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

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

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, reduces cardiovascular related hospitalizations and it is safe and well tolerated in patients with stage IIIb AL amyloidosis.

Study Overview

• Status: Active, not recruiting
• Conditions: AL Amyloidosis
• Intervention / Treatment: Drug: CAEL-101; Drug: cyclophosphamide, bortezomib, and Dexamethasone (CyBorD) regimen; Other: Placebo

Detailed Description

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. The primary evaluation treatment period (PETP) part of the study will stop when the last patient is randomized in the PETP plus 18 months. Approximately 124 patients will be enrolled using a 2:1 randomization ratio. Stratification will be based on geographic region across investigator sites. The primary endpoint is a composite endpoint of all-cause mortality and frequency of cardiovascular hospitalizations. Patients in both study intervention groups will be followed from randomization until death from any cause, heart transplant, left wall assist device (LVAD) implantation or until the end of study.

• Study Type: Interventional
• Enrollment (Actual): 125
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Box Hill, Australia, 3128
    • Research Site
  • Brisbane, Australia, 4102
    • Research Site
  • Westmead, Australia, 2145
    • Research Site
• Austria
  • Linz, Austria, 4020
    • Research Site
  • Vienna, Austria, 1090
    • Research Site
• Belgium
  • Anderlecht, Belgium, 1070
    • Research Site
  • Leuven, Belgium, 3000
    • Research Site
• Brazil
  • Porto Alegre, Brazil, 90110-270
    • Research Site
  • Ribeirão Preto, Brazil, 14048-900
    • Research Site
  • Salvador, Brazil, 41253-190
    • Research Site
  • São José do Rio Preto, Brazil, 15090-000
    • Research Site
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N2
      • Research Site
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Research Site
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Research Site
• China
  • Beijing, China, 100730
    • Research Site
  • Guangzhou, China, 510180
    • Research Site
  • Hangzhou, China, 310009
    • Research Site
  • Wenzhou, China, 325000
    • Research Site
  • Wuhan, China, 430022
    • Research Site
• Czechia
  • Ostrava - Poruba, Czechia, 70852
    • Research Site
  • Prague, Czechia, 12808
    • Research Site
• France
  • Caen, France, 14033
    • Research Site
  • Créteil, France, 94000
    • Research Site
  • Limoges, France, 87042
    • Research Site
  • Marseille, France, 13009
    • Research Site
  • Paris, France, 75010
    • Research Site
  • Pessac, France, 33604
    • Research Site
  • Pierre-Bénite, France, 69310
    • Research Site
  • Poitiers, France, 86021
    • Research Site
  • Rennes, France, 35033
    • Research Site
  • Toulouse, France, 31100
    • Research Site
  • Tours, France, 37044
    • Research Site
• Germany
  • Berlin, Germany, 13353
    • Research Site
  • Düsseldorf, Germany, 40225
    • Research Site
  • Essen, Germany, 45147
    • Research Site
  • Hamburg, Germany, 22767
    • Research Site
  • Heidelberg, Germany, 69120
    • Research Site
  • Würzburg, Germany, 97080
    • Research Site
• Greece
  • Athens, Greece, 11528
    • Research Site
  • Rio, Greece, 26504
    • Research Site
• Israel
  • Haifa, Israel, 31096
    • Research Site
  • Jerusalem, Israel, 91120
    • Research Site
  • Tel Litwinsky, Israel, 52621
    • Research Site
• Italy
  • Napoli, Italy, 80131
    • Research Site
  • Pavia, Italy, 27100
    • Research Site
  • Pisa, Italy, 56126
    • Research Site
  • Roma, Italy, 00128
    • Research Site
• Japan
  • Fukushima, Japan, 960-1295
    • Research Site
  • Nagoya, Japan, 467-8602
    • Research Site
  • Shibuya-ku, Japan, 150-8935
    • Research Site
• Netherlands
  • Groningen, Netherlands, 9713 GZ
    • Research Site
  • Utrecht, Netherlands, 3508 GA
    • Research Site
• Poland
  • Gdansk, Poland, 80-214
    • Research Site
  • Poznan, Poland, 60-569
    • Research Site
  • Warsaw, Poland, 01-748
    • Research Site
• South Korea
  • Seoul, South Korea, 03080
    • Research Site
  • Seoul, South Korea, 06351
    • Research Site
• Spain
  • Barcelona, Spain, 08036
    • Research Site
  • Barcelona, Spain, 8035
    • Research Site
  • Gijón, Spain, 33394
    • Research Site
  • Majadahonda, Spain, 28222
    • Research Site
  • Pamplona, Spain, 31008
    • Research Site
  • Seville, Spain, 41013
    • Research Site
• United Kingdom
  • London, United Kingdom, WC1E 6AG
    • Research Site
• United States
  • California
    • Duarte, California, United States, 91010
      • Research Site
    • Palo Alto, California, United States, 94304
      • Research Site
    • San Francisco, California, United States, 94143
      • Research Site
  • Florida
    • Weston, Florida, United States, 33331
      • Research Site
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Research Site
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Research Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Research Site
    • Boston, Massachusetts, United States, 02215
      • Research Site
    • Boston, Massachusetts, United States, 02118
      • Research Site
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Research Site
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Research Site
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Research Site
  • New York
    • New York, New York, United States, 10032
      • Research Site
    • New York, New York, United States, 10065
      • Research Site
    • Rochester, New York, United States, 14642
      • Research Site
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Research Site
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Research Site
    • Columbus, Ohio, United States, 43210
      • Research Site
  • Oregon
    • Portland, Oregon, United States, 97239
      • Research Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Research Site
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Research Site
  • Texas
    • Dallas, Texas, United States, 75390
      • Research Site
    • Houston, Texas, United States, 77030
      • Research Site
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Research Site
  • Washington
    • Seattle, Washington, United States, 98109
      • Research Site
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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:

  1. Involved/uninvolved free light chain difference (dFLC) > 4 mg/dL or
  2. Involved free light chain (iFLC) > 4 mg/dL with abnormal Kappa/Lambda ratio or
  3. 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:

  1. Immunohistochemistry/Immunofluorescence or
  2. Mass spectrometry or
  3. Characteristic electron microscopy appearance/Immunoelectron microscopy

• Cardiac involvement as defined by:

  1. 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
  2. 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo combined with SoC plasma cell dyscrasia; Patients randomized to receive placebo will receive 0.9% normal saline in an equivalent volume to a CAEL-101 infusion (approximately 250 cc). It is planned that all patients will continue their double-blind treatment until the last patient is randomized in the study plus 18 months.	Drug: cyclophosphamide, bortezomib, and Dexamethasone (CyBorD) regimen; According to institutional standard of care.; Other: Placebo; Commercially available 0.9% Normal Saline will be used as the placebo.
Experimental: CAEL-101 combined with SoC plasma cell dyscrasia; CAEL-101 is administered as an intravenous (IV) infusion over approximately 2 hours. It is planned that all patients will continue their double-blind treatment until the last patient is randomized in the study plus 18 months. The study is divided into 2 parts, the Primary Evaluation Treatment period part and the Open-Label Extension period of Study.	Drug: CAEL-101; 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.; Drug: cyclophosphamide, bortezomib, and Dexamethasone (CyBorD) regimen; According to institutional standard of care.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
A hierarchical combination of Time to All-cause Mortality and Frequency of Cardiovascular hospitalizations	From the date of randomization to date of death or Primary Evaluation Treatment Period (PETP) (up to 51 months)
Number of Participants with Treatment Emergent Adverse Events (TEAEs)	From date of randomization to Primary Evaluation Treatment Period (PETP) (up to 56 months)

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
Time to All-cause Mortality		From the date of randomization to date of death or Primary Evaluation Treatment Period (PETP) (up to 51 months)
Frequency of cardiovascular-related hospitalizations (CVH)		From the date of randomization to date of death or Primary Evaluation Treatment Period (PETP) (up to 51 months)
Change from Baseline to Week 50 in N - Terminal Pro-B-type Natriuretic Peptide (NT-proBNP) in blood samples	To assess improvement in cardiomyopathy as measured by NT-proBNP. For each participant, blood sample will be assayed for NT-proBNP, comparing the participant's baseline value over time to assess improvement in the heart by reduced amyloidosis as measured by an increase or decrease in amyloidosis-related biomarkers: NT-proBNP.	Baseline, Week 50

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measure of N-terminal pro b-type natriuretic peptide (NT-proBNP) in blood samples	For each subject, blood sample will be assayed for NT-proBNP, comparing the subject's baseline value over time to assess improvement in the heart by reduced amyloidosis as measured by an increase or decrease in amyloidosis-related biomarkers: NT-proBNP.	50 weeks
Measure of Cardiac troponin (cTnT) in blood samples	For each subject, blood sample will be assayed for cTnT, comparing the subject's baseline value over time to assess improvement in the heart by reduced amyloidosis as measured by changes in amyloidosis-related biomarkers: cTnT.	50 weeks
Measure of involved/uninvolved free light chain difference (dFLC)	For each subject, blood sample will be assayed for dFLC, comparing the subject's baseline value over time to assess improvement in the heart by reduced amyloidosis as measured by changes in amyloidosis-related biomarkers: dFLC	50 weeks
Measure of C-reactive protein (CRP) in blood samples	For each subject, blood sample will be assayed for CRP, comparing the subject's baseline value over time to assess improvement in the heart by reduced amyloidosis as measured by changes in amyloidosis-related biomarkers: CRP.	50 weeks
Measure of aspartate aminotransferase (AST)	For each subject, blood sample will be assayed for AST to determine effects on liver function relative to normal values.	50 weeks
Measure of alanine aminotransferase (ALT)	For each subject, blood sample will be assayed for ALT to determine effects on liver function relative to normal values.	50 weeks
Measure of alkaline phosphatase (ALP)	For each subject, blood sample will be assayed for ALP to determine effects on liver function relative to normal values.	50 weeks
Measure of Kidney Glomerular Filtration Rate	For each subject, blood sample will be tested for creatine level that is used to calculate an estimate of how much blood filters through the kidney. A glomeruli filtration rate above 60 mL/min is considered normal.	50 weeks
Measure of Serum Creatinine	For each subject, blood sample will be assayed for creatinine to determine changes during treatment that reflect kidney function.	50 weeks
24-hour Urine Protein Measure	For each subject, urine samples will be collected over a period of 24 hours to determine how much protein is in your urine. Increasing levels of protein suggest decreasing kidney function.	50 weeks
Quality of Life (QoL) by Short Form-36 (SF-36) v2 scaled domain scores	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.). Changes in the different domains can help assess the benefit or challenges of the disease and your treatment.	50 weeks
EuroQual 5-dimension health survey (EQ-5D-5L™)	The EQ-5D-5L™ is a descriptive system assessing mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Patients are asked to indicate the status of each of the dimensions by selecting one of the three levels (no problems, some problems, and extreme problems). The responses are compiled to create a 5-digit number that describe the patient's health state. The EQ-5D-5L™ includes a visual analogue scale for the patient to rate their health that reflects the patient's judgement of their own health. Changes in the different dimensions can help assess the benefit or challenges of the disease and your treatment.	50 weeks
Measure of Plasma Levels of CAEL-101	For each subject, blood sample will be assayed for the plasma levels of CAEL-101 to determine how much is in the blood and how long it stays in the blood.	50 weeks
Determination of immunogenicity of CAEL-101	The presence of anti-drug antibodies will be assayed and, if present, further evaluation will confirm positivity for anti-drug antibodies and determine specificity, neutralizing ability, cell-mediated immune response and correlation with clinical responses. These data will help inform the overall treatment assessment.	50 weeks
Assessment of limitation during physical activity	Patients will be assessed for the NYHA Functional Classification. The NYHA Functional Classification classifies patients in one of four categories based on their limitations during physical activity; the limitations/symptoms are in regard to normal breathing and varying degrees of shortness of breath and/or angina pain.	50 weeks

Collaborators and Investigators

• Sponsor: Alexion Pharmaceuticals, Inc.
• Investigators: Study Director: Scott Swenson, MD, Alexion, AstraZeneca Rare Disease

Study record dates

Study Major Dates

• Study Start (Actual): August 25, 2020
• Primary Completion (Actual): May 10, 2025
• Study Completion (Estimated): October 22, 2027

Study Registration Dates

• First Submitted: July 20, 2020
• First Submitted That Met QC Criteria: August 5, 2020
• First Posted (Actual): August 7, 2020

Study Record Updates

• Last Update Posted (Actual): March 17, 2026
• Last Update Submitted That Met QC Criteria: March 16, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: AL Amyloidosis; cyclophosphamide, bortezomib and dexamethasone (CyBorD); Amyloid, Light chain Amyloidosis; Plasma Cell Dyscrasia; treatment-naïve; Mayo Stage IIIb
• Additional Relevant MeSH Terms: Neoplasms; Metabolic Diseases; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Neoplasms, Plasma Cell; Blood Protein Disorders; Proteostasis Deficiencies; Amyloidosis; Nutritional and Metabolic Diseases; Hemic and Lymphatic Diseases; Immunoglobulin Light-chain Amyloidosis; Paraproteinemias; Health Care Quality, Access, and Evaluation; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Therapeutics; Hydrocarbons; Health Care Evaluation Mechanisms; Quality of Health Care; Polycyclic Compounds; Inorganic Chemicals; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Steroids, Fluorinated; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Pregnadienetriols; Boronic Acids; Acids, Noncarboxylic; Acids; Boron Compounds; Pyrazines; Epidemiologic Study Characteristics; Bortezomib; Dexamethasone; Cyclophosphamide; Clinical Protocols
• Other Study ID Numbers: CAEL101-301

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Each patient will be assigned a unique identifier after signing the Informed Consent Form (ICF). Patient numbers will not be reassigned. Any patient records or datasets transferred to the Sponsor must contain only the unique identifier and must not include patient names or any information which would make the patient identifiable. Patients will be informed that their personal study-related data will be used by the Sponsor in accordance with local data protection laws and that their medical records may be examined by representatives of the Sponsor, Institutional Review Board (IRB)/Independent Ethics Committee (IEC) members and by inspectors from regulatory authorities. Study monitors will inspect all documents and records that are required to be maintained by the Investigator for this study.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No