Clinical trial NCT04504825: A Study to Evaluate the Efficacy and Safety of CAEL-101 in Patients With Mayo Stage IIIb AL Amyloidosis (CARES)
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 IIIb AL Amyloidosis
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: AL Amyloidosis
Keywords: Plasma Cell Dyscrasia
cyclophosphamide, bortezomib and dexamethasone (CyBorD)
AL Amyloidosis
Amyloid, Light chain Amyloidosis
treatment-naïve
Mayo Stage IIIb
Lead sponsor: Alexion Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2020-08-07
Enrollment: 125
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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 IIIb PCD treatment-naïve AL amyloidosis patients.

Approximately 124 patients will be enrolled using a 2:1 randomization ratio and stratification will be based on geographic region across investigator sites.

The primary evaluation treatment period (PETP) part of the study will stop when the last patient is randomized in the PETP plus 18 months. Patients in both study intervention groups will be followed from randomization until death from any cause, heart transplant, left valve assist device (LVAD) implantation or until the end of study.
Primary purpose: TREATMENT

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

Eligibility criteria: 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

Primary outcomes:
measure: A hierarchical combination of Time to All-cause Mortality and Frequency of Cardiovascular hospitalizations
timeFrame: From the date of randomization to date of death or Primary Evaluation Treatment Period (PETP) (up to 51 months)
measure: Number of Participants with Treatment Emergent Adverse Events (TEAEs)
timeFrame: From date of randomization to Primary Evaluation Treatment Period (PETP) (up to 56 months)
Secondary outcomes:
measure: Time to All-cause Mortality
timeFrame: From the date of randomization to date of death or Primary Evaluation Treatment Period (PETP) (up to 51 months)
measure: Frequency of cardiovascular-related hospitalizations (CVH)
timeFrame: From the date of randomization to date of death or Primary Evaluation Treatment Period (PETP) (up to 51 months)
measure: Change from Baseline to week 50 in the Kansas City Cardiomyopathy Questionnaire-Overall Score (KCCQ-OS)
timeFrame: Baseline, Week 50
measure: Change from Baseline to Week 50 in N - Terminal Pro-B-type Natriuretic Peptide (NT-proBNP) in blood samples
timeFrame: Baseline, Week 50
measure: Change from Baseline to Week 50 in Cardiac Improvement by Global Longitudinal Strain (GLS%)
timeFrame: Baseline, Week 50
measure: Change from Baseline to Week 50 in distance walked (in meters) during a six-minute walk test (6MWT)
timeFrame: Baseline, Week 50
measure: Change from Baseline to Week 50 the Short Form-36 (SF-36) v2 Physical Component Score (PCS)
timeFrame: Baseline, Week 50
Other outcomes:
Locations:
city: Duarte
country: United States
facility: Research Site
state: California
city: Palo Alto
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state: California
city: San Francisco
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state: California
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state: Massachusetts
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city: New York
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city: Linz
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city: Vienna
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city: Anderlecht
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city: Leuven
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city: S.J. Do Rio Preto
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city: Salvador
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city: Calgary
country: Canada
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state: Alberta
city: Edmonton
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state: Alberta
city: Toronto
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state: Ontario
city: Beijing
country: China
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city: Guangzhou
country: China
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city: Hangzhou
country: China
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city: Wenzhou
country: China
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city: Wuhan
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city: Ostrava - Poruba
country: Czechia
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city: Prague
country: Czechia
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city: Caen
country: France
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city: Creteil
country: France
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city: Limoges
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country: France
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city: Poitiers
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city: Rennes
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city: Toulouse
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city: Tours
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country: Germany
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city: Duesseldorf
country: Germany
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city: Essen
country: Germany
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city: Hamburg
country: Germany
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city: Heidelberg
country: Germany
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city: Wuerzburg
country: Germany
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city: Athens
country: Greece
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city: Rio
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city: Haifa
country: Israel
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city: Jerusalem
country: Israel
facility: Research Site
city: Tel Hashomer
country: Israel
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city: Napoli
country: Italy
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city: Pavia
country: Italy
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city: Pisa
country: Italy
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city: Roma
country: Italy
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city: Fukushima-shi
country: Japan
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city: Nagoya-shi
country: Japan
facility: Research Site
city: Shibuya-ku
country: Japan
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city: Seoul
country: Korea, Republic of
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city: Seoul
country: Korea, Republic of
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city: Groningen
country: Netherlands
facility: Research Site
city: Utrecht
country: Netherlands
facility: Research Site
city: Gdańsk
country: Poland
facility: Research Site
city: Poznan
country: Poland
facility: Research Site
city: Warszawa
country: Poland
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Gijón
country: Spain
facility: Research Site
city: Majadahonda
country: Spain
facility: Research Site
city: Pamplona
country: Spain
facility: Research Site
city: Sevilla
country: Spain
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
Study officials:
affiliation: Alexion, AstraZeneca Rare Disease
name: Scott Swenson, MD
role: STUDY_DIRECTOR
References: