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

AL Amyloidosis Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04512235
• Other study ID #: CAEL101-302
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: November 12, 2020
• Est. completion date: March 15, 2027

Study information

• Verified date: November 2023
• Source: Alexion Pharmaceuticals, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 88 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 267
• Est. completion date: March 15, 2027
• Est. primary completion date: March 15, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 (eg, multiple myeloma and POEMS syndrome) 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 umol/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

Related Conditions & MeSH terms

• AL Amyloidosis
• Amyloidosis
• Immunoglobulin Light-chain Amyloidosis
• Paraproteinemias

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.

Locations

Country	Name	City	State
Australia	Clinical Trial Site	Adelaide
Australia	Clinical Trial Site	Box Hill
Australia	Clinical Trial Site	Brisbane
Australia	Clinical Trial Site	Murdoch
Australia	Clinical Trial Site	Sydney
Austria	Clinical Trial Site	Linz
Austria	Clinical Trial Site	Linz
Belgium	Clinical Trial Site	Bruxelles
Belgium	Clinical Trial Site	Bruxelles
Belgium	Clinical Trial Site	Leuven
Brazil	Clinical Trial Site	Porto Alegre
Brazil	Clinical Trial Site	Recife
Brazil	Clinical Trial Site	Ribeirao Preto
Brazil	Clinical Trial Site	Santo Amaro
Brazil	Clinical Trial Site	Sao Jose do Rio Preto
Brazil	Clinical Trial Site	Sao Paulo
Brazil	Clinical Trial Site	São Paulo
Canada	Clinical Trial Site	Calgary	Alberta
Canada	Clinical Trial Site	Edmonton	Alberta
Canada	Clinical Trial Site	Toronto	Ontario
China	Clinical Trial Site	Beijing	Beijing
China	Clinical Trial Site	Beijing
China	Clinical Trial Site	Beijing
China	Clinical Trial Site	Beijing
China	Clinical Trial Site	Guangzhou
China	Clinical Trial Site	Hangzhou
China	Clinical Trial Site	Hangzhou
China	Clinical Trial Site	Suzhou
China	Clinical Trial Site	Wenzhou
China	Clinical Trial Site	Wuhan
Czechia	Clinical Trial Site	Ostrava
France	Clinical Trial Site	Caen
France	Clinical Trial Site	Créteil
France	Clinical Trial Site	Dijon
France	Clinical Trial Site	Lille
France	Clinical Trial Site	Limoges
France	Clinical Trial Site	Marseille
France	Clinical Trial Site	Paris
France	Clinical Trial Site	Pessac
France	Clinical Trial Site	Pierre-Bénite
France	Clinical Trial Site	Poitiers
France	Clinical Trial Site	Rennes
France	Clinical Trial Site	Tours
Germany	Clinical Trial Site	Berlin
Germany	Clinical Trial Site	Dusseldorf
Germany	Clinical Trial Site	Essen
Germany	Clinical Trial Site	Hamburg
Germany	Clinical Trial Site	Heidelberg
Germany	Clinical Trial Site	Mainz
Germany	Clinical Trial Site	Münster
Germany	Clinical Trial Site	Würzburg
Greece	Clinical Trial Site	Athens
Greece	Clinical Trial Site	Patras
Greece	Clinical Trial Site	Thessaloníki
Israel	Clinical Trial Site	Haifa
Israel	Clinical Trial Site	Jerusalem
Israel	Clinical Trial Site	Petach Tikva
Israel	Clinical Trial Site	Tel Aviv
Israel	Clinical Trial Site	Tel-Hashomer
Italy	Clinical Trial Site	Brescia
Italy	Clinical Trial Site	Naples
Italy	Clinical Trial Site	Pavia
Italy	Clinical Trial Site	Rome
Japan	Clinical Trial Site	Chiba
Japan	Clinical Trial Site	Fukushima
Japan	Clinical Trial Site	Ishikawa
Japan	Clinical Trial Site	Kumamoto-shi	Kumamoto
Japan	Clinical Trial Site	Kyoto
Japan	Clinical Trial Site	Nagoya
Japan	Clinical Trial Site	Tokyo
Korea, Republic of	Clinical Trial Site	Seoul
Korea, Republic of	Clinical Trial Site	Seoul
Korea, Republic of	Clinical Trial Site	Seoul
Korea, Republic of	Clinical Trial Site	Seoul
Netherlands	Clinical Trial Site	Amsterdam
Netherlands	Clinical Trial site	Groningen
Poland	Clinical Trial Site	Gdansk
Poland	Clinical Trial Site	Poznan
Poland	Clinical Trial Site	Warsaw
Russian Federation	Clinical Trial Site	Saint Petersburg
Spain	Clinical Trial Site	Barcelona
Spain	Clinical Trial Site	Barcelona
Spain	Clinical Trial Site	Gijon
Spain	Clinical Trial Site	Granada
Spain	Clinical Trial Site	Madrid
Spain	Clinical Trial Site	Madrid
Spain	Clinical Trial Site	Madrid
Spain	Clinical Trial Site	Pamplona
Spain	Clinical Trial Site	Salamanca
Spain	Clinical Trial Site	Sevilla
Spain	Clinical Trial Site	Valencia
United Kingdom	Clinical Trial Site	Glasgow
United Kingdom	Clinical Trial Site	London
United Kingdom	Clinical Trial Site	London
United Kingdom	Clinical Trial Site	London
United States	Clinical Trial Site	Baltimore	Maryland
United States	Clinical Trial Site	Boston	Massachusetts
United States	Clinical Trial Site	Boston	Massachusetts
United States	Clinical Trial Site	Boston	Massachusetts
United States	Clinical Trial Site	Chapel Hill	North Carolina
United States	Clinical Trial Site	Cleveland	Ohio
United States	Clinical Trial Site	Columbus	Ohio
United States	Clinical Trial Site	Dallas	Texas
United States	Clinical Trial Site	Detroit	Michigan
United States	Clinical Trial Site	Duarte	California
United States	Clinical Trial Site	Durham	North Carolina
United States	Clinical Trial Site	Houston	Texas
United States	Clinical Trial Site	Indianapolis	Indiana
United States	Clinical Trial Site	Jacksonville	Florida
United States	Clinical Trial Site	Madison	Wisconsin
United States	Clinical Trial Site	Milwaukee	Wisconsin
United States	Clinical Trial Site	Nashville	Tennessee
United States	Clinical Trial Site	New Orleans	Louisiana
United States	Clinical Trial Site	New York	New York
United States	Clinical Trial Site	New York	New York
United States	Clinical Trial Site	New York	New York
United States	Clinical Trial Site	Palo Alto	California
United States	Clinical Trial Site	Philadelphia	Pennsylvania
United States	Clinical Trial Site	Phoenix	Arizona
United States	Clinical Trial Site	Portland	Oregon
United States	Clinical Trial Site	Rochester	New York
United States	Clinical Trial Site	Rochester	Minnesota
United States	Clinical Trial Site	Saint Louis	Missouri
United States	Clinical Trial Site	Salt Lake City	Utah
United States	Clinical Trial Site	San Francisco	California
United States	Clinical Trial Site	Scottsdale	Arizona
United States	Clinical Trial Site	Seattle	Washington
United States	Clinical Trial Site	Weston	Florida
United States	Clinical Trial Site	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Alexion Pharmaceuticals, Inc.

Countries where clinical trial is conducted

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time to All-cause Mortality		From the date of randomization to date of death or Primary Evaluation Treatment Period (PETP) (Up to Week 52)
Primary	Number of Participants with Treatment emergent Adverse Events (TEAEs)		Up to Week 52
Secondary	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. 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)	Baseline, Week 50
Secondary	Change From Baseline to Week 50 in 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
Secondary	Change From Baseline to Week 50 in Distance Walked (in Meters) during a Six-minute Walk Test (6MWT)	The 6MWT measures the distance a patient can quickly walk on a flat, hard surface in a period of 6 minutes. It evaluates the global and integrated response of all the systems involved during exercise. This is a self-paced test; patients choose their own intensity of exercise and are allowed to stop and rest during the test.	Baseline, Week 50
Secondary	Change From Baseline to Week 50 in the Short Form-36 (SF-36) Version 2 (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