An Optimized Treatment for Patients With Primary Systemic Light Chain Amyloidosis
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 39
- 试验地点
- 3
- 主要终点
- hematological ≥VGPR rate within four cycles of induction therapy
研究概览
简要总结
The goal of this study is to evaluate the efficacy and safety of Sonrotoclax combined Regimen in patients with t(11;14) AL amyloidosis. Participants will receive the Sonrotoclax Plus Dexamethasone regimen with or without Daratumumab for 12 cycles. The Hematologic Response, Organ Response, Survival, and Safety will be evaluated.
详细描述
Treatment options for AL amyloidosis are limited. Before the approval of daratumumab, newly diagnosed light-chain amyloidosis was often managed with anti-myeloma regimens such as bortezomib. For patients with relapsed/refractory (R/R) disease, there is currently a lack of standard treatment options both domestically and internationally. Guidelines recommend enrollment in clinical trials or the use of regimens containing previously unexposed agents, such as bortezomib or daratumumab.
Based on preliminary data of BCL-2 inhibitors in t(11;14) amyloidosis, this study aims to explore the efficacy and safety of sonrotoclax and dexamethasone with or without Daratumumab. Newly diagnosed patients with t（11;14）will receive the combination of sonrotoclax, daratumumab, and dexamethasone. t(11;14) Patients with relapsed/refractory AL amyloidosis (RRAL) will be treated with sonrotoclax plus dexamethasone. For transplant-eligible patients, stem cell collection is permitted during the induction phase of therapy. The timing of ASCT may be assessed after the primary endpoint evaluation (completion of 4 treatment cycles) and determined by the investigator.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients who meet the diagnostic criteria for Primary Systemic Light Chain Amyloidosis (according to the Systemic Light Chain Amyloidosis Diagnosis and Treatment Guidelines (2021 Revision)).
- •Age ≥ 18 years.
- •Confirmed FISH test result of t(11;14) positive by each center or a third-party laboratory, or a prior FISH test report indicating t(11;14) positivity
- •ECOG Performance Status score of 0-
- •Presence of measurable disease, defined by at least one of the following criteria:
- •Serum M-protein ≥ 0.5 g/dL
- •Serum free light chain (FLC) level ≥ 40 mg/L with an abnormal kappa/lambda ratio.
- •Adequate organ function, defined as:
- •Hemoglobin (HGB) > 80 g/L
- •Platelet count > 50 × 10⁹/L
- •Absolute neutrophil count (ANC) > 1.0 × 10⁹/L
- •Total bilirubin ≤ 2.0 × ULN; AST and ALT ≤ 3.0 × ULN
- •Creatinine clearance (CrCl) ≥ 30 mL/min
- •Oxygen saturation ≥ 90%
- •Life expectancy greater than 6 months.
- •Patient understands and voluntarily signs an informed consent form (ICF).
- •Cohort Assignment:
- •Cohort A: Includes patients who are newly diagnosed or have not been previously exposed to anti-CD38 monoclonal antibody therapy.
- •Cohort B: Includes patients who are insensitive to or have relapsed after anti-CD38 monoclonal antibody therapy.Insensitivity to anti-CD38 monoclonal antibody therapy is defined as failure to achieve at least a Partial Response (PR) after 1 cycle, or failure to achieve at least a Very Good Partial Response (VGPR) after 3 cycles of an anti-CD38-containing regimen.
排除标准
- •Meets the diagnostic criteria for active multiple myeloma or active lymphoplasmacytic lymphoma
- •Presence of other malignancies at an advanced stage with systemic metastases.
- •IgM-type AL amyloidosis.
- •Prior treatment with a BCL-2 inhibitor (BCL-2i).
- •Presence of any of the following severe cardiovascular diseases
- •Mayo 2004 stage IIIb: NT-proBNP >8500 ng/L.
- •NYHA class IIIb-IV
- •Left ventricular ejection fraction (LVEF) <40%.
- •QT interval corrected by Fridericia's formula (QTcF) >480 ms
- •Investigator assessment that heart failure is due to ischemic heart disease (e.g., prior history of myocardial infarction with elevated cardiac enzymes and ECG changes) or uncorrected valvular disease, rather than primarily caused by AL amyloidosis.
- •Hospitalization for unstable angina or myocardial infarction within 6 months prior to the first dose, or cardiac interventional therapy or coronary artery bypass grafting within 6 months.
- •For patients with congestive heart failure, hospitalization for cardiovascular disease within 4 weeks prior to Cycle 1 Day
- •History of sustained ventricular tachycardia or aborted ventricular fibrillation, or history of atrioventricular node or sinus node dysfunction requiring a pacemaker/implantable cardioverter-defibrillator (ICD) but not implanted.
- •Severe or persistent infection that is not effectively controlled. (Acute infection requiring antibacterial, antifungal, or antiviral therapy that has not resolved within 14 days prior to dosing).
- •Positive status for human immunodeficiency virus (HIV) antibody (HIVAb).
- •Serological status reflecting active viral hepatitis B (HBV) or hepatitis C (HCV) infection, as follows:
- •Positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb). Patients who are positive for HBcAb but negative for HBsAg are eligible if HBV DNA is undetectable and they are willing to undergo monthly monitoring for HBV reactivation.
- •Positive for hepatitis C virus (HCV) antibody. Patients who are positive for HCV antibody are eligible if HCV RNA is undetectable.
- •Patients receiving renal replacement therapy.
- •Patients with known hypersensitivity to any component of the investigational regimen.
- •Any condition that, in the investigator's judgment, would increase the risk to the subject or affect the study results.
- •Patients with AL amyloidosis currently participating in other investigational drug clinical studies.
- •Patients who are pregnant, breastfeeding, or planning to become pregnant during the study participation.
- •Patients who are receiving any moderate or strong CYP3A4 inhibitors (within ≤7 days or 5 half-lives, whichever is shorter) or strong CYP3A4 inducers (within ≤14 days or 5 half-lives, whichever is shorter) prior to the first dose of the study drug; or patients who require continuous treatment with moderate or strong CYP3A inhibitors or strong CYP3A inducers
研究组 & 干预措施
Sond±D
Cohort A: (sample size 20) sonrotoclax combined with daratumumab and dexamethasone in t(11;14) AL amyloidosis, newly diagnosed or previously untreated with anti-CD38 mAb therapy.
Cohort B: (sample size 19) sonrotoclax combined with dexamethasone in t(11;14) AL patients insensitive to or relapsed after anti-CD38 mAb therapy
All patients will receive up to 12 cycles therapy until major organ deterioration (MOD)-progression free survival (PFS) event, death, withdrawal of informed consent, need for alternative therapy, intolerance, or study termination, whichever occurs first.
Transplant-eligible patients could undergo stem cell collection during induction; autologous transplantation was permitted after completion of the primary endpoint assessment (after cycle 4) at investigator discretion
干预措施: sonrotoclax (Drug)
Sond±D
Cohort A: (sample size 20) sonrotoclax combined with daratumumab and dexamethasone in t(11;14) AL amyloidosis, newly diagnosed or previously untreated with anti-CD38 mAb therapy.
Cohort B: (sample size 19) sonrotoclax combined with dexamethasone in t(11;14) AL patients insensitive to or relapsed after anti-CD38 mAb therapy
All patients will receive up to 12 cycles therapy until major organ deterioration (MOD)-progression free survival (PFS) event, death, withdrawal of informed consent, need for alternative therapy, intolerance, or study termination, whichever occurs first.
Transplant-eligible patients could undergo stem cell collection during induction; autologous transplantation was permitted after completion of the primary endpoint assessment (after cycle 4) at investigator discretion
干预措施: Dexamethasone (Drug)
Sond±D
Cohort A: (sample size 20) sonrotoclax combined with daratumumab and dexamethasone in t(11;14) AL amyloidosis, newly diagnosed or previously untreated with anti-CD38 mAb therapy.
Cohort B: (sample size 19) sonrotoclax combined with dexamethasone in t(11;14) AL patients insensitive to or relapsed after anti-CD38 mAb therapy
All patients will receive up to 12 cycles therapy until major organ deterioration (MOD)-progression free survival (PFS) event, death, withdrawal of informed consent, need for alternative therapy, intolerance, or study termination, whichever occurs first.
Transplant-eligible patients could undergo stem cell collection during induction; autologous transplantation was permitted after completion of the primary endpoint assessment (after cycle 4) at investigator discretion
干预措施: Daratumumab (Drug)
结局指标
主要结局
hematological ≥VGPR rate within four cycles of induction therapy
时间窗: At the end of Cycle 4 (each cycle is 28 days)
Defined as the proportion of patients achieving VGPR, or CR within four cycles of therapy
Best hematological ≥VGPR rate within four cycles of therapy
时间窗: At the end of Cycle 4 (each cycle is 28 days)
Defined as the proportion of patients achieving VGPR, or CR within four cycles of therapy
次要结局
- 1-year MOD-PFS rate(1 year)
- 1-year PFS rate(1 year)
- Time to VGPR(1 year)
- Time to Cardiac Response(1 year)
- Time to Renal Response(1 year)
- Adverse Events (AEs), Serious Adverse Events (SAEs), and laboratory abnormalities(1 year)
- Cardiac response rate at the end of 6 cycles of treatment(At the end of Cycle 6 (each cycle is 28 days))
- Hepatic response rate at the end of 6 cycles of treatment(At the end of Cycle 6 (each cycle is 28 days))
- Hematological ORR after four cycles of therapy(At the end of Cycle 4 (each cycle is 28 days))
- Hematological CR rate at the end of four cycles of therapy(at the end of 4 cycles of therapy (each cycle is 28 days))
- Cardiac response rate at the end of 6 cycles of treatment(At the end of Cycle 6 (each cycle is 28 days))
- Hepatic response rate at the end of 6 cycles of treatment(At the end of Cycle 6 (each cycle is 28 days))
- Renal response rate at the end of 6 cycles of treatment(At the end of 6 cycles of treatment (each cycle is 28 days))
- 1-year MOD-PFS rate(1 year)
- 1-year PFS rate(1 year)
- 1-year OS rate(1 year)
- Time to Response (TTR)(1 year)
- Time to VGPR(1 year)
- Time to Cardiac Response(1 year)
- Time to Renal Response(1 year)
- Time to Hepatic Response(1 year)
- Adverse Events (AEs), Serious Adverse Events (SAEs), and laboratory abnormalities(1 year)
- Correlation analysis between different MRD satus groups and MOD-PFS, PFS and OS(1 year)
研究者
Jin Lu, MD
chief physician
Peking University People's Hospital