start date: August 25, 2020
estimated completion: February 24, 2023
last updated: December 7, 2021
phase of development:
Phase 3
size / enrollment: 111
study description:
This is a double-blind, randomized, multicenter international Phase 3 study of CAEL-101 combined with the standard of care (SoC) for plasma cell dyscrasia (PCD) versus placebo combined with standard of care PCD treatment in patients with Mayo stage IIIb AL amyloidosis that have not received prior treatment. 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.
Approximately 111 patients will be enrolled using a 2:1 randomization ratio of CAEL-101: placebo and will involve approximately 100 investigator sites.
The primary objective of this study is to assess the effects of CAEL-101 versus placebo on all-cause mortality.
primary outcomes:
- Time from the date of randomization to date of death or end of study. [ Time Frame: 50 weeks ]
Number of patients with treatment emergent adverse events as assessed by CTCAE v5.0 [ Time Frame: 50 weeks ]
secondary outcomes:
- Change in distance walked (in meters) during a six-minute walk test [ Time Frame: 50 weeks ]
Quality of Life (QOL) by the Kansas City Cardiomyopathy Questionnaire-Overall Score (KCCQ-OS) [ Time Frame: 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
Quality of Life (QOL) by the Short Form-36 (SF-36) v2 Physical Component Score (PCS) [ Time Frame: 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.)
Cardiac Improvement by Global Longitudinal Strain (GLS%) [ Time Frame: 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.
inclusion criteria:
• Eligible Ages: 18 - 120
• Eligible Sexes: all
Inclusion Criteria:
Each patient must meet the following criteria to be enrolled in this study.
Be able to and provide written informed consent and be willing and able to comply with all study procedures
Adult, 18 years and older
AL amyloidosis Mayo stage IIIb based on the 2013 European Modification of the 2004 Standard Mayo Clinic Staging in patients with advanced cardiac involvement at the time of Screening
Measurable hematologic disease at Screening as defined by at least one of the following:
Involved/Uninvolved Free Light Chain Difference (dFLC) > 4 mg/dL or
Involved Free Light Chain (iFLC) > 4 mg/dL with abnormal ratio or
Serum Protein Electrophoresis (SPEP) m-spike > 0.5 g/dL
Histopathological diagnosis of amyloidosis AND confirmation of AL derived amyloid deposits by at least one of the following:
Immunohistochemistry or
Mass spectrometry or
Characteristic electron microscopy appearance
Cardiac involvement as defined by:
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
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 MRI with gadolinium contrast agent diagnostic or cardiac amyloidosis
Planned first-line treatment for plasma cell disorder is a CyBorD-based regimen administered as Standard of Care (SoC)
Adequate bone marrow reserve and hepatic function as demonstrated by:
Absolute neutrophil count ≥ 1.0 x 109/L
Platelet count ≥ 75 x 109/L
Hemoglobin ≥ 9 g/dL
Total direct bilirubin ≤ 2 times the upper limit of normal (x ULN) unless due to Gilbert's syndrome.
Aspartate aminotransferase (AST) ≤ 3 x ULN
Alanine aminotransferase (ALT) ≤ 3 x ULN
Alkaline phosphatase (ALP) ≤ 5 x ULN (except for patients with hepatomegaly and isozymes specific to liver, rather than bone)
Women of childbearing potential (WOCBP) must have a negative pregnancy test during Screening and must agree to use highly effective physician approved 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 effective physician approved 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 his PCD therapy, whichever is longer.
exclusion criteria: Criteria:
Patients who meet any of the following criteria will not be permitted entry to the study.
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 syndrome or multiple myeloma defined as clonal bone marrow plasma cells > 10% or biopsy-proven bony or extramedullary plasmacytoma AND any 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, specifically:
i. Hypercalcemia: serum calcium > 0.25 mmol/L (> 1mg/dL) higher than the ULN or > 2.75 mmol/L (> 11mg/dL)
ii. Renal insufficiency: creatinine clearance < 40 mL per minute or serum creatinine > 177mol/L (> 2mg/dL)
iii. Anemia: hemoglobin value of > 20g/L below the lowest limit of normal, or a hemoglobin value < 100g/L
iv. Bone lesions: one or more osteolytic lesion on skeletal radiography, CT, or PET/CT. 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
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
Taking prednisone or its equivalent > 10 mg/day
Taking doxycycline
Receiving dialysis
Planned stem cell transplant during the first 6 months of protocol therapy. Stem cell collection during the protocol therapy is permitted.
Have had myocardial infarction, uncontrolled angina, severe uncontrolled ventricular arrhythmias within 6 months prior to screening or percutaneous cardiac intervention with recent stent or coronary artery bypass grafting within 4 months prior to screening. Exacerbation of chronic condition or new acute condition will require discussion and approval by the Medical Monitor.
Left Ventricular Ejection Fraction (LVEF) is < 40% by echocardiogram at Screening
Have severe valvular stenosis (e.g., aortic or mitral stenosis with a valve area < 1.0 cm2) or severe congenital heart disease
Have history of sustained ventricular tachycardia or aborted ventricular fibrillation or a history of atrioventricular nodal or sinoatrial nodal dysfunction for which a pacemaker/implantable cardioverter-defibrillator (ICD) is indicated but not placed. (Participants who do have a pacemaker or ICD are allowed in the study.)
QT corrected by Fridericia (QTcF) is > 550 msec. Participants who have a pacemaker may be included regardless of calculated QTc interval.
There is evidence of acute ischemia or active conduction system abnormalities with the exception of any of the following:
First degree Atrioventricular (AV)-block
Second degree AV-block Type 1 (Mobitz Type 1/Wenckebach type)
Right or left bundle branch block
Atrial fibrillation with a controlled ventricular rate. (An uncontrolled ventricular rate [i.e., > 110 beats per minute] determined by an average of three beats in lead II or representative beats in lead II is not allowed)
Have had major surgery within 4 weeks of randomization or is planning major surgery during the study. Patients with surgical procedures conducted under local anesthesia may participate
There is active malignancy (including lymphoma) with the exception of any of the following:
Adequately treated basal cell carcinoma, squamous cell carcinoma, or in situ cervical cancer
Adequately treated stage I cancer from which the patient is currently in remission and has been in remission for > 2 years
Low-risk prostate cancer with Gleason score < 7 and prostate-specific antigen < 10 mg/mL
Other localized and/or low risk malignancies may be permitted with Medical Monitor approval.
Have received an investigational drug/device in another clinical investigational study within 60 days before Screening
Hypersensitivity to the study drug
Have received a live vaccine within 4 weeks prior to first dose of CyBorD
Women who are breast feeding
Have any other medical, social or psychological factors that could affect the patient's safety or ability to consent personally or comply with study procedures.
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