BCOR and ZC3H12 gene‑knockout CD19 CAR‑T therapy for adults with relapsed/refractory B‑cell ALL

A Phase I/II Single-center Study Evaluating the Safety and Efficacy of BCOR and ZC3H12 Genes Knock-out CD19-targeting CAR-T Cell Therapy in Adults With Refractory/Relapsed B-cell Acute Lymphoblastic Leukaemia

This will test whether autologous CD19‑targeting CAR‑T cells with BCOR and ZC3H12 genes knocked out can be safe and produce durable remissions in adults with relapsed or refractory B‑cell acute lymphoblastic leukemia.

Quick facts

• Phase: Phase1; Phase2
• Study type: Interventional
• Enrollment: 30 (estimated)
• Ages: 18 Years to 70 Years
• Sex: All
• Sponsor: Chinese PLA General Hospital (Academic / other)
• Drugs / interventions: CAR-T, chemotherapy, CAR T, chimeric antigen receptor
• Locations: 2 sites (Beijing, Biotherapeutic Department of Chinese PLA General Hospital and 1 other locations)
• Trial ID: NCT07008885 on ClinicalTrials.gov

What this trial studies

This single‑center, single‑arm Phase 1/2 trial will administer autologous CD19 CAR‑T cells lacking BCOR and ZC3H12 (termed CAR19TIF) to adults with relapsed or refractory B‑cell ALL. Phase 1 uses a 3+3 dose‑escalation/decline design starting at 5×10^5 cells/kg with fludarabine/cyclophosphamide lymphodepletion to establish a recommended Phase 2 dose (RP2D), and Phase 2 will treat 10–12 subjects at the RP2D. Investigators report preclinical immunocompetent mouse data showing enhanced expansion, persistence, and long‑term B‑cell depletion even at low doses and without conditioning. Key outcomes include safety (dose‑limiting toxicities), initial remission rate (CR/CRi), and durability of response.

Who should consider this trial

Good fit: Adults aged 18–70 with CD19‑positive relapsed or refractory B‑ALL who have exhausted standard treatment options and are eligible for lymphodepleting chemotherapy are the intended candidates.

Not a fit: Patients with CD19‑negative disease, uncontrolled infections, significant organ dysfunction, active graft‑versus‑host disease, or who are unfit for lymphodepletion are unlikely to benefit from this therapy.

Why it matters

Potential benefit: If successful, this approach could increase CAR‑T cell persistence and lower relapse rates, producing more durable remissions for patients with r/r B‑ALL.

How similar studies have performed: CD19‑targeted CAR‑T therapies have achieved high initial remission rates in r/r B‑ALL but substantial relapse rates, and the specific BCOR/ZC3H12 double‑knockout strategy is novel and so far supported only by preclinical data.

Eligibility criteria

Inclusion Criteria:

1. Age 18-70 (inclusive),gender unrestricted.
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.
   * who has exhausted alternative treatment options.

   Relapsed disease is defined as:
   * second or subsequent bone marrow relapse or,
   * any bone marrow relapse after allogenic hematopoiesis stem cell transplant (allo-HSCT).

   Refractory disease is defined by not achieving an initial complete response (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×ULN; Total bilirubin ≤ 1.5×ULN.
   * 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 ×ULN, and Activated Partial Thromboplastin Time (APTT) ≤ 1.5×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. Previous or concurrent cancer within 3 years prior to treatment start EXCEPT for curatively treated cervical cancer in situ, non-melanoma skin cancer, superficial bladder tumors \[Ta (non-invasive tumor), Tis (carcinoma in situ) and T1 (tumor invades lamina propria)\].
3. Prior CD19 targeted therapy
4. Prior CAR-T therapy or other genetically modified T cell therapy.
5. Active central nervous system (CNS) leukaemia (CNS-3).
6. B-ALL with clinically suspected extra-medullary involvement.
7. Burkitt cell (L3 ALL) or mixed lineage acute leukaemia.
8. Clinically active significant CNS dysfunction

   * History or presence of CNS disorder such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement.
   * Known history of irreversible severe neurological toxicity related to previous antileukaemic treatment leading to organic central nervous system lesions.
   * Radioimmunotherapy, radiotherapy, within 8 weeks (except prophylaxis of CNS involvement) before Inclusion.
9. Use of previous anti-leukemic therapy within 5 half-lives prior to CAR19TIF cells administration; participation in non-interventional registries or epidemiological studies is allowed.
10. History of severe, immediate hypersensitivity reaction attributed to lymphodepletion drugs or any component of CAR19TIF cells.
11. Presence or suspicion of fungal, bacterial, viral, or other infection that is uncontrolled or requiring intravenous (IV) antimicrobials for management.
12. 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.
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. 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, Biotherapeutic Department of Chinese PLA General Hospital and 1 other locations

• China — Beijing, Biotherapeutic Department of Chinese PLA General Hospital, China (Recruiting)
• China — Beijing, Biotherapeutic Department of Chinsese PLA Gereral Hospital, China (Not_yet_recruiting)

Study contacts

• Principal investigator: Weidong Han, Ph.D — Biotherapeutic Department, Chinese PLA General Hospital
• Study coordinator: Weidong Han, Ph.D

Conditions Acute Lymphocytic Leukemia; CAR-T cells; ALL; CD19