Sonrotoclax and BCMA Bispecific Antibody in Newly Diagnosed Systemic AL Amyloidosis Based on t(11;14) Genetic Stratification

A Phase Ib/II, Non-Randomized, Biomarker-Stratified Umbrella Study of Chemotherapy-Free Strategies in Newly Diagnosed Systemic AL Amyloidosis Based on t(11;14) Status: Sonrotoclax and a BCMA/CD3 Bispecific Antibody (AL-005)

This study is a prospective, single-center, phase Ib/II clinical trial designed to evaluate the tolerability of sonrotoclax plus dexamethasone in this phase Ib/II umbrella study and to determine the recommended phase II dose (RP2D). It also aims to assess the safety and hematologic response rate of sonrotoclax plus dexamethasone in patients with newly diagnosed systemic light-chain amyloidosis (NDAL) harboring t(11;14), and of a BCMA/CD3 bispecific antibody in patients with NDAL without t(11;14). In addition, this study seeks to explore a chemotherapy-free treatment strategy based on t(11;14)-guided genetic stratification.

Inclusion Criteria:

• Able to understand and voluntarily sign the informed consent form (ICF).

• Age ≥18 years and ≤70 years.

• Confirmed diagnosis of primary light-chain amyloidosis, according to the diagnostic and treatment guidelines for primary light-chain amyloidosis, 2021 revised edition.

  1. Subjects entering the phase Ib dose-escalation stage must also have confirmed t(11;14) translocation by FISH or other genetic testing.

Newly diagnosed systemic AL amyloidosis, with no prior systemic anti-tumor therapy for AL amyloidosis.

• Measurable disease at screening, defined as:

  a) Difference between involved and uninvolved serum free light chains (dFLC) >20 mg/L.

• Eastern Cooperative Oncology Group (ECOG) performance status ≤3.

• Adequate hepatic function, defined as total bilirubin <1.5 × upper limit of normal (ULN) (total bilirubin <3 × ULN for patients with Gilbert syndrome), and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <3 × ULN.

• Adequate renal function, defined as creatinine clearance ≥30 mL/min, calculated using the Cockcroft-Gault formula.

• Baseline oxygen saturation >92% on room air.

• Hematologic parameters within 7 days before the start of screening meeting the following criteria: absolute neutrophil count ≥1.0 × 10⁹/L, hemoglobin ≥70 g/L without whole blood or red blood cell transfusion within 7 days, and platelet count ≥70 × 10⁹/L without whole blood transfusion, platelet transfusion, or thrombopoietin receptor agonist treatment within 7 days; or deemed suitable for enrollment by the investigator based on clinical judgment.

• Women of non-childbearing potential are eligible. Female patients of childbearing potential must have a negative serum β-human chorionic gonadotropin or urine pregnancy test at screening.

• Male patients, women of childbearing potential, and their partners must voluntarily use effective contraceptive measures, as judged by the investigator, during the treatment period.

• Male patients must agree not to donate sperm from the initial screening period until 90 days after the last dose of study treatment.

• Patients must be willing and able to complete study procedures and follow-up assessments.

Note: Women of childbearing potential are defined as all women who have experienced menarche and are not postmenopausal and have not undergone surgical sterilization, such as hysterectomy, bilateral tubal ligation, or bilateral oophorectomy. Postmenopausal status is defined as amenorrhea for more than 12 consecutive months without another specified cause. Women using oral contraceptives or mechanical contraceptive methods, such as intrauterine devices, should be considered to be of childbearing potential.

Male subjects, including those who have undergone vasectomy, must agree to use condoms during sexual intercourse with women of childbearing potential and must have no plan to father a child from the date of signing the ICF, throughout the period of study drug administration, and for 3 months after the last dose of study treatment.

Exclusion Criteria:

• Non-AL amyloidosis, including hereditary amyloidosis and other non-AL types of amyloidosis.

• Diagnosis of symptomatic multiple myeloma, according to the Chinese Guidelines for the Diagnosis and Treatment of Multiple Myeloma, 2022 revised edition. Patients whose diagnosis is based solely on a serum free light-chain ratio ≥100 are not excluded.

• Peripheral neuropathy > grade 2 or painful neuropathy ≥ grade 2 at screening, regardless of whether the patient is currently receiving medication.

• History of another malignancy, other than AL amyloidosis, within 5 years before randomization.

• Known intolerance, allergy, or contraindication to the active ingredients of the BCMA/CD3 bispecific antibody or sonrotoclax.

• Unstable or active cardiovascular or cerebrovascular disease, meeting any of the following criteria:

  1. Unstable angina, symptomatic myocardial ischemia, myocardial infarction, or coronary revascularization within 180 days before the first dose;
  2. NT-proBNP >8500 ng/L;
  3. Congestive heart failure with hospitalization for cardiovascular disease within 4 weeks before randomization;
  4. Heart failure judged by the investigator to be caused by ischemic heart disease, such as prior myocardial infarction with elevated cardiac enzymes and electrocardiographic changes, or uncorrected valvular disease, rather than AL amyloid cardiomyopathy;
  5. History of sustained ventricular tachycardia or ventricular fibrillation, or history of atrioventricular (AV) node or sinoatrial (SA) node dysfunction requiring a pacemaker or implantable cardioverter-defibrillator (ICD) but without implantation. Patients with an implanted pacemaker or ICD may be enrolled;
  6. Corrected QT interval using Fridericia's formula (QTcF) >500 msec. Patients with an implanted pacemaker may be enrolled regardless of the corrected QT interval result;
  7. Supine systolic blood pressure <90 mmHg;
  8. Any other cardiovascular or cerebrovascular disease that, in the investigator's judgment, makes the subject unsuitable for participation in this study.

Known active human immunodeficiency virus (HIV) infection or HIV seropositivity.

• Active hepatitis B or hepatitis C infection. Hepatitis serology testing is required at screening. If hepatitis B surface antigen is positive, a negative DNA polymerase chain reaction (PCR) result must be confirmed before enrollment. -For patients receiving anti-HBV therapy, a negative HBV DNA PCR result must be confirmed before enrollment. If hepatitis C antibody is positive, RNA PCR testing must be performed, and a negative result must be confirmed before enrollment.
• Pregnant or breastfeeding women.
• Any active gastrointestinal dysfunction that affects the patient's ability to swallow tablets, or any active gastrointestinal dysfunction that may affect the absorption of study treatment.
• Major surgery, such as surgery requiring general anesthesia, within 2 weeks before enrollment, incomplete recovery from prior surgery, or planned surgery during the study period. Kyphoplasty or vertebroplasty is not considered major surgery. Patients scheduled to undergo procedures under local anesthesia may participate in the study.
• Receipt of a live attenuated vaccine within 4 weeks before the first dose of study treatment.
• Any active severe psychiatric or psychological disorder, medical disease, or other symptom or condition that, in the investigator's judgment, may affect treatment, compliance, or the ability to provide informed consent.

Contraindication to any required concomitant medication or supportive care.

• Any disease or complication that may interfere with study procedures.
• Unwillingness or inability to comply with the protocol.