AL Amyloidosis
Conditions
Keywords
Plasma Cell Dyscrasia, cyclophosphamide, bortezomib and dexamethasone (CyBorD), AL Amyloidosis, Amyloid, Light chain Amyloidosis, treatment-naïve, Mayo Stage IIIa
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 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. Approximately 267 patients will be enrolled using a 2:1 randomization ratio. 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.
Interventions
DRUGCAEL-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.
OTHERPlacebo
Commercially available 0.9% Normal Saline will be used as the placebo.
According to institutional standard of care.
Sponsors
Alexion Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
This is a double-blind, randomized, multicenter international Phase 3 study.
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. Approximately 267 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 end of study.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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 (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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Kansas City Cardiomyopathy Questionnaire-Overall Score (KCCQ-OS) | Baseline, Week 50 | The KCCQ-OS is a 23-item self-administered questionnaire that quantifies physical function, symptoms, social function, self-efficacy and knowledge and quality of life. It uses an ordinal, adjectival (Likert) scale. Participants provide their level of agreement or disagreement with an agree-disagree scale for a series of statements. The questionnaire captures how the participants feel physically. The overall score was calculated as the sum from all 23 items and ranges from 0 to 100, where higher scores reflected better health status (fewer symptoms, fewer social or physical limitations, and better quality of life). |
| Change From Baseline in Distance Walked During a Six-minute Walk Test (6MWT) | Baseline, Week 50 | The 6MWT measures the distance a participant 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; participants choose their own intensity of exercise and are allowed to stop and rest during the test. |
| All-cause Mortality | Day 1 through end of the participant's PETP (Participants were enrolled on a rolling basis. Therefore, analysis for the study was conducted 18-49 months after the study randomization.) | All-cause mortality was defined as death on or before the end of the PETP. Otherwise, participants who were alive at the end of the PETP (last participant randomized plus 18 months) were censored at their last known alive date recorded within the PETP. All deaths, regardless of causality or whether they were reported as a reason for study discontinuation, are reported in the All-Cause Mortality section. |
| Frequency of CVHs | Day 1 through end of the participant's PETP (Participants were enrolled on a rolling basis. Therefore, analysis for the study was conducted 18-49 months after the study randomization.) | CVHs were those events that were adjudicated and confirmed as such by the CEAC. Frequency of CVH was calculated using negative binomial regression analysis with study intervention, study, geographic region, daratumumab usage at Baseline, and offset term equal to log of each participant's follow-up time for cardiovascular hospitalization included in the model. |
| Change From Baseline in Global Longitudinal Strain (GLS%) | Baseline, Week 50 | Change in heart function was measured by GLS%, a noninvasive imaging technique that uses echocardiography to assess heart. GLS% expresses longitudinal shortening as a percentage (change in length as a proportion to baseline length) and is reported as a negative value. A more negative value is usually associated with cardiac enhancement. |
| Change From Baseline in the Short Form-36 (SF-36) Version 2 (v2) Physical Component Score (PCS) | Baseline, Week 50 | The SF-36v2 is a self-administered questionnaire containing 36 items that measure health on functional status, well-being, and overall evaluation of health in 8 domains, including vitality, physical functioning, bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning, and mental health, using scaled, ordinal responses (for example, All of the time, Most of the time, A good bit of the time). The SF-36v2 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale, with higher scores indicating an increased quality of life. The 8 multi-item scales are aggregated and summed to give the final PCS. The final score ranges from 0-100, with higher scores indicating an increased quality of life. |
| Change From Baseline in N-Terminal Pro-B-type Natriuretic Peptide (NT-proBNP) in Blood Samples | Baseline, Week 50 | For each participant, blood samples were assayed for NT-proBNP, comparing the participant's baseline value over time to assess reduced amyloidosis, as measured by a decrease in NT-proBNP. A decrease indicates cardiac enhancement. Results reported as nanograms/milliliter (ng/mL). |
Countries
Australia, Austria, Belgium, Brazil, Canada, China, Czechia, France, Germany, Greece, Israel, Italy, Japan, Poland, Russia, South Korea, Spain, United Kingdom, United States
Contacts
STUDY_DIRECTORScott Swenson, MD
Alexion, AstraZeneca Rare Disease
Participant flow
Recruitment details
This study consisted of 2 periods: the Primary Evaluation Treatment Period (PETP) and the Open-label Extension Period (OLEP). Primary analysis data reported based only on data collected through the end of the participant's PETP (last participant in \[LPI\] plus 18 months). Final data will be reported after study completion.
Pre-assignment details
Subgroup analyses reported for 2 free light chain (FLC) isotypes (Kappa, Lambda) as following subgroups, 'Kappa FLC Subtype' and 'Lambda FLC Subtype'.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Customized Kappa FLC Subtype | 67.5 Years STANDARD_DEVIATION 8.38 |
| Age, Customized Lambda FLC Subtype | 67.0 Years STANDARD_DEVIATION 9.23 |
| Age, Customized Overall (All Randomized Participants) | 64.1 Years STANDARD_DEVIATION 9.97 |
| Race/Ethnicity, Customized Kappa FLC Subtype American Indian or Alaska Native | 0 Participants |
| Race/Ethnicity, Customized Kappa FLC Subtype Asian | 5 Participants |
| Race/Ethnicity, Customized Kappa FLC Subtype Black or African American | 3 Participants |
| Race/Ethnicity, Customized Kappa FLC Subtype Hispanic or Latino | 1 Participants |
| Race/Ethnicity, Customized Kappa FLC Subtype Missing | 0 Participants |
| Race/Ethnicity, Customized Kappa FLC Subtype Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized Kappa FLC Subtype Not Hispanic or Latino | 21 Participants |
| Race/Ethnicity, Customized Kappa FLC Subtype Not Reported | 3 Participants |
| Race/Ethnicity, Customized Kappa FLC Subtype Other | 3 Participants |
| Race/Ethnicity, Customized Kappa FLC Subtype Unknown | 1 Participants |
| Race/Ethnicity, Customized Kappa FLC Subtype White | 15 Participants |
| Race/Ethnicity, Customized Lambda FLC Subtype American Indian or Alaska Native | 0 Participants |
| Race/Ethnicity, Customized Lambda FLC Subtype Asian | 27 Participants |
| Race/Ethnicity, Customized Lambda FLC Subtype Black or African American | 8 Participants |
| Race/Ethnicity, Customized Lambda FLC Subtype Hispanic or Latino | 7 Participants |
| Race/Ethnicity, Customized Lambda FLC Subtype Missing | 0 Participants |
| Race/Ethnicity, Customized Lambda FLC Subtype Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race/Ethnicity, Customized Lambda FLC Subtype Not Hispanic or Latino | 66 Participants |
| Race/Ethnicity, Customized Lambda FLC Subtype Not Reported | 10 Participants |
| Race/Ethnicity, Customized Lambda FLC Subtype Other | 11 Participants |
| Race/Ethnicity, Customized Lambda FLC Subtype Unknown | 4 Participants |
| Race/Ethnicity, Customized Lambda FLC Subtype White | 48 Participants |
| Race/Ethnicity, Customized Overall (All Randomized Participants) American Indian or Alaska Native | 0 Participants |
| Race/Ethnicity, Customized Overall (All Randomized Participants) Asian | 11 Participants |
| Race/Ethnicity, Customized Overall (All Randomized Participants) Black or African American | 16 Participants |
| Race/Ethnicity, Customized Overall (All Randomized Participants) Hispanic or Latino | 2 Participants |
| Race/Ethnicity, Customized Overall (All Randomized Participants) Missing | 0 Participants |
| Race/Ethnicity, Customized Overall (All Randomized Participants) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized Overall (All Randomized Participants) Not Hispanic or Latino | 81 Participants |
| Race/Ethnicity, Customized Overall (All Randomized Participants) Not Reported | 10 Participants |
| Race/Ethnicity, Customized Overall (All Randomized Participants) Other | 18 Participants |
| Race/Ethnicity, Customized Overall (All Randomized Participants) Unknown | 0 Participants |
| Race/Ethnicity, Customized Overall (All Randomized Participants) White | 126 Participants |
| Sex/Gender, Customized Kappa FLC Subtype Female | 4 Participants |
| Sex/Gender, Customized Kappa FLC Subtype Male | 19 Participants |
| Sex/Gender, Customized Lambda FLC Subtype Female | 50 Participants |
| Sex/Gender, Customized Lambda FLC Subtype Male | 51 Participants |
| Sex/Gender, Customized Overall (All Randomized Participants) Female | 29 Participants |
| Sex/Gender, Customized Overall (All Randomized Participants) Male | 132 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 44 / 187 | 30 / 94 |
| other Total, other adverse events | 179 / 187 | 91 / 94 |
| serious Total, serious adverse events | 132 / 187 | 68 / 94 |
Outcome results
None listed