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

• ClinicalTrials.gov Identifier: NCT04512235
• Recruitment Status: Recruiting
• First Posted: August 13, 2020
• Last Update Posted: May 23, 2023
• Sponsor: Alexion
• Information provided by (Responsible Party): Alexion

Tracking Information

• First Submitted Date: August 10, 2020
• First Posted Date: August 13, 2020
• Last Update Posted Date: May 23, 2023
• Actual Study Start Date: November 12, 2020
• Estimated Primary Completion Date: March 15, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 11, 2021)

• Time from the date of randomization to date of death or end of study [ Time Frame: 50 weeks ]
• Number of patients with treatment emergent adverse events as assessed by CTCAE v5.0 [ Time Frame: 50 weeks ]

Original Primary Outcome Measures (submitted: August 12, 2020)

• Time from the first dose of study drug until death or end of study [ Time Frame: 50 weeks ]
• Number of patients with treatment emergent adverse events as assessed by CTCAE v5.0 [ Time Frame: 50 weeks ]

Current Secondary Outcome Measures (submitted: August 4, 2022)

• Quality of Life (QOL) by the Kansas City Cardiomyopathy Questionnaire-Overall Score (KCCQ-OS) [ Time Frame: 50 weeks ]
  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. Patients will provide their level of agreement or disagreement with a agree-disagree scale for a series of statements. This questionnaire captures how the patients feel physically. Scores range from 0 to 100, where higher scores reflected better health status (fewer symptoms, fewer social or physical limitations, and better quality of life)
• Cardiac Improvement by Global Longitudinal Strain (GLS%) [ Time Frame: 50 weeks ]
  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.
• Change in distance walked (in meters) during a six-minute walk test [ Time Frame: 50 weeks ]
• Quality of Life (QOL) by the Short Form-36 (SF-36) v2 Physical Component Score (PCS) [ Time Frame: 50 weeks ]
  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.).

Original Secondary Outcome Measures (submitted: August 12, 2020)

• Change in distance walked (in meters) during a six-minute walk test [ Time Frame: 50 weeks ]
• Quality of Life (QOL) by the Kansas City Cardiomyopathy Questionnaire-Overall Score (KCCQ-OS) [ Time Frame: 50 weeks ]
  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. Patients will provide their level of agreement or disagreement with a agree-disagree scale for a series of statements. This questionnaire captures how the patients feel physically. Scores range from 0 to 100, where higher scores reflected better health status (fewer symptoms, fewer social or physical limitations, and better quality of life)
• Quality of Life (QOL) by the Short Form-36 (SF-36) v2 Physical Component Score (PCS) [ Time Frame: 50 weeks ]
  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.).
• Cardiac Improvement by Global Longitudinal Strain (GLS%) [ Time Frame: 50 weeks ]
  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.

Current Other Pre-specified Outcome Measures (submitted: August 4, 2022)

• Measure of N-terminal pro b-type natriuretic peptide (NT-proBNP) in blood samples [ Time Frame: 50 weeks ]
  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.
• Measure of Cardiac troponin (cTnT) in blood samples [ Time Frame: 50 weeks ]
  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.
• Measure of involved/uninvolved free light chain difference (dFLC) in blood [ Time Frame: 50 weeks ]
  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 an increase or decrease in amyloidosis-related biomarkers: dFLC
• Measure of C-reactive protein (CRP) in blood samples [ Time Frame: 50 weeks ]
  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.
• Changes in Amyloid Load of the Heart, Liver and Spleen [ Time Frame: 50 weeks ]
  To assess changes in amyloid load of the heart, liver and spleen as measured by changes on magnetic resonance imaging (MRI). Reductions in amyloid load are indicative of improvement.
• Measure of aspartate aminotransferase (AST) [ Time Frame: 50 weeks ]
  For each subject, blood sample will be assayed for AST to determine effects on liver function relative to normal values.
• Measure of alanine aminotransferase (ALT) [ Time Frame: 50 weeks ]
  For each subject, blood sample will be assayed for ALT to determine effects on liver function relative to normal values.
• Measure of alkaline phosphatase (ALP) [ Time Frame: 50 weeks ]
  For each subject, blood sample will be assayed for ALP to determine effects on liver function relative to normal values.
• Measure of Kidney Glomerular Filtration Rate [ Time Frame: 50 weeks ]
  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.
• Measure of Serum Creatinine [ Time Frame: 50 weeks ]
  For each subject, blood sample will be assayed for creatinine to determine changes during treatment that reflect kidney function.
• 24-hour Urine Protein Measure [ Time Frame: 50 weeks ]
  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.
• Quality of Life (QoL) by Short Form-36 (SF-36) v2 scaled domain scores [ Time Frame: 50 weeks ]
  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.
• EuroQual 5-dimension health survey (EQ-5D-5L™) [ Time Frame: 50 weeks ]
  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.
• Measure of Plasma Levels of CAEL-101 [ Time Frame: 50 weeks ]
  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.
• Determination of immunogenicity of CAEL-101 [ Time Frame: 50 weeks ]
  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.
• Assessment of limitation during physical activity [ Time Frame: 50 weeks ]
  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.

Original Other Pre-specified Outcome Measures (submitted: August 12, 2020)

• Measure of N-terminal pro b-type natriuretic peptide (NT-proBNP) in blood samples [ Time Frame: 50 weeks ]
  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.
• Measure of Cardiac troponin (cTnT) in blood samples [ Time Frame: 50 weeks ]
  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.
• Changes in Amyloid Load of the Heart, Liver and Spleen [ Time Frame: 50 weeks ]
  To assess changes in amyloid load of the heart, liver and spleen as measured by changes on magnetic resonance imaging (MRI). Reductions in amyloid load are indicative of improvement.
• Measure of aspartate aminotransferase (AST) [ Time Frame: 50 weeks ]
  For each subject, blood sample will be assayed for AST to determine effects on liver function relative to normal values.
• Measure of alanine aminotransferase (ALT) [ Time Frame: 50 weeks ]
  For each subject, blood sample will be assayed for ALT to determine effects on liver function relative to normal values.
• Measure of alkaline phosphatase (ALP) [ Time Frame: 50 weeks ]
  For each subject, blood sample will be assayed for ALP to determine effects on liver function relative to normal values.
• Measure of change in liver size [ Time Frame: 50 weeks ]
  For each subject, blood sample will be assayed to identify liver enzyme levels and viruses that are present and synonymous with an enlarged liver. Elevated liver enzyme levels often indicate inflammation in the liver.
• Measure of Kidney Glomeruli Filtration Rate [ Time Frame: 50 weeks ]
  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.
• Measure of Serum Creatinine [ Time Frame: 50 weeks ]
  For each subject, blood sample will be assayed for creatinine to determine changes during treatment that reflect kidney function.
• 24-hour Urine Protein Measure [ Time Frame: 50 weeks ]
  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.
• Quality of Life (QoL) by Short Form-36 (SF-36) v2 scaled domain scores [ Time Frame: 50 weeks ]
  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.
• EuroQual 5-dimension health survey (EQ-5D-5L™) [ Time Frame: 50 weeks ]
  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.
• Measure of Plasma Levels of CAEL-101 [ Time Frame: 50 weeks ]
  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.
• Determination of immunogenicity of CAEL-101 [ Time Frame: 50 weeks ]
  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.

Descriptive Information

• Brief Title: A Study to Evaluate the Efficacy and Safety of CAEL-101 in Patients With Mayo Stage IIIa AL Amyloidosis
• Official Title: 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 IIIa AL Amyloidosis

Brief Summary

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 IIIa AL amyloidosis.

• 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 IIIa PCD treatment-naïve AL amyloidosis patients. As this is an event-driven study, the study will enroll until at least 79 deaths have been observed. Approximately 267 patients will be enrolled using a 2:1 randomization ratio. An interim analysis (IA) may also be performed when at least 75% of the events 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.
• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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 IIIa PCD treatment-naïve AL amyloidosis patients. As this is an event-driven study, the study will enroll until at least 79 deaths have been observed. Approximately 267 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) may also be performed when at least 75% of the events 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 (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

This is a double-blind, randomized, multicenter international Phase 3 study.

Primary Purpose: Treatment

• Condition: AL Amyloidosis

Intervention

• 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.
• Other: Placebo
  Commercially available 0.9% Normal Saline will be used as the placebo.
• Drug: cyclophosphamide, bortezomib, and dexamethasone (CyBorD) regimen
  According to institutional standard of care.

Study Arms

• Experimental: CAEL-101 combined with SoC plasma cell dyscrasia
  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. As this is an event driven study, the study will continue, and all patients will continue to receive study treatment until at least 79 deaths have been observed.
  Interventions:

  • Drug: CAEL-101
  • Drug: cyclophosphamide, bortezomib, and dexamethasone (CyBorD) regimen
• 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). 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. As this is an event driven study, the study will continue, and all patients will continue to receive study treatment until at least 79 deaths have been observed.
  Interventions:

  • Other: Placebo
  • Drug: cyclophosphamide, bortezomib, and dexamethasone (CyBorD) regimen

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: August 12, 2020): 267
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: March 15, 2025
• Estimated Primary Completion Date: March 15, 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Key Inclusion Criteria:

• AL amyloidosis stage IIIa based on the European Modification of the 2004 Standard Mayo Clinic Staging who also have NT-proBNP > 650 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/Immunofluroescence
  2. Mass spectrometry or
  3. Characteristic electron microscopy appearance/Immunoelectron microscopy

• Cardiac involvement as defined by:

  a. 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 b. 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 a 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 from Screening to at least 5 months following the last study drug administration or 12 months following the last dose of his 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, specifically: i. Hypercalcemia: serum calcium > 0.25 mmol/L (> 1 mg/dL) higher than the upper limit of normal (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, computed tomography (CT), or positron emission tomography (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 5 mm 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Alexion Pharmaceuticals, Inc; 1-855-752-2356; clinicaltrials@alexion.com

• Listed Location Countries: Australia, Austria, Belgium, Brazil, Canada, China, Czechia, France, Germany, Greece, Israel, Italy, Japan, Korea, Republic of, Netherlands, Poland, Russian Federation, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT04512235
• Other Study ID Numbers: CAEL101-302
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• 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.

• Current Responsible Party: Alexion
• Original Responsible Party: Same as current
• Current Study Sponsor: Alexion
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Cristina C Quarta, MD, PhD; Alexion, AstraZeneca Rare Disease

• PRS Account: Alexion
• Verification Date: May 2023