TCR Reserved and Power3 (SPPL3) Gene Knock-out Allogeneic CD19-targeting CAR-T Cell Therapy in r/r B-ALL

NCT06481735 | Recruiting Phase 1

• 1 other identifier: CHN-PLAGH-BT-087
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 6

Brief Summary

The safety and efficacy of the chimeric antigen receptor (CAR)-T, a CD19-targeting, TRAC and Power3 (SPPL3) double gene deleted allogeneic CAR-T cell product, are undergoing rigorous evaluation in non-Hodgkin's lymphoma (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 human leukocyte antigen (HLA)-mismatched fratricide between host T cells and TCR-reserved Power3 (SPPL3)-deleted allogenic CAR T cells was markedly slashed, which in combination with investigators' observed clinical safety data supported the notion that only genomic deletion of Power3 (SPPL3) 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 (SPPL3) 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 (SPPL3) knock-out CD19 CAR-T in B-cell acute lymphoblastic leukaemia (B-ALL).

Conditions

Acute Lymphocytic Leukemia

Outcome Measures

Primary Outcomes (5)

• Phase 1: Incidence of adverse events (AE) defined as DLT

  DLT is defined as any AE related to the investigational drug that occurs within 28 days after administration of the allogeneic Power3 (SPPL3) knock-out CD19 CAR-T and meets any one of the criteria listed in the DLT criteria. The severity of AE will be assessed according to NCI-CTCAE v5.0. cytokine release syndrome (CRS) and immune cell-associated neurotoxicity syndrome (ICANS) will be evaluated according to the standards released by ASTCT in 2019. GvHD according to criteria defined by the Mount Sinai Acute GVHD International Consortium. * Grade 3 aGVHD that does not resolve to Grade 1 or 2 within 7 days, with the exception of isolated skin involvement aGVHD; * 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 aGVHD or CRS or ICANS; * Any other Grade ≥ 4 and Grade 3 AE related to the allogeneic Power3 (SPPL3) knock-out CD19 CAR-T that lasts for ≥ 14 days, except hematology toxicity.

  First infusion date of CAR-T cells up to 28 days

• Phase 1: RP2D

  The RP2D 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 (7)

• 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

  Up to 28 days after infusion

• Phase 1 and phase 2: Level of interleukin 6 (IL-6) in peripheral blood

  Up to 28 days after infusion

• Phase 1: 3-month ORR

  3 months

• Phase 1: OS

  24 months

Other Outcomes (2)

• Phase 1: Level of donor-specific antibodies (DSAs) in blood.

  12 months

• Phase 1: Level of human anti-mouse antibodies (HAMA)

  12 months

Study Arms (1)

Patients with refractory or relapsed B-ALL

EXPERIMENTAL

A conditioning chemotherapy regimen of fludarabine and cyclophosphamide will be administered followed by investigational treatment, Power3 (SPPL3) Gene Knock-out Allogeneic CD19-targeting CAR-T.

Biological: TCR reserved and Power3 (SPPL3) Gene Knock-out Allogeneic CD19-targeting CAR-T cell; Drug: Fludarabine; Drug: Cyclophosphamide

Interventions

TCR reserved and Power3 (SPPL3) Gene Knock-out Allogeneic CD19-targeting CAR-T cell BIOLOGICAL

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.

Also known as: Allogeneic Power3 (SPPL3) knock-out CD19 CAR-T

Patients with refractory or relapsed B-ALL

Fludarabine DRUG

Intravenous fludarabine 30\~50 mg/m\^2/day on days -5, -4, and -3.

Also known as: Fludarabine Phosphate for Injection

Patients with refractory or relapsed B-ALL

Cyclophosphamide DRUG

Intravenous cyclophosphamide 500\~1000 mg/m\^2/day on days -5, -4, and -3.

Also known as: Cyclophosphamide for Injection

Patients with refractory or relapsed B-ALL

Eligibility Criteria

• Age: 16 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 16-70 (inclusive).
• 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.
• 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 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.
• 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).
• Voluntarily participate in this clinical trial and sign an informed consent form.

You may not qualify if:

• Expected survival time \< 3 months per Principal Investigator's opinion.
• 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.
• Patients who received any immunocellular or HSCT therapy within 3 months before enrollment.
• Active central nervous system (CNS) leukaemia (CNS-3).
• Clinically active significant CNS dysfunction.
• 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 allogeneic Power3 (SPPL3) knock-out CD19 CAR-T administration; participation in non-interventional registries or epidemiological studies is allowed.
• History of severe immediate hypersensitivity reaction to any of the agents or any component used in this study.
• 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.
• History or presence of CNS disorder such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement.
• Subjects with cardiac atrial or cardiac ventricular lymphoma involvement.
• History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 12 months of enrollment.
• Expected or possible requirement for urgent therapy within 6 weeks due to ongoing or impending oncologic emergency (eg, tumor mass effect, tumor lysis syndrome).
• Primary immunodeficiency.

Sponsors & Collaborators

• Peking University: collaborator
• Chinese PLA General Hospital: lead

Study Sites (6)

Biotherapeutic Department of Chinese PLA General Hospital

Beijing, Beijing Municipality, 100853, 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

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

Central Study Contacts

Weidong Han, Ph.D.

CONTACT

+86-010-55499341; hanwdrsw@sina.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: June 22, 2024
• First Posted: July 1, 2024
• Study Start: February 15, 2025
• Primary Completion (Estimated): February 15, 2027
• Study Completion (Estimated): February 15, 2028
• Last Updated: March 16, 2026

Record last verified: 2026-03

Locations

CN (6)