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

Official title

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

Overview

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 (purified CAR-positive T cells \> 90%). 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).

Detailed description

Phase 1 (dose escalation)

In phase 1, 6-18 subjects will be enrolled. Subjects will receive 3 doses of allogeneic Power3 (SPPL3) 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 (SPPL3) 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 (SPPL3) 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 (SPPL3) 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 (SPPL3) knock-out CD19 CAR-T in the above population.

Interventions

• Biological TCR reserved and Power3 (SPPL3) Gene Knock-out Allogeneic CD19-targeting CAR-T cell
  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.
• Drug Fludarabine
  Intravenous fludarabine 30\~50 mg/m\^2/day on days -5, -4, and -3.
• Drug Cyclophosphamide
  Intravenous cyclophosphamide 500\~1000 mg/m\^2/day on days -5, -4, and -3.

Primary outcome measures

• Phase 1: Incidence of adverse events (AE) defined as DLT [Time frame: First infusion date of CAR-T cells up to 28 days]
• Phase 1: RP2D [Time frame: 12 months]
• Phase 2: Objective response rate (ORR) [Time frame: 24 months]
• Phase 2: Overall Survival (OS) [Time frame: 24 months]
• Phase 2: Progression Free Survival (PFS) [Time frame: 24 months]

Secondary outcome measures (7)

• Phase 1 and phase 2: Level of CAR-positive T cells circulating in blood over time [Time frame: 12 months]
• Phase 1 and phase 2: Level of CD19+ cells in peripheral blood [Time frame: Up to 28 days after infusion]
• Phase 1 and phase 2: Level of interleukin 6 (IL-6) in peripheral blood [Time frame: Up to 28 days after infusion]
• Phase 1: 3-month ORR [Time frame: 3 months]
• Phase 1: OS [Time frame: 24 months]
• Phase 1: PFS [Time frame: 24 months]
• Phase 2: Incidence of AE [Time frame: 24 months]

Eligibility criteria

Inclusion criteria

• 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.

Exclusion criteria

• 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.
• Radioimmunotherapy, radiotherapy, within 8 weeks (except prophylaxis of CNS involvement) before Inclusion.
• 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.
• 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.
• History of symptomatic deep vein thrombosis or pulmonary embolism requiring systemic anticoagulation within 6 months of enrollment.
• Any medical condition likely to interfere with assessment of safety or efficacy of study treatment.
• Vaccine ≤ 6 weeks prior to planned start of conditioning regimen.
• Presence of DSAs directed against allogeneic SPPL3 knock-out CD19 CAR-T.
• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 6 centers

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

Identifiers

NCT: NCT06481735 · CHN-PLAGH-BT-087

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗