A Study to Evaluate the Efficacy and Safety of CAEL-101 in Patients With Mayo Stage IIIb AL Amyloidosis

Study Overview
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Brief Summary
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AL (or light chain) amyloidosis begins in the bone marrow where abnormal proteins misfold and create free light chains that cannot be broken down. These free light chains bind together to form amyloid fibrils that build up in the extracellular space of organs, affecting the kidneys, heart, liver, spleen, nervous system and digestive tract. The primary purpose of this study is to determine whether CAEL-101, a monoclonal antibody that removes AL amyloid deposits from tissues and organs, improves overall survival and it is safe and well tolerated in patients with stage IIIb AL amyloidosis.

Detailed Description
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This is a double-blind, randomized, multicenter international Phase 3 study of CAEL-101 combined with standard of care (SoC) plasma cell dyscrasia (PCD) treatment versus placebo combined with SoC PCD treatment in Mayo stage IIIb PCD treatment-naïve AL amyloidosis patients. As this is an event-driven study, the study will enroll until at least 101 deaths have been observed. Approximately 124 patients will be enrolled using a 2:1 randomization ratio. Stratification will be based on geographic region across investigator sites. An interim analysis (IA) may be performed when approximately 75% (76/101) of the expected deaths has been observed. Patients in both study intervention groups will be followed from randomization until death from any cause or until the end of study.

Official Title
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A Phase 3, Double-Blind, Multicenter Study to Evaluate the Efficacy and Safety of CAEL-101 and Plasma Cell Dyscrasia Treatment Versus Placebo and Plasma Cell Dyscrasia Treatment in Plasma Cell Dyscrasia Treatment Naïve Patients With Mayo Stage IIIb AL Amyloidosis

Conditions
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AL Amyloidosis

Intervention / Treatment
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* Drug: CAEL-101
* Other: Placebo
* Drug: cyclophosphamide, bortezomib, and Dexamethasone (CyBorD) regimen


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: AL amyloidosis stage IIIb based on the European Modification of the 2004 Standard Mayo Clinic Staging (NT-proBNP > 8,500 ng/L) at the time of Screening Measurable hematologic disease at Screening as defined by at least one of the following: Involved/uninvolved free light chain difference (dFLC) > 4 mg/dL or Involved free light chain (iFLC) > 4 mg/dL with abnormal Kappa/Lambda ratio or Serum protein electrophoresis (SPEP) m-spike > 0.5 g/dL Histopathological diagnosis of amyloidosis based on polarizing light microscopy of green bi-refringent material in Congo red stained tissue specimens AND confirmation of AL derived amyloid deposits by at least one of the following: Immunohistochemistry/Immunofluorescence or Mass spectrometry or Characteristic electron microscopy appearance/Immunoelectron microscopy Cardiac involvement as defined by: Documented clinical signs and symptoms supportive of a diagnosis of heart failure in the setting of a confirmed diagnosis of AL amyloidosis in the absence of an alternative explanation for heart failure AND At least one of the following: i. Endomyocardial biopsy demonstrating AL cardiac amyloidosis or ii. Echocardiogram demonstrating a mean left ventricular wall thickness (calculated as [IVSd+LPWd]/2) of > 12 mm at diastole in the absence of other causes (e.g., severe hypertension, aortic stenosis), which would adequately explain the degree of wall thickening or iii. Cardiac magnetic resonance imaging (MRI) with gadolinium contrast agent diagnostic of cardiac amyloidosis Planned first-line treatment for plasma cell dyscrasia is cyclophosphamide-bortezomib-dexamethasone (CyBorD)-based regimen administered as SoC Women of childbearing potential (WOCBP) must have a negative pregnancy test during Screening and must agree to use highly effective contraception from Screening to at least 5 months following the last study drug administration or 12 months following the last dose of her PCD therapy, whichever is longer Men must be surgically sterile or must agree to use highly effective contraception and refrain from donating sperm from Screening to at least 5 months following the last study drug administration or 12 months following the last dose of their PCD therapy, whichever is longer Key Exclusion Criteria: Have any other form of amyloidosis other than AL amyloidosis Received prior therapy for AL amyloidosis or multiple myeloma. A maximum exposure of 2 weeks of a CyBorD-based PCD treatment after Screening laboratory samples are obtained and prior to randomization is allowed Has POEMS (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes) syndrome or multiple myeloma defined as clonal bone marrow plasma cells > 10% from a bone marrow biopsy (performed ≤ 3 months prior to signing the ICF) or biopsy-proven (performed ≤ 3 months prior to signing the ICF) bony or extramedullary plasmacytoma AND one or more of the following CRAB features: a. Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder (e.g., multiple myeloma and POEMS syndrome), specifically: i. Hypercalcemia: serum calcium > 0.25 mmol/L (> 1 mg/dL) higher than the ULN or > 2.75 mmol/L (> 11 mg/dL) OR ii. Renal insufficiency: creatinine clearance < 40 mL per minute or serum creatinine > 177 mol/L (> 2 mg/dL) OR iii. Anemia: hemoglobin value of > 20 g/L below the lowest limit of normal, or a hemoglobin value < 100 g/L OR iv. Bone lesions: one or more osteolytic lesion on imaging tests (performed ≤ 3 months prior to signing the ICF): skeletal radiography, CT, or PET/CT, or MRI. If bone marrow has < 10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement OR b. Any one of the following biomarkers of malignancy: i. 60% or greater clonal plasma cells on bone marrow examination OR ii. More than one focal lesion on MRI that is at least 5mm or greater in size Have supine systolic blood pressure < 90 mmHg or symptomatic orthostatic hypotension, defined as a decrease in systolic blood pressure upon standing of > 30 mmHg despite medical management (e.g., midodrine, fludrocortisones) in the absence of volume depletion

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
Interventional Model Description: This is a double-blind, randomized, multicenter, international Phase 3 study of CAEL-101 combined with SoC PCD treatment versus placebo combined with SoC PCD treatment in Mayo stage IIIb PCD treatment-naïve AL amyloidosis patients. As this is an event-driven study, the study will enroll until at least 101 deaths have been observed. Approximately 124 patients will be enrolled using a 2:1 randomization ratio and stratification will be based on geographic region across investigator sites. An interim analysis (IA) with stopping rules for early efficacy may be performed when approximately 75% (76/101) of the expected deaths have been observed. Patients in both study intervention groups will be followed from randomization until death from any cause or until the end of study.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CAEL-101 combined with SoC plasma cell dyscrasia<br>CAEL-101 is administered as an intravenous (IV) infusion over approximately 2 hours. The minimum planned treatment time for each patient will be at least 50 weeks or until the patient's death. It is planned that all patients will continue their double-blind treatment until the last patient completes at least 50 weeks of treatment. The study is divided into 2 parts, the Primary Evaluation Treatment period part and the Open-Label Extension period of Study. | Drug: CAEL-101<br>* The investigational product, CAEL-101, is formulated as a sterile liquid solution of protein plus excipients for dilution in a single-use, stoppered, glass vial. Each 10 mL vial contains 300 mg of CAEL-101 at a concentration of 30 mg/mL. CAEL-101 will be diluted with commercially available 0.9% Normal Saline.<br>Drug: cyclophosphamide, bortezomib, and Dexamethasone (CyBorD) regimen<br>* According to institutional standard of care.<br>|
| Placebo Comparator: Placebo combined with SoC plasma cell dyscrasia<br>Patients randomized to receive placebo will receive 0.9% normal saline in an equivalent volume to a CAEL-101 infusion (approximately 250 cc). The minimum planned treatment time for each patient will be at least 50 weeks or until the patient's death. It is planned that all patients will continue their double-blind treatment until the last patient completes at least 50 weeks of treatment. | Other: Placebo<br>* Commercially available 0.9% Normal Saline will be used as the placebo.<br>Drug: cyclophosphamide, bortezomib, and Dexamethasone (CyBorD) regimen<br>* According to 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 or to the end of the PETP |  | Up to week 52 | 
| Number of Participants with Treatment Emergent Adverse Events (TEAEs) |  | Up to week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline to week 50 in the Kansas City Cardiomyopathy Questionnaire-Overall Score (KCCQ-OS) | A 23-item self-administered questionnaire that quantifies physical function, symptoms, social function, self-efficacy and knowledge and quality of life. It requires an average of 4-6 minutes to complete and uses an ordinal, adjectival (Likert) scale | Baseline, Week 50 | 
| Change from Baseline to Week 50 in Cardiac Improvement by Global Longitudinal Strain (GLS%) | To assess improvement in heart function as measured by percent Global Longitudinal Strain (GLS%). GLS% is a non-invasive imaging technique to assess heart function where a higher/lower percentage is indicative of improvement. | Baseline, Week 50 | 
| Change from Baseline to Week 50 in distance walked (in meters) during a six-minute walk test (6MWT) |  | Baseline, Week 50 | 
| Change from Baseline to Week 50 the Short Form-36 (SF-36) v2 Physical Component Score (PCS) | A self-administered questionnaire containing 36 items that measures health on functional status, well-being and overall evaluation of health in 8 domains. It requires approximately 5 minutes to complete and uses scaled, ordinal responses (e.g., All of the time, Most of the time, A good bit of the time, etc.) | Baseline, Week 50 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Plasma Cell Dyscrasia, cyclophosphamide, bortezomib and dexamethasone (CyBorD), treatment-naïve, AL Amyloidosis, Amyloid, Light chain Amyloidosis, Mayo Stage IIIb