AzTrials
AzTrials

Non-hodgkin LymphomaPhase 1/2NCT06323525

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

A Phase 1/2 study testing TCR reserved and Power3 (SPPL3) gene knock-out allogeneic CD19-targeting CAR-T cell (ATHENA-2 CAR-T), Fludarabine and Cyclophosphamide in people with Non-hodgkin Lymphoma, run by Chinese PLA General Hospital at 3 sites in China.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
Search all trials

Trial summary

The safety and efficacy of the chimeric antigen receptor (CAR)-T, a CD19-targeting, TRAC and Power3 (SPPL3) double genes deleted allogeneic CAR-T cell product, are undergoing rigorous evaluation in non-Hodgkin's lymphoma (NHL) subjects from our ATHENA trial (NCT06014073). Read more about this study

Who is it for?
Ages 18 to 70 years
Conditions the study is for
Non-hodgkin Lymphoma
What is being tested?
TCR reserved and Power3 (SPPL3) gene knock-out allogeneic CD19-targeting CAR-T cell (ATHENA-2 CAR-T), Fludarabine and Cyclophosphamide
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
30 participants
Where
3 sitesChina
Study dates
17 Apr 2024to 25 Apr 2027
Phase
Phase 1/2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 70 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Age 18-70 (inclusive).
  • Subjects who meet the following requirements:
  • 2.1 Histologically confirmed refractory/relapsed B cell NHL, including the following types defined by WHO 2016:
  • Diffuse large B-cell lymphoma not otherwise specified (DLBCL-NOS);
  • Primary mediastinal (thymic) large B-cell lymphoma (PMBCL);
  • Transformed follicular lymphoma (TFL);
Show all 39Show fewer
  • High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBCL);
  • Follicular lymphoma (FL);
  • Mantle cell lymphoma (MCL) (pathologically confirmed, with documentation of monoclonal B cells that have a chromosome translocation t(11;14)(q13;q32) and/or overexpress cyclin D1);
  • Marginal zone lymphoma (MZL), including nodal or splenic marginal zone B-cell lymphoma and mucosa-associated lymphoid tissue (MALT) lymphoma.
  • 2.2 Relapsed disease is defined as disease progression (PD) after achieving disease remission (including CR and PR) with the latest standard regimen.
  • 2.3 Refractory disease is defined as no CR to first-line therapy:
  • Evaluation of PD (never reached response or SD) after standard first-line treatment, or
  • SD as best response after at least 4 cycles of first-line therapy (eg,4 cycles of R-CHOP), or
  • PR as best response after at least 6 cycles and biopsy-proven residual disease or disease progression ≤ 6 months of therapy, or
  • Refractory post-autologous stem cell transplant (ASCT): i. Disease progression or relapsed less than or equal to 12 months of ASCT (must have biopsy proven recurrence in relapsed individuals); ii. If salvage therapy is given post-ASCT, the individual must have had no response to or relapsed after the last line of therapy.
  • 2.4 Individuals who are intolerant to standard treatment can also be included in the study in the investigator's judgment.
  • Individuals must have received adequate prior therapy:
  • 3.1 For MCL, prior therapy must have included:
  • Anthracycline or bendamustine-containing chemotherapy and
  • Anti-CD20 monoclonal antibody (unless investigator determines that tumor is CD20-negative) and
  • Bruton's tyrosine kinase inhibitor (BTKi).
  • 3.2 For other types, prior therapy must have included:
  • Anti-CD20 monoclonal antibody (unless investigator determines that tumor is CD20-negative) and
  • Anthracycline containing chemotherapy regimen.
  • 3.3 For individual with transformed FL must have relapse or refractory disease after transformation to DLBCL.
  • At least 1 measurable lesion: lymph node site with a long axis >1.5cm, extranodal site with a long axis >1.0cm (according to the Lugano2014 criteria). Lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy.
  • CD19 positive (detected by immunohistochemistry [IHC]).
  • 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.
  • Absolute neutrophil count (ANC) ≥ 1 x 10^9/L, Platelet count ≥50 x 10^9/L, hemoglobin (Hgb) ≥ 80g/L (hemocytopenia caused by lymphoma invasion of bone marrow is not subject to conditions above).
  • Adequate renal, hepatic, pulmonary and cardiac function defined as:
  • 9.1 Serum creatinine≤1.5 upper limit of normal (ULN) or creatinine clearance (as estimated by Cockcroft Gault) ≥ 60 mL/min.
  • 9.2 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.
  • 9.3 Cardiac ejection fraction ≥ 50%, no evidence of pericardial effusion as determined by an echocardiogram (ECHO), and no clinically significant electrocardiogram (ECG) findings.
  • 9.4 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.
  • 9.5 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.

Who cannot join

  • 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) or follicular lymphoma unless disease free for at least 3 years.
  • Autologous stem cell transplant with therapeutic intent within 3 months of planned ATHENA-2 CAR-T infusion.
  • History of allogeneic stem cell transplantation.
  • Patients who received any immunocellular therapy within 3 months before enrollment.
  • Patients who have used any of the following agents or treatments within a specific period of time:
Show all 25Show fewer
  • 6.1 Received any chemotherapy drugs or small molecule targeted drugs within 2 weeks prior to lymphodepletion;
  • 6.2 Received any monoclonal antibodies, antibody drug conjugates (ADCs), or bispecific antibodies within 3 weeks prior to lymphodepletion;
  • 6.3 Received radiotherapy within 6 weeks prior to lymphodepletion. However, if disease progressed at the site of radiotherapy, or if there are positive lesions detected by PET-CT at non-radiotherapy sites, enrollment is allowed.
  • Subjects with detectable cerebrospinal fluid malignant cells, or brain metastases, or with a history of central nervous system (CNS) lymphoma or primary CNS lymphoma.
  • Presence of donor-specific anti-HLA antibodies directed against ATHENA-2 CAR-T.
  • History of severe, immediate hypersensitivity reaction attributed to lymphodepletion drugs or any component of ATHENA-2 CAR-T.
  • 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.
  • History of severe immediate hypersensitivity reaction to any of the agents used in this study.
  • Vaccine ≤ 6 weeks prior to planned start of conditioning regimen.
  • 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.

Trial locations and contacts

3 sites in 1 country. Contact the study team or a site near you to ask about taking part.

Weidong Han, Ph.D contact

+86-010-55499341

hanwdrsw@sina.com

China3 sites, 3 recruiting

  • Biotherapeutic Department of Chinese PLA General Hospital

    Beijing, Beijing Municipality, 100853

    Weidong Han, M.D, +86-010-66937463, hanwdrsw@sina.com

    Qingming Yang, M.D

    Recruiting

  • Biotherapeutic Department of Chinese PLA General Hospital

    Beijing

    Weidong Han, Ph.D, +86-010-55499341, hanwdrsw@sina.com

    Recruiting

  • School of Life Sciences, Peking University

    Beijing

    Wensheng Wei, Ph.D, 010-62757794, wswei@pku.edu.cn

    Recruiting

Other trials in China

About this study

Official title: A Phase 1/2 Single-center Study Evaluating the Safety and Efficacy of TCR Reserved and Power3 (SPPL3) Gene Knock-out Allogeneic CD19-targeting CAR-T Cell (ATHENA-2) Therapy in Adults With Refractory/Relapsed B-cell Lymphoma

The safety and efficacy of the chimeric antigen receptor (CAR)-T, a CD19-targeting, TRAC and Power3 (SPPL3) double genes deleted allogeneic CAR-T cell product, are undergoing rigorous evaluation in non-Hodgkin's lymphoma (NHL) subjects from our 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 HLA-mismatched fratricide between host T cells and TCR-reserved Power3 (SPPL3)-deleted allogenic CAR T cells was markedly slashed, which in combination with our observed clinical safety date 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 the ATHENA-2 study, our design is to preserve the expression of the TCR on T cells from healthy donors while selectively disabling the Power3 (SPPL3) gene to prepare ATHENA-2 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 ATHENA-2 in B-cell NHL.

Read the detailed description

Phase 1 (dose escalation)

In phase 1, 6-18 subjects will be enrolled. Subjects will receive 3 doses of ATHENA-2 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 ATHENA-2 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 ATHENA-2 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 ATHENA-2 CAR-T 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 are to evaluate the tolerability and safety of ATHENA-2 CAR-T in patients with r/r B-cell NHL, and determine RP2D. The primary purpose of the phase 2 study is to evaluate the efficacy of ATHENA-2 CAR-T in the above population.

Being tested
TCR reserved and Power3 (SPPL3) gene knock-out allogeneic CD19-targeting CAR-T cell (ATHENA-2 CAR-T), Fludarabine, Cyclophosphamide
Medical subject headings
Lymphoma, Non-Hodgkin

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • TCR reserved and Power3 (SPPL3) gene knock-out allogeneic CD19-targeting CAR-T cell (ATHENA-2 CAR-T)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.

  • FludarabineDrug

    Also called Fludarabine Phosphate for Injection

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

  • CyclophosphamideDrug

    Also called Cyclophosphamide for Injection

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

Study groups in NCT06323525
Study groupRoleWhat they receive
Patients with refractory or relapsed B-cell lymphomaExperimentalA conditioning chemotherapy regimen of fludarabine and cyclophosphamide will be administered followed by investigational treatment, Power3 (SPPL3) gene knock-out allogeneic CD19-targeting CAR-T.
Receives: Biological: TCR reserved and Power3 (SPPL3) gene knock-out allogeneic CD19-targeting CAR-T cell (ATHENA-2 CAR-T); Drug: Fludarabine; Drug: Cyclophosphamide

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Phase 1: Incidence of adverse events (AEs) defined as DLT

    DLT is defined as any AE related to the investigational drug that occurs within 28 days after administration of the ATHENA-2 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 acute GVHD (aGVHD) that is not resolved to Grade 1 or 2 within 7 days, with the exception of isolated skin involvement aGVHD;
    • Grade 4 CRS or grade 3 CRS that is not resolved to grade 2 or lower within 2 weeks;
    • Grade 3 ICANS lasting for ≥7 days or Grade 4 ICANS;
    • Any other Grade ≥4 and Grade 3 AEs related to the ATHENA-2 CAR-T that lasts for ≥14 days, except hematology toxicity.

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

  2. Phase 1: Recommended phase 2 dose (RP2D)

    The RP2D will be determined based on the maximum tolerated dose, occurrence of dose-limiting toxicity, the obtained efficacy results, pharmacokinetics/pharmacodynamics and other data according to the phase 1.

    Measured: 12 months

  3. Phase 2: 3-month objective response rate (ORR)

    ORR is defined as the proportion of patients who have achieved complete response (CR) and partial response (PR) assessed by investigators.

    Measured: 3 months

  4. Phase 2: Complete response (CR) rate

    CR is assessed by investigators and based on the Lugano 2014 assessment criterion. CR rate is defined as the proportion of patients who have achieved CR assessed by investigators.

    Measured: 24 months

  5. Phase 2: Duration of Response (DOR)

    DOR is defined as the date of their first CR or PR (which is subsequently confirmed) to PD assessed by investigators, or death regardless of cause.

    Measured: 24 months

  6. 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 their last contact date.

    Measured: 24 months

  7. 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 their last evaluable disease assessment date.

    Measured: 24 months

Secondary outcomes (7)

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

    The absolute count of ATHENA CAR-T cells in peripheral blood is assessed by flow cytometry. Blood samples were collected before and one year after cell infusion (until CAR-T cells were not detected for two consecutive times) to detect the number and copy number of CAR-T cells, and to evaluate the pharmacokinetics of CAR-T.

    Measured: 12 months

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

    The level of CD19+ cells in peripheral blood will be detected by flow cytometry.

    Measured: 12 months

  3. Phase 1 and phase 2: Level of serum cytokines in peripheral blood

    The level of serum cytokines in peripheral blood will be detected by enzyme-linked immuno sorbent assay.

    Measured: Up to 28 days after infusion

  4. Phase 1: 3-month ORR

    ORR is defined as the proportion of patients who have achieved CR and PR assessed by investigators and based on the Lugano 2014 assessment criterion.

    Measured: 3 months

  5. Phase 1: OS

    The definition of OS has already been mentioned above.

    Measured: 24 months

  6. Phase 1: PFS

    The definition of PFS has already been mentioned above.

    Measured: 24 months

  7. Phase 2: Incidence of AEs

    AEs are defined as any adverse medical event from the date of enrollment to 24 months after CAR-T cells infusion.

    Measured: 24 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted21 Mar 2024
  2. Study start17 Apr 2024
  3. Primary completion25 Apr 2026 (estimated)
  4. Study completion25 Apr 2027 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
30 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT06323525
Sponsor's protocol ID
CHN-PLAGH-BT-083
Status last verified
May 2025
First submitted
8 Mar 2024
Last updated
25 May 2025
Results posted
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing TCR reserved and Power3 (SPPL3) gene knock-out allogeneic CD19-targeting CAR-T cell (ATHENA-2 CAR-T), Fludarabine and Cyclophosphamide in people with Non-hodgkin Lymphoma, run by Chinese PLA General Hospital at 3 sites in China.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 39 inclusion and 25 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 25 May 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in China. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Weidong Han, Ph.D (+86-010-55499341, hanwdrsw@sina.com), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Phase 1: Incidence of adverse events (AEs) defined as DLT (time frame: First infusion date of CAR-T cells up to 28 days). The study lists 7 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT06323525.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 May 2025.

AzTrials uses cookies for analytics and advertising. You can accept or reject them; the site works either way. Privacy Policy.

Free account

Log in to keep searching

You’ve used your 3 free searches. AzTrials is free: log in or create a free account to keep searching clinical trials and save the ones you want to follow.

Create a free accountLog in