Autologous BCMA-targeted CAR-T Cell Injection for Relapsed/Refractory Light Chain Amyloidosis

An Exploratory Clinical Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of Autologous BCMA-targeted CAR-T Cell Injection in Participants With Relapsed/Refractory Light Chain Amyloidosis

Systemic light chain amyloidosis (AL amyloidosis) is the most common type of systemic amyloidosis, with diverse clinical manifestations and difficulties in diagnosis and treatment. AL amyloidosis may involve multiple organs; the kidney and heart are the most commonly involved organs. The treatment goal is to reduce monoclonal immunoglobulin light-chain levels, prevent further amyloid deposition in important organs, and alleviate or reverse organ dysfunction caused by amyloid deposition. The principal approach to achieve this goal is to eliminate the plasma-cell or B-cell clones producing abnormal light chains. For patients with relapsed/refractory AL amyloidosis, the protocol states that there is currently no suitable treatment method and that participation in clinical trials is recommended.

This study evaluates targeted BCMA autologous CART cell injection in participants with relapsed/refractory light chain amyloidosis. The main purpose is to evaluate safety, preliminarily verify efficacy, and explore in vivo pharmacokinetics, pharmacodynamics, immunogenicity and related characteristics after infusion.

This is an open-label, fixed-dose exploratory clinical study to observe the safety and efficacy of targeted BCMA autologous CART cell injection in participants with relapsed/refractory light chain amyloidosis. The study is expected to enroll 30 participants and uses a fixed dose of 1.0×10^6 CAR-T/kg. The safety observation period is 28 days after CAR-T administration.

The study process includes screening, PBMC leukapheresis, pre-lymphodepletion examination, lymphodepleting conditioning, infusion of targeted BCMA autologous CART cell injection with the infusion day defined as Day 0, and the main follow-up period.

Before infusion, participants receive fludarabine plus cyclophosphamide lymphodepleting conditioning from Day -5 to Day -3 for three consecutive days. The recommended regimen is cyclophosphamide 250 mg/m²/day by intravenous infusion once daily for three days and fludarabine 25 mg/m²/day by intravenous infusion once daily for three days. The investigator may adjust the conditioning regimen according to renal function and creatinine clearance, such as replacing fludarabine with bendamustine or reducing the dose.

The targeted BCMA autologous CART cell injection is infused once on Day 0 by intravenous injection and completed within 30 minutes. If an adverse event occurs after conditioning and before infusion and the investigator determines that infusion should be suspended, infusion may be delayed until the adverse event recovers to a state allowing infusion. Before infusion, the investigator should reassess whether repeated lymphodepleting conditioning is needed.

The main follow-up period lasts from infusion of targeted BCMA autologous CART cell injection until the participant meets the criteria for exit from main follow-up or completes the 2-year main follow-up visit at Day 720. Efficacy assessments are performed at Day 28, Day 60 and Day 90, and then every 90 days until the end of main follow-up. Participants who complete the 2-year main follow-up enter long-term follow-up. Participants who meet criteria to exit main follow-up enter long-term visits until death, withdrawal from the study, or 15 years after cell infusion.

Inclusion Criteria:

• The participant must personally sign an ethics-committee-approved informed consent form before study start.

• Age ≥18 years.

• Pathologically confirmed light chain amyloidosis.

• Relapsed/refractory light chain amyloidosis previously treated with 2 or more lines of therapy.

• dFLC >50 mg/L.

• Expected survival ≥12 weeks.

• ECOG score ≤2.

• Diagnosis of AL amyloidosis must meet the following conditions: (1) clinical manifestations, physical examination, laboratory or imaging examinations confirm tissue or organ involvement; (2) tissue biopsy pathology confirms amyloid deposition, and the precursor protein of amyloid protein is immunoglobulin light chain or heavy and light chain; and the participant is relapsed/refractory.

• Female participants of childbearing potential should agree to use effective contraception from the date of signing informed consent until 365 days after infusion. Effective contraception is defined as abstinence or contraception using methods specified in the protocol with an annual failure rate <1%.

• Adequate organ function before enrollment, meeting all of the following:

  • Absolute neutrophil count ≥1.0×10^9/L; granulocyte colony-stimulating factor (G-CSF) support is permitted.
  • Platelet count ≥50×10^9/L.
  • Hemoglobin ≥8 g/dL.
  • Bilirubin ≤1.5×upper limit of normal (ULN), except biliary obstruction caused by tumor compression.
  • ALT or AST ≤2.5×ULN; for participants with liver involvement, ≤5×ULN.
  • Mayo 2004 stage I-IIIa.
  • Stable coagulation function: INR ≤1.5 and APTT ≤1.2×ULN, except tumor-related anticoagulant therapy.
  • Baseline oxygen saturation on room air >92%.

Exclusion Criteria:

• Participants who have received the following prior treatments:

  • Prior gene therapy before enrollment.
  • Live vaccine injection within 4 weeks before enrollment.
  • Other interventional clinical study drug treatment within 12 weeks before leukapheresis.

• Central nervous system involvement or complete intestinal obstruction.

• Moderate or higher pleural effusion or ascites that is difficult to control with conventional treatment and requires continuous catheter drainage.

• Active malignancy within the past 5 years, unless it is a curable tumor and has been clearly cured.

• HBsAg positivity with abnormal peripheral blood HBV DNA testing; HCV antibody positivity with peripheral blood HCV RNA positivity; HIV antibody positivity; CMV DNA positivity; or positive syphilis RPR test.

• Uncontrolled active infection, except CTCAE grade <2 urogenital infection and upper respiratory tract infection.

• Severe heart disease, including but not limited to unstable angina, myocardial infarction within 6 months before screening, congestive heart failure (New York Heart Association [NYHA] class ≥III), positive six-minute walk test, interventricular septum and left ventricular posterior wall thickness >1.5 cm, or ventricular arrhythmia and atrioventricular block indicated by ambulatory electrocardiography.

• Hypertension that cannot be controlled by medication.

• Toxicity from prior treatment not recovered to baseline or ≤grade 1 according to NCI CTCAE v5.0, except alopecia and clinically insignificant laboratory abnormalities.

• Major surgery within 2 weeks before enrollment, or planned surgery during the waiting period before infusion or within 12 weeks after study treatment, except planned local anesthesia surgery.

• Solid organ transplantation.

• Pregnant or breastfeeding women.

• History of central nervous system disease, such as cerebral aneurysm, epilepsy, stroke, senile dementia or psychiatric disease, or disturbance of consciousness.

• Other systemic disease judged unstable by the investigator, including but not limited to severe hepatic, renal or metabolic disease requiring medication.

• Known life-threatening allergic reaction, hypersensitivity or intolerance to the CAR-T cell product or its components.

• Bleeding or severe thrombosis as judged by the investigator, hereditary/acquired bleeding or severe thrombosis, including hemophilia, coagulopathy, thrombocytopenia and hypersplenism, or current thrombolytic or anticoagulant therapy.

• Other conditions that the investigator considers unsuitable for enrollment.