Study of Eque-cel CAR-T Therapy in Newly Diagnosed Severe AL Amyloidosis

Exploratory Clinical Study of Fully Human BCMA Chimeric Antigen Receptor Autologous T-cell Injection (Equecabtagene Autoleucel, Eque-cel) for the Treatment of Newly Diagnosed Mayo Stage IIIb AL Amyloidosis Patients

The goal of this clinical trial is to learn if Equecabtagene Autoleucel(Eque-cel), a Chimeric Antigen Receptor T-cell (CAR-T) therapy, works to treat severe Light Chain (AL) Amyloidosis in newly diagnosed adults with Mayo Stage IIIb. It will also learn about the safety and effects of Eque-cel. The main questions it aims to answer are:

Does Eque-cel lead to hematologic remission (achieving a very good partial response or better) in AL amyloidosis? How safe is Eque-cel for these patients, and what side effects might occur?

Participants will:

Undergo blood cell collection to create personalized Eque-cel therapy. Receive pre-treatment to prepare their body for the therapy (lymphodepletion). Receive a single infusion of Eque-cel. Be monitored closely for 24 weeks after infusion, followed by long-term checkups for up to 15 years.

This exploratory clinical trial investigates the efficacy and safety of Eque-cel , a fully human B-cell Maturation Antigen (BCMA)-targeted CAR-T cell therapy, in treating newly diagnosed Mayo Stage IIIb AL amyloidosis, a rare and severe systemic disorder characterized by abnormal plasma cell proliferation and amyloid fibril deposition leading to organ dysfunction. Current treatments, such as high-dose chemotherapy with stem cell transplantation or daratumumab-based regimens, fail to meet the urgent needs of Stage IIIb patients due to severe cardiac involvement, poor tolerability, and lack of approved standard therapies, necessitating rapid, low-cardiotoxicity interventions. Eque-cel, approved for relapsed/refractory multiple myeloma in China, has shown promise in prior studies with high hematologic response rates and rapid action, offering a potential solution for this high-risk population.

This study is an interventional clinical trial focused on treating newly diagnosed Mayo Stage IIIb AL Amyloidosis patients. It is a Phase II exploratory study aimed at initially validating the efficacy and safety of Eque-cel. The study employs a single-arm, open-label design, with all participants receiving Eque-cel CAR-T cell therapy (at a dose of 1.0×10⁶ CAR-T cells/kg), without randomization or blinding, to directly assess treatment outcomes. The trial is conducted at a single center (Zhongshan Hospital, Fudan University) and plans to enroll up to 17 participants. The process includes peripheral blood mononuclear cell (PBMC) collection, optional bridging therapy, lymphodepletion preconditioning, and cell infusion, followed by a 24-week primary follow-up period and long-term monitoring for up to 15 years. The study aims to complete patient enrollment within 2 years. The primary endpoint is to evaluate the hematologic response rate post-treatment, while secondary endpoints include safety and survival-related metrics. Through innovative CAR-T therapy, this study seeks to address unmet clinical needs and provide new treatment hope for this high-risk population.

Inclusion Criteria:

1. Subjects aged ≥18 years, regardless of gender.

2. Performance status: Eastern Cooperative Oncology Group (ECOG) performance status score ≤2.

3. Clinically diagnosed with newly diagnosed AL (light chain) amyloidosis, classified as Mayo Stage IIIb per the revised 2004 Mayo Clinic staging system at screening, with serum N-terminal pro-brain natriuretic peptide (NT-proBNP) >8500 ng/L and serum cardiac troponin T (cTnT) >0.035 μg/L or cardiac troponin I (cTnI) >0.01 g/L.

4. Presence of measurable hematologic disease at screening, defined as at least one of the following:

   1. Difference in free light chains (dFLC) >4 mg/dL, or
   2. Involved free light chain (iFLC) >4 mg/dL with abnormal kappa/lambda (κ/λ) ratio, or
   3. Serum protein electrophoresis (SPEP) M protein >0.5 g/dL.

5. Histopathological diagnosis of amyloidosis based on polarized light microscopy of Congo red-stained tissue specimens showing green birefringence, with confirmation of AL-derived amyloid deposits by at least one of the following methods:

   1. Immunohistochemistry/immunofluorescence,
   2. Mass spectrometry,
   3. Electron microscopy for characteristic appearance/immunoelectron microscopy.

6. Presence of clonal plasma cells in bone marrow, detectable by light microscopy or flow cytometry.

7. Presence of M protein in blood or urine, with exclusion of multiple myeloma, Waldenström macroglobulinemia, or other lymphoplasmacytic proliferative disorders.

8. Organ involvement: At least one organ affected (kidney, heart, liver, nervous system, gastrointestinal tract, lung, soft tissue) as per consensus guidelines.

9. Expected survival time ≥12 weeks.

10. Subjects must have adequate organ function, meeting all of the following laboratory criteria prior to enrollment:

    1. Complete blood count: Absolute neutrophil count (ANC) ≥1×10⁹/L; absolute lymphocyte count (ALC) ≥0.3×10⁹/L.
    2. Hemoglobin >60 g/L (no red blood cell [RBC] transfusion within 7 days prior to testing; use of recombinant human erythropoietin allowed).
    3. Liver function: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5× upper limit of normal (ULN); total serum bilirubin ≤1.5× ULN.
    4. Renal function: Creatinine clearance (CrCl) ≥30 mL/min as calculated by the Cockcroft-Gault formula.
    5. Coagulation function: Fibrinogen ≥1.0 g/L; activated partial thromboplastin time (APTT) ≤1.5× ULN; prothrombin time (PT) ≤1.5× ULN.
    6. Blood oxygen saturation >91%.
    7. Echocardiogram showing left ventricular ejection fraction (LVEF) ≥40%.
    8. Systolic blood pressure (SBP) ≥90 mmHg (oral vasopressor support allowed).

11. Subjects and their spouses agree to use effective contraceptive methods (tools or medications) from the time of signing the informed consent form until one year after CAR-T cell infusion.

12. Subjects voluntarily sign the informed consent form (ICF).

Exclusion Criteria:

1. Subjects who have received any of the following treatments prior to enrollment:

   1. Gene therapy before enrollment;
   2. Live vaccine within 4 weeks before enrollment;
   3. Other interventional clinical trial drugs within 12 weeks before leukapheresis.

2. Positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) with detectable hepatitis B virus (HBV) DNA in peripheral blood; positive for hepatitis C virus (HCV) antibody with detectable HCV RNA in peripheral blood; positive for human immunodeficiency virus (HIV) antibody; positive for cytomegalovirus (CMV) DNA; positive for syphilis testing.

3. Use of therapeutic doses of corticosteroids (defined as prednisone or equivalent >20 mg/day) within 7 days before screening, though physiological replacement, topical, and inhaled steroids are permitted.

4. Presence of uncontrolled active infection within 7 days before peripheral blood mononuclear cell (PBMC) collection (excluding genitourinary system infections and upper respiratory tract infections <CTCAE Grade 2).

5. Receipt of any systemic therapy for AL amyloidosis within 14 days before PBMC collection.

6. Undergoing major surgery within 14 days before PBMC collection, or planning surgery within 2 weeks after study treatment (subjects planning local anesthesia surgery are eligible to participate).

7. Unresolved non-hematologic toxicity from prior therapy to baseline or ≤Grade 1 (per NCI-CTCAE v5.0, excluding alopecia and Grade 2 peripheral neuropathy).

8. Known life-threatening allergic reaction, hypersensitivity, or intolerance to cellular products or their components.

9. Subjects with suspected or confirmed symptoms of central nervous system (CNS) involvement by plasma cell tumors.

10. Bone marrow plasma cells >30% with clinical symptoms of multiple myeloma accompanied by osteolytic bone lesions.

11. Severe active cardiovascular disease with significant clinical symptoms despite treatment, including but not limited to unstable angina, myocardial infarction, and severe arrhythmia (excluding those with implanted implantable cardioverter-defibrillator [ICD] or pacemaker).

12. Subjects with bleeding or severe thrombosis symptoms as judged by the investigator, or with genetic/acquired bleeding and severe thrombosis conditions (including hemophilia, coagulopathy, thrombocytopenia, splenomegaly), or currently receiving thrombolytic or anticoagulant therapy.

13. Subjects with hypertension that cannot be controlled by medication.

14. Subjects who have received solid organ transplantation.

15. Subjects with a history of central nervous system disorders (e.g., cerebral aneurysm, epilepsy, stroke, dementia, psychosis) or consciousness impairment.

16. Subjects with unstable systemic diseases as judged by the investigator, including but not limited to severe liver, kidney, or metabolic diseases requiring medical treatment.

17. Diagnosis of malignancy other than multiple myeloma within 5 years before screening, excluding adequately treated cervical carcinoma in situ, basal cell or squamous cell skin cancer, localized prostate cancer post-radical surgery, or ductal carcinoma in situ of the breast post-radical surgery.

18. Participation in another interventional clinical trial within 1 month before signing the ICF.

19. Women who are pregnant, breastfeeding, or planning to become pregnant.

20. Subjects who do not agree to or have not completed the signing of the ICF.

21. Other conditions deemed unsuitable for enrollment by the investigator.