Selinexor, Daratumumab, and Dexamethasone (XDd) for Light-Chain Cardiac Amyloidosis

Официальное название

Selinexor Combined With Daratumumab and Dexamethasone (XDd) for the Treatment of Patients With Advanced Light-Chain Cardiac Amyloidosis: A Prospective, Multicenter, Phase II Clinical Study

Обзор

The goal of this clinical trial is to evaluate whether selinexor combined with daratumumab and dexamethasone (XDd) can treat patients with advanced light-chain cardiac amyloidosis. The main questions it aims to answer are: Does XDd regimen achieve hematologic complete response in patients with advanced light-chain cardiac amyloidosis? Does XDd regimen improve cardiac response, organ response, progression-free survival, overall survival, quality of life, and safety?

Вмешательства

• Препарат XDd
  Selinexor (X): 40 mg orally once weekly (QW) Daratumumab (D): 1800 mg per dose, subcutaneous injection; administered once weekly during cycles 1-2, once every 2 weeks during cycles 3-6, and once every 4 weeks from cycle 7 onward. One cycle is 4 weeks. Dexamethasone (d): 20-40 mg once weekly (QW)

Первичные конечные точки

• Hematologic complete response rate [Срок оценки: From enrollment to the end of treatment at 1 year]

Вторичные конечные точки (11)

• Cardiac organ response rate [Срок оценки: From enrollment to the end of treatment at 1 year]
• Organ response rate (heart, kidney, and liver) [Срок оценки: From enrollment to the end of treatment at 1 year]
• Duration of response [Срок оценки: From first documented response until documented progression or death, assessed up to 1 years.]
• Time to response [Срок оценки: From first dose until first documented response, assessed up to 1 years]
• Progression-free survival [Срок оценки: From first dose until date of first documented progression or date of death from any cause, whichever came first, assessed up to 12 months.]
• Overall survival [Срок оценки: From first dose until date of death from any cause, assessed up to 12 months.]
• Quality of life assessed by EORTC QLQ-C30 [Срок оценки: Through study completion, up to 1 year.]
• Incidence and Severity of Adverse Events [Срок оценки: From the first dose through 28 days after the last dose]
• Biomarker Outcome: dFLC [Срок оценки: Baseline and every 4 weeks during treatment, up to 12 months.]
• Biomarker outcome: NT-proBNP [Срок оценки: Baseline and every 4 weeks during treatment, up to 12 months.]
• Biomarker outcome: MRD [Срок оценки: Baseline and at end of treatment, up to 12 months.]

Критерии участия

Критерии включения

• Age ≥ 18 years.
• Confirmed systemic light-chain amyloidosis, meeting both of the following:

• Tissue biopsy confirms amyloid deposition, and the amyloid precursor protein is immunoglobulin light chain or heavy-light chain. Pathologic evidence includes at least one of the following: Congo red staining positive with apple-green birefringence under polarized light microscopy; Light-chain restricted expression demonstrated by immunohistochemistry, immunofluorescence, or immunoelectron microscopy, or mass spectrometry confirming the precursor protein as immunoglobulin light chain; Electron microscopy showing nonbranching, rigid, randomly arranged fibrils with a diameter of 8 to 14 nm.
• Evidence of monoclonal immunoglobulin or free light chain in serum or urine, or detection of monoclonal plasma cells/B cells in bone marrow examination.
• Clinical manifestations, physical examination, laboratory tests, or imaging studies confirm involvement of one or more organs, with mandatory cardiac involvement. Cardiac involvement is defined as either:

• Mean ventricular wall thickness > 12 mm on echocardiography, with other cardiac diseases excluded; or
• NT-proBNP > 332 ng/L in the absence of renal insufficiency and atrial fibrillation.
• Mayo 2004 stage IIIa or IIIb disease, including newly diagnosed and relapsed/refractory patients.
• Measurable disease in light-chain amyloidosis, defined by at least one of the following:

• Serum monoclonal protein ≥ 0.5 g/dL by serum protein electrophoresis and immunofixation performed by the central laboratory;
• Serum free light chain ≥ 50 mg/L with an abnormal kappa/lambda ratio; or
• Difference between involved and uninvolved free light chains (dFLC) ≥ 50 mg/L. Note: Urine Bence Jones proteinuria alone is not sufficient to define measurable disease for eligibility.
• Not pregnant or breastfeeding. Men and women of childbearing potential must agree to use appropriate contraception before treatment, during treatment, during any treatment interruption, and for 4 weeks after treatment completion.
• Written informed consent has been signed by the participant. If the participant is unable to sign because of their medical condition, informed consent may be signed by a legal guardian or immediate family member.

Критерии исключения

• Active hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection, or other acquired or congenital immunodeficiency disorders.
• Baseline peripheral neuropathy or neuropathic pain of grade ≥ 2 according to NCI CTCAE v4.0.
• Major surgery within 30 days before enrollment.
• Epilepsy requiring medication, dementia, or other psychiatric conditions that prevent understanding of or compliance with the study protocol.
• Any severe physical or psychiatric illness that may interfere with participation in this clinical study.
• Any other condition that the investigator considers unsuitable for enrollment.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Список центров уточняется — проверьте первичный протокол.

Публикации

• Morikawa K, Izumiya Y, Takashio S, Kawano Y, Oguni T, Kuyama N, Oike F, Yamamoto M, Tabata N, Ishii M, Hanatani S, Hoshiyama T, Kanazawa H, Matsuzawa Y, Usuku H, Yamamoto E, Ueda M, Tsujita K. Early experience with daratumumab-containing regimens in patients with light-chain cardiac amyloidosis. J Cardiol. 2025 Jun;85(6):440-446. doi: 10.1016/j.jjcc.2024.11.003. Epub 2024 Dec 4. PMID 39577830
• Gregory Kaufman, Ronald Witteles, Matthew Wheeler, Patricia Ulloa, Marie Lugtu, Sally Arai, Stanley Schrier, Richard Lafayette, Michaela Liedtke; Hematologic Responses and Cardiac Organ Improvement in Patients with Heavily Pretreated Cardiac Immunoglobulin Light Chain (AL) Amyloidosis Receiving Daratumumab. Blood 2016; 128 (22): 4525.
• 戈程, 李佳月, 刘博罕, 等. 心肌淀粉样变性临床特点及远期预后的影响因素[J]. 中华老年多器官疾病杂志, 2020, 19(6):405-409.
• Huang XH, Liu ZH. The Clinical Presentation and Management of Systemic Light-Chain Amyloidosis in China. Kidney Dis (Basel). 2016 Apr;2(1):1-9. doi: 10.1159/000444287. Epub 2016 Feb 25. PMID 27536686
• Nienhuis HL, Bijzet J, Hazenberg BP. The Prevalence and Management of Systemic Amyloidosis in Western Countries. Kidney Dis (Basel). 2016 Apr;2(1):10-9. doi: 10.1159/000444206. Epub 2016 Feb 25. PMID 27536687
• 中国系统性轻链型淀粉样变性协作组, 国家肾脏疾病临床医学研究中心, 国家血液系统疾病临床医学研究中心. 系统性轻链型淀粉样变性诊断和治疗指南（2021年修订） [J] . 中华医学杂志, 2021, 101(22) : 1646-1656.
• Hou JH, Zhu HX, Zhou ML, Le WB, Zeng CH, Liang SS, Xu F, Liang DD, Shao SJ, Liu Y, Liu ZH. Changes in the Spectrum of Kidney Diseases: An Analysis of 40,759 Biopsy-Proven Cases from 2003 to 2014 in China. Kidney Dis (Basel). 2018 Feb;4(1):10-19. doi: 10.1159/000484717. Epub 2017 Dec 8. PMID 29594138

Идентификаторы

NCT: NCT07743957 · XDd-LCA-Phase2

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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