A Study to Evaluate the Efficacy and Safety of Birtamimab in Mayo Stage IV Patients With AL Amyloidosis

Study Overview
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Brief Summary
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A Phase 3 study to evaluate the efficacy and safety of birtamimab plus standard of care compared to placebo plus standard of care in Mayo Stage IV patients with AL amyloidosis.

Detailed Description
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This is a Phase 3 multicenter, global, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of birtamimab in Mayo Stage IV patients with AL amyloidosis. The primary objective is to evaluate the efficacy of birtamimab by assessing time to all-cause mortality. All patients will receive bortezomib-containing chemotherapy regimen as standard of care. Approximately 150 newly diagnosed Mayo Stage IV patients with AL amyloidosis will be enrolled and randomized in a 2:1 ratio to birtamimab or placebo. Subjects will remain on study until study completion, when the pre-defined number of events (all-cause mortality) have been reached.

Official Title
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A Phase 3, Randomized, Multicenter, Double-Blind, Placebo-Controlled, Efficacy and Safety Study of Birtamimab Plus Standard of Care vs. Placebo Plus Standard of Care in Mayo Stage IV Subjects With Light Chain (AL) Amyloidosis

Conditions
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Light Chain (AL) Amyloidosis

Intervention / Treatment
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* Drug: Birtamimab
* Other: Placebo
* Drug: Standard of Care Chemotherapy


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Aged ≥18 years and legal age of consent according to local regulations Newly diagnosed and AL amyloidosis treatment-naïve with cardiac involvement Confirmed diagnosis of AL amyloidosis Confirmed Mayo Stage IV AL Amyloidosis as defined by NT-proBNP ≥1800 pg/mL and Troponin-T ≥0.025 ng/mL or high sensitivity cardiac troponin T≥40ng/L and dFLC ≥18 mg/dL Planned first-line chemotherapy contains bortezomib administered subcutaneously weekly. Key Exclusion Criteria: Non-AL amyloidosis. NT-proBNP >8500 pg/mL. Meets the International Myeloma Working Group (IMWG) definition of multiple myeloma except for malignancy biomarker of involved/uninvolved serum free light chain ratio ≥100 Subject is eligible for and plans to undergo ASCT or organ transplant during the study. Myocardial infarction, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or ECG evidence of acute ischemia, within 6 months prior to the Month 1-Day 1 Visit. Severe valvular stenosis (e.g., aortic or mitral stenosis with a valve area <1.0 cm2) or severe congenital heart disease. ECG evidence of acute ischemia or active conduction system abnormalities Prior treatment with hematopoietic growth factors, transfusions of blood or blood products within 1 week of Month 1-Day 1. Prior radiotherapy within 4 weeks of Month 1-Day 1. Prior treatment with plasma cell-directed chemotherapy, birtamimab, daratumumab, 11- 1F4, anti-serum amyloid P antibody, doxycycline for amyloid, or other investigational treatment directed at amyloid . Waldenström's macroglobulinemia and/or immunoglobulin M monoclonal gammopathy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Birtamimab plus Standard of Care Chemotherapy<br>Intravenous administration of 24 mg/kg birtamimab every 28 days. Drug: Standard of Care Chemotherapy. Bortezomib-containing chemotherapy regimen (e.g. cyclophosphamide, bortezomib, and dexamethasone (CyBorD) according to the institutional standard of care. Initiation of daratumumab at randomization allowed at the discretion of the investigator | Drug: Birtamimab<br>* Intravenous administration of 24 mg/kg birtamimab every 28 days<br>Drug: Standard of Care Chemotherapy<br>* Bortezomib-containing chemotherapy regimen (e.g. cyclophosphamide, bortezomib, and dexamethasone (CyBorD)) according to the institutional standard of care<br>|
| Placebo Comparator: Placebo plus Standard of Care Chemotherapy<br>Intravenous 0.9% Saline administration as a placebo every 28 days. Drug: Standard of Care Chemotherapy. Bortezomib-containing chemotherapy regimen (e.g. cyclophosphamide, bortezomib, and dexamethasone (CyBorD) according to the institutional standard of care. Initiation of daratumumab at randomization allowed at the discretion of the investigator | Other: Placebo<br>* Intravenous 0.9% Saline administration as a placebo every 28 days<br>Drug: Standard of Care Chemotherapy<br>* Bortezomib-containing chemotherapy regimen (e.g. cyclophosphamide, bortezomib, and dexamethasone (CyBorD)) according to the institutional standard of care<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to all-cause mortality | Comparison of time to all-cause mortality for birtamimab and placebo control. | Time from the first dose of study drug until the pre-defined number of events (all-cause mortality) have been reached. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6MWT distance | Change from baseline to Month 9 in the 6-Minute Walk Test (6MWT) distance | Month 9 | 
| Physical Component Summary (PCS) score of the Short Form-36, version 2 (SF-36v2) | The Short Form-36, version 2 (SF-36v2) is a 36-item self-administered quality-of-life (QoL) questionnaire that measures health on functional status, well-being, and overall evaluation of health. Higher SF-36 scores represent better health. The Physical Component Summary (PCS) is derived primarily from questions regarding physical functioning, physical problems, bodily pain, and general health questions | Month 9 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Light Chain (AL) Amyloidosis, Mayo Stage IV, birtamimab