Active, not recruiting
Phase 3
A Study to Evaluate the Efficacy and Safety of CAEL-101 in Patients With Mayo Stage IIIa AL Amyloidosis (CARES)
Condition(s) studied
AL Amyloidosis
Investigational drug(s) / intervention(s)
CAEL-101Placebocyclophosphamide, bortezomib, and dexamethasone (CyBorD) regimen
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.
Placebo: Commercially available 0.9% Normal Saline will be used as the placebo.
cyclophosphamide, bortezomib, and dexamethasone (CyBorD) regimen: According to institutional standard of care.
Study 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 IIIa AL amyloidosis.
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
Primary outcome measure(s)
- A Hierarchical Combination of Time to All-cause Mortality and Frequency of Cardiovascular Hospitalizations (CVHs) Analyzed by Win Ratio — Day 1 through end of the participant's PETP (Participants were enrolled on a rolling basis. Therefore, the primary analysis for the study was conducted 18-49 months after the study randomization.)
Time to all-cause mortality was defined as the number of weeks from the date of randomization to the date of death if it is on or before the end of PETP. Participants alive at the end of PETP (LPI+18 months) were censored at their last known alive date recorded within the PETP. CVHs were events adjudicated and confirmed as such by the Clinical Event Adjudication Committee (CEAC). Hypothesis testing with the Finkelstein-Schoenfeld test and treatment effect estimation with the win-ratio method based on pairwise comparisons of participant outcomes with comparisons performed in a hierarchical manner. To calculate win ratio, participant outcomes based on time to all-cause mortality were first compared and if there was no 'winner' due to censoring then a comparison based on frequency of cardiovascular hospitalization was made. A win ratio \>1 represents a more favorable outcome for CAEL-101 over placebo.
- Number of Participants With Treatment-emergent Adverse Events (TEAEs) — Day 1 through end of the participant's PETP (Participants were enrolled on a rolling basis. Therefore, the primary analysis for the study was conducted 18-49 months after the study randomization.)
An adverse event (AE) was defined as any untoward medical occurrence in a participant administered a pharmaceutical product, at any dose, that was not necessarily related to the treatment. A TEAE was an AE with an occurrence defined as follows: last study intervention day-first study intervention day + 140 days. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section.
Trial sites (110)
| Facility | City | Region | Status |
| Research Site |
Scottsdale |
Arizona |
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| Research Site |
Duarte |
California |
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Palo Alto |
California |
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| Research Site |
San Francisco |
California |
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Jacksonville |
Florida |
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Weston |
Florida |
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Indianapolis |
Indiana |
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New Orleans |
Louisiana |
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Baltimore |
Maryland |
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Boston |
Massachusetts |
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Boston |
Massachusetts |
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Boston |
Massachusetts |
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Detroit |
Michigan |
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| Research Site |
Rochester |
Minnesota |
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St Louis |
Missouri |
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New York |
New York |
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New York |
New York |
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Rochester |
New York |
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Chapel Hill |
North Carolina |
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Durham |
North Carolina |
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Winston-Salem |
North Carolina |
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| Research Site |
Cleveland |
Ohio |
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| Research Site |
Columbus |
Ohio |
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| Research Site |
Portland |
Oregon |
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Philadelphia |
Pennsylvania |
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Nashville |
Tennessee |
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Dallas |
Texas |
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Houston |
Texas |
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Salt Lake City |
Utah |
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| Research Site |
Seattle |
Washington |
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Madison |
Wisconsin |
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Milwaukee |
Wisconsin |
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Box Hill |
Australia |
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Murdoch |
Australia |
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| Research Site |
Westmead |
Australia |
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| Research Site |
Woolloongabba |
Australia |
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| Research Site |
Linz |
Austria |
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| Research Site |
Vienna |
Austria |
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| Research Site |
Anderlecht |
Belgium |
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| Research Site |
Leuven |
Belgium |
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+ 70 more sites — see the full list on the official registry below.