, CAR T, chimeric antigen receptor
• Locations: 6 sites (Beijing, Beijing Municipality and 5 other locations)
• Trial ID: NCT06481735 on ClinicalTrials.gov

What this trial studies

This clinical trial evaluates the safety and efficacy of a novel allogeneic CAR-T cell therapy targeting CD19 in patients with refractory or relapsed B-cell acute lymphoblastic leukemia (B-ALL). The study consists of two phases: Phase 1 focuses on dose escalation to determine the maximum tolerated dose and assess safety, while Phase 2 aims to evaluate the efficacy of the recommended dose. Participants will receive three doses of the CAR-T cells, with careful monitoring for dose-limiting toxicities and immune responses. The trial also investigates the dynamics of CAR-T cell expansion and its impact on tumor recurrence.

Who should consider this trial

Good fit: Ideal candidates are individuals aged 16-70 with refractory or relapsed CD19-positive B-ALL.

Not a fit: Patients with significant comorbidities or those who have not recovered from prior therapies may not benefit from this study.

Why it matters

Potential benefit: If successful, this therapy could provide a new treatment option for patients with difficult-to-treat B-ALL, potentially improving survival rates.

How similar studies have performed: Other studies using CAR-T cell therapies have shown promising results in treating B-ALL, indicating potential for success with this approach.

Eligibility criteria

Inclusion Criteria:

1. Age 16-70 (inclusive).
2. Patient with r/r CD19+ B-ALL, as per guidelines (NCCN, 2019)

   * For patients with bone marrow involvement, morphologically confirmed with ≥ 5% leukaemic blasts in the bonemarrow.
   * Definition of relapsed disease: Bone marrow or extramedullary relapse after achieving CR with initial treatment, or any bone marrow or extramedullary relapse after allogeneic hematopoietic stem cell transplantation (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. Patients who received any immunocellular or HSCT therapy within 3 months before enrollment.
4. Active central nervous system (CNS) leukaemia (CNS-3).
5. Clinically active significant CNS dysfunction.
6. Known history of irreversible severe neurological toxicity related to previous antileukaemic treatment leading to organic central nervous system lesions.
7. Use of previous anti-leukemic therapy within 5 half-lives prior to allogeneic Power3 (SPPL3) knock-out CD19 CAR-T administration; participation in non-interventional registries or epidemiological studies is allowed.
8. Radioimmunotherapy, radiotherapy, within 8 weeks (except prophylaxis of CNS involvement) before Inclusion.
9. History of severe immediate hypersensitivity reaction to any of the agents or any component used in this study.
10. Presence or suspicion of fungal, bacterial, viral, or other infection that is uncontrolled or requiring intravenous (IV) antimicrobials for management.
11. 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.
12. History or presence of CNS disorder such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement.
13. Subjects with cardiac atrial or cardiac ventricular lymphoma involvement.
14. History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 12 months of enrollment.
15. Expected or possible requirement for urgent therapy within 6 weeks due to ongoing or impending oncologic emergency (eg, tumor mass effect, tumor lysis syndrome).
16. Primary immunodeficiency.
17. 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.
18. History of symptomatic deep vein thrombosis or pulmonary embolism requiring systemic anticoagulation within 6 months of enrollment.
19. Any medical condition likely to interfere with assessment of safety or efficacy of study treatment.
20. Vaccine ≤ 6 weeks prior to planned start of conditioning regimen.
21. Presence of DSAs directed against allogeneic SPPL3 knock-out CD19 CAR-T.
22. 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.

Where this trial is running

Beijing, Beijing Municipality and 5 other locations

• Biotherapeutic Department of Chinese PLA General Hospital — Beijing, Beijing Municipality, China (RECRUITING)
• Department of Hematology, Chinese PLA General Hospital — Beijing, China (RECRUITING)
• Department of Hematology, Peking Union Medical College Hospital — Beijing, China (NOT_YET_RECRUITING)
• Department of Hematology, Heping Hospital Affiliated to Changzhi Medical College — Changzhi, China (RECRUITING)
• Department of Hematology, Tianjin First Central Hospital — Tianjin, China (RECRUITING)
• Immune Cell Therapy Center, Blood Disease Hospital, Chinese Academy of Medical Sciences — Tianjin, China (RECRUITING)

Study contacts

• Study coordinator: Weidong Han, Ph.D.

Conditions: Acute Lymphocytic Leukemia