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

Sponsor
Alexion Pharmaceuticals (Industry)
Overall Status
Recruiting
CT.gov ID
NCT04512235
Collaborator
AstraZeneca (Industry)
267
102
2
52
2.6
0.1

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
  • Drug: CAEL-101
  • Other: Placebo
  • Drug: cyclophosphamide, bortezomib, and dexamethasone (CyBorD) regimen
Phase 3

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 Design

Study Type:
Interventional
Anticipated Enrollment :
267 participants
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.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
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
Actual Study Start Date :
Nov 12, 2020
Anticipated Primary Completion Date :
Mar 15, 2025
Anticipated Study Completion Date :
Mar 15, 2025

Arms and Interventions

Arm Intervention/Treatment
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.

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.

Drug: cyclophosphamide, bortezomib, and dexamethasone (CyBorD) regimen
According to institutional standard of care.

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.

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.

Outcome Measures

Primary Outcome Measures

  1. Time from the date of randomization to date of death or end of study [50 weeks]

  2. Number of patients with treatment emergent adverse events as assessed by CTCAE v5.0 [50 weeks]

Secondary Outcome Measures

  1. Quality of Life (QOL) by the Kansas City Cardiomyopathy Questionnaire-Overall Score (KCCQ-OS) [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)

  2. Cardiac Improvement by Global Longitudinal Strain (GLS%) [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.

  3. Change in distance walked (in meters) during a six-minute walk test [50 weeks]

  4. Quality of Life (QOL) by the Short Form-36 (SF-36) v2 Physical Component Score (PCS) [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.).

Other Outcome Measures

  1. Measure of N-terminal pro b-type natriuretic peptide (NT-proBNP) in blood samples [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.

  2. Measure of Cardiac troponin (cTnT) in blood samples [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.

  3. Measure of involved/uninvolved free light chain difference (dFLC) in blood [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

  4. Measure of C-reactive protein (CRP) in blood samples [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.

  5. Changes in Amyloid Load of the Heart, Liver and Spleen [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.

  6. Measure of aspartate aminotransferase (AST) [50 weeks]

    For each subject, blood sample will be assayed for AST to determine effects on liver function relative to normal values.

  7. Measure of alanine aminotransferase (ALT) [50 weeks]

    For each subject, blood sample will be assayed for ALT to determine effects on liver function relative to normal values.

  8. Measure of alkaline phosphatase (ALP) [50 weeks]

    For each subject, blood sample will be assayed for ALP to determine effects on liver function relative to normal values.

  9. Measure of Kidney Glomerular Filtration Rate [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.

  10. Measure of Serum Creatinine [50 weeks]

    For each subject, blood sample will be assayed for creatinine to determine changes during treatment that reflect kidney function.

  11. 24-hour Urine Protein Measure [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.

  12. Quality of Life (QoL) by Short Form-36 (SF-36) v2 scaled domain scores [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.

  13. EuroQual 5-dimension health survey (EQ-5D-5L™) [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.

  14. Measure of Plasma Levels of CAEL-101 [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.

  15. Determination of immunogenicity of CAEL-101 [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.

  16. Assessment of limitation during physical activity [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.

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
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:
  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 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:

  1. 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
  1. 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

Contacts and Locations

Locations

Site City State Country Postal Code
1 Clinical Trial Site Phoenix Arizona United States 85054
2 Clinical Trial Site Scottsdale Arizona United States 85054
3 Clinical Trial Site Duarte California United States 91010
4 Clinical Trial Site Palo Alto California United States 94305
5 Clinical Trial Site San Francisco California United States 94143
6 Clinical Trial Site Jacksonville Florida United States 32224
7 Clinical Trial Site Weston Florida United States 33331
8 Clinical Trial Site Indianapolis Indiana United States 46202
9 Clinical Trial Site New Orleans Louisiana United States 70112
10 Clinical Trial Site Baltimore Maryland United States 21201
11 Clinical Trial Site Boston Massachusetts United States 02111
12 Clinical Trial Site Boston Massachusetts United States 02115
13 Clinical Trial Site Boston Massachusetts United States 02118
14 Clinical Trial Site Detroit Michigan United States 48201
15 Clinical Trial Site Rochester Minnesota United States 55905
16 Clinical Trial Site Saint Louis Missouri United States 63110
17 Clinical Trial Site New York New York United States 10021
18 Clinical Trial Site New York New York United States 10032
19 Clinical Trial Site New York New York United States 10065
20 Clinical Trial Site Rochester New York United States 14642
21 Clinical Trial Site Chapel Hill North Carolina United States 27599-7295
22 Clinical Trial Site Durham North Carolina United States 27705
23 Clinical Trial Site Winston-Salem North Carolina United States 27157
24 Clinical Trial Site Cleveland Ohio United States 44195
25 Clinical Trial Site Columbus Ohio United States 43210
26 Clinical Trial Site Portland Oregon United States 97239
27 Clinical Trial Site Philadelphia Pennsylvania United States 19104
28 Clinical Trial Site Pittsburgh Pennsylvania United States 15232
29 Clinical Trial Site Charleston South Carolina United States 29425
30 Clinical Trial Site Nashville Tennessee United States 37232
31 Clinical Trial Site Dallas Texas United States 75390
32 Clinical Trial Site Houston Texas United States 77030
33 Clinical Trial Site Salt Lake City Utah United States 84112
34 Clinical Trial Site Seattle Washington United States 98109
35 Clinical Trial Site Madison Wisconsin United States 53792
36 Clinical Trial Site Milwaukee Wisconsin United States 53226
37 Clinical Trial Site Adelaide Australia SA 5000
38 Clinical Trial Site Box Hill Australia VIC 3128
39 Clinical Trial Site Brisbane Australia QLD 4102
40 Clinical Trial Site Murdoch Australia WA 6150
41 Clinical Trial Site Sydney Australia NSW 2145
42 Clinical Trial Site Linz Austria 1090
43 Clinical Trial Site Linz Austria 4020
44 Clinical Trial Site Bruxelles Belgium 1000
45 Clinical Trial Site Bruxelles Belgium 1200
46 Clinical Trial Site Leuven Belgium 3000
47 Clinical Trial Site Calgary Alberta Canada T2N 4N2
48 Clinical Trial Site Edmonton Alberta Canada T6G 1Z2
49 Clinical Trial Site Toronto Ontario Canada M5G 2M9
50 Clinical Trial Site Caen France 14033
51 Clinical Trial Site Créteil France 94010
52 Clinical Trial Site Dijon France 21079
53 Clinical Trial Site Lille France 59037
54 Clinical Trial Site Limoges France 87042
55 Clinical Trial Site Marseille France 13009
56 Clinical Trial Site Paris France 75010
57 Clinical Trial Site Pessac France 33604
58 Clinical Trial Site Pierre-Bénite France 69310
59 Clinical Trial Site Poitiers France 86021
60 Clinical Trial Site Rennes France 35033
61 Clinical Trial Site Tours France 37000
62 Clinical Trial Site Berlin Germany 12203
63 Clinical Trial Site Hamburg Germany 22767
64 Clinical Trial Site Mainz Germany 55131
65 Clinical Trial Site Münster Germany 48149
66 Clinical Trial Site Würzburg Germany 97080
67 Clinical Trial Site Athens Greece 11528
68 Clinical Trial Site Patras Greece 26504
69 Clinical Trial Site Thessaloníki Greece 546 36
70 Clinical Trial Site Jerusalem Israel 911200
71 Clinical Trial Site Tel Aviv Israel 6423906
72 Clinical Trial Site Pavia Italy 27100
73 Clinical Trial Site Chiba Japan 277-8567
74 Clinical Trial Site Fukushima Japan 960-1295
75 Clinical Trial Site Ishikawa Japan 920-8641
76 Clinical Trial Site Kyoto Japan 603-8151
77 Clinical Trial Site Nagoya Japan 467-8602
78 Clinical Trial Site Tokyo Japan 150-8935
79 Clinical Trial Site Seoul Korea, Republic of 3080
80 Clinical Trial Site Seoul Korea, Republic of 3722
81 Clinical Trial Site Seoul Korea, Republic of 6351
82 Clinical Trial Site Seoul Korea, Republic of 6591
83 Clinical Trial Site Gdansk Poland 80-214
84 Clinical Trial Site Warszawa Poland 02-097
85 Clinical Trial Site Saint Petersburg Russian Federation 197022
86 Clinical Trial Site Saint Petersburg Russian Federation 197341
87 Clinical Trial Site Barcelona Spain 08035
88 Clinical Trial Site Barcelona Spain 08036
89 Clinical Trial Site Gijon Spain 33203
90 Clinical Trial Site Granada Spain 18014
91 Clinical Trial Site Madrid Spain 28003
92 Clinical Trial Site Madrid Spain 28040
93 Clinical Trial Site Madrid Spain 28222
94 Clinical Trial Site Pamplona Spain 31008
95 Clinical Trial Site Salamanca Spain 37007
96 Clinical Trial Site Sevilla Spain 41013
97 Clinical Trial Site Valencia Spain 46009
98 Clinical Trial Site Coventry United Kingdom CV2 2DX
99 Clinical Trial Site Glasgow United Kingdom G12 0YN
100 Clinical Trial Site London United Kingdom NW1 2BU
101 Clinical Trial Site London United Kingdom NW1 2PG
102 Clinical Trial Site London United Kingdom NW3 2QG

Sponsors and Collaborators

  • Alexion Pharmaceuticals
  • AstraZeneca

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
Alexion Pharmaceuticals
ClinicalTrials.gov Identifier:
NCT04512235
Other Study ID Numbers:
  • CAEL101-302
First Posted:
Aug 13, 2020
Last Update Posted:
Aug 8, 2022
Last Verified:
Aug 1, 2022
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by Alexion Pharmaceuticals
Additional relevant MeSH terms:

Study Results

No Results Posted as of Aug 8, 2022