BCOR and ZC3H12 Genes Knock-out CD19-targeting CAR-T Cell Therapy in r/r B-ALL

NCT07008885 | Recruiting Phase 1

• 1 other identifier: CHN-PLAGH-BT-090
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 2

Brief Summary

In this single-center, single-arm, prospective, Phase 1/2 study, the safety and efficacy of autologous BCOR and ZC3H12 genes knock-out CD19-targeting chimeric antigen receptor (CAR) T-cell therapy will be evaluated in patients with refractory/relapsed (r/r) B-cell acute lymphoblastic leukaemia (B-ALL). In phase 1, 3 eligible patients will be enrolled and receive BCOR and ZC3H12 genes knock-out CD19 CAR T cell therapy at a initial dose of 5×10\^5 cells/kg. Based on the results, . Subsequently an additional 3-15 patients will be enrolled in a "3+3" dose-escalation/decline design to adjust the dose of BCOR and ZC3H12 genes knock-out CD19 CAR T cells to achieve optimal safety and efficacy. The recommended Phase 2 dose (RP2D) will then be established. 10 to 12 subjects will be enrolled and receive BCOR and ZC3H12 genes knock-out CD19 CAR T cell infusion at dose of RP2D.

Conditions

Acute Lymphocytic Leukemia

Keywords

CAR-T cells; ALL; CD19

Outcome Measures

Primary Outcomes (6)

• Phase 1: Incidence of Adverse Events (AEs)

  AE is defined as any adverse medical event from the date of randomization to 12 months after CAR T cells infusion. Among them, cytokine release syndrome(CRS) and immune cell-associated neurotoxicity syndrome (ICANS) were graded according to American Society for Transplantation and Cellular Therapy (ASTCT) criteria. Other AEs were graded according to common terminology criteria for adverse events (CTCAE) v5.0.

  Up to 12 months since the initiation of CAR-T cell therapy.

• Phase 1:Incidence of Incidence of Dose-Limiting Toxicities (DLTs)

  DLT is defined as any AE related to the investigational drug that occurs within 28 days after administration of the CAR19TIF cells and meets any one of the criteria listed in the DLT criteria: * Grade 3 CRS that does not resolve to grade 2 or lower within 2 weeks; * Grade 3 ICANS lasting for ≥ 7 days; * Any Grade ≥ 4 CRS or ICANS; * Any other Grade ≥ 4 and Grade 3 AEs related to the CAR19TIF cells that lasts for ≥ 14 days, except hematology toxicity.

  [Time Frame: Up to 28 days since the initiation of CAR-T cell therapy]

• Phase 1:RP2D

  The recommended dose for phase 2 was determined through phase 1 study.

  12 months

• Phase 2:Objective response rate (ORR)

  Objective response definition: a molecular response (MRD \< 10\^-4 post treatment) assessed by multiparameter flow cytometry and/or qPCR, or a morphologic complete response (CR), or a CR with incomplete blood count recovery (CRi). ORR is defined as the proportion of patients who have achieved objective response assessed by investigators.

  24 months

• Phase 2:Overall Survival (OS)

  OS is defined as the time from CAR-T cells infusion to the date of death. Subjects who have not died by the analysis data cutoff date will be censored at the last contact date.

  24 months

• Phase 2: Progression Free Survival (PFS)

  PFS is defined as the time from the CAR-T cells infusion date to the date of disease progression assessed by investigators, or death any cause. Participants not meeting the criteria for progression by the analysis data cutoff date were censored at the last evaluable disease assessment date.

  24 months

Secondary Outcomes (2)

• Phase 1 and phase 2: Level of CAR-positive T cells circulating in blood over time

  12 months

• Phase 1 and phase 2: Level of CD19+ cells in peripheral blood

  12 months

Other Outcomes (2)

• Relationship between infusion dose of CAR T cells and efficacy.

  24 months

• To analyze the dynamic changes of CAR T cells after infusion

  24 months

Study Arms (1)

CAR19TIF cells

EXPERIMENTAL

Patients with r/r B-ALL A conditioning chemotherapy regimen of fludarabine and cyclophosphamide will be administered followed by investigational treatment, CAR19TIF cells.

Biological: CAR19TIF cells; Drug: Fludarabine; Drug: Cyclophosphamide

Interventions

CAR19TIF cells BIOLOGICAL

Phase 1 dose escalation/decline (3+3) : starting dose: 5×10\^5 cells/kg, According to effective expansion and clinical efficacy data, a descending dose escalation model will be adopted: such as 1×10\^5 cells/kg, 5×10\^4 cells/kg. If the 5×10\^5 cells/kg dose group does not achieve efficient expansion and clinical benefit, an ascending dose escalation model will be adopted, such as 2×10\^6 cells/kg, 6×10\^6 cells/kg. Phase 2 : dose of RP2D.

Also known as: BCOR and ZC3H12 genes knock-out CD19 CAR T cells

CAR19TIF cells

Fludarabine DRUG

Intravenous fludarabine 25\~30 mg/m\^2/day on days -5, -4, and -3.

Also known as: Fludarabine Phosphate for Injection

CAR19TIF cells

Cyclophosphamide DRUG

Intravenous cyclophosphamide 250\~500 mg/m\^2/day on days -5, -4, and -3.

Also known as: Cyclophosphamide for Injection

CAR19TIF cells

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18-70 (inclusive),gender unrestricted.
• 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.
• 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).
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
• 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.

You may not qualify if:

• Expected survival time \< 3 months per Principal Investigator's opinion.
• 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 \[Ta (non-invasive tumor), Tis (carcinoma in situ) and T1 (tumor invades lamina propria)\].
• Prior CD19 targeted therapy
• Prior CAR-T therapy or other genetically modified T cell therapy.
• Active central nervous system (CNS) leukaemia (CNS-3).
• B-ALL with clinically suspected extra-medullary involvement.
• Burkitt cell (L3 ALL) or mixed lineage acute leukaemia.
• 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.
• 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.
• History of severe, immediate hypersensitivity reaction attributed to lymphodepletion drugs or any component of CAR19TIF cells.
• Presence or suspicion of fungal, bacterial, viral, or other infection that is uncontrolled or requiring intravenous (IV) antimicrobials for management.
• 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.
• Subjects with cardiac atrial or cardiac ventricular lymphoma involvement.

Sponsors & Collaborators

• Chinese PLA General Hospital: lead

Study Sites (2)

China

Beijing, Biotherapeutic Department of Chinese PLA General Hospital, China

RECRUITING

China

Beijing, Biotherapeutic Department of Chinsese PLA Gereral Hospital, China

NOT YET RECRUITING

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Interventions

fludarabine; fludarabine phosphate; Injections; Cyclophosphamide

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Drug Administration Routes; Drug Therapy; Therapeutics; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Study Officials

• Weidong Han, Ph.D

  Biotherapeutic Department, Chinese PLA General Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Weidong Han, Ph.D

CONTACT

010-66937231; hanwdrsw@sina.com

Yang Liu, M.D

CONTACT

010-66939460; liuyang301blood@163.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director of Biotherapeutic Department

Study Record Dates

• First Submitted: May 21, 2025
• First Posted: June 6, 2025
• Study Start: June 20, 2025
• Primary Completion (Estimated): May 31, 2026
• Study Completion (Estimated): May 31, 2027
• Last Updated: June 25, 2025

Record last verified: 2025-06

Locations

CN (2)