Purpose

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 if CAEL-101 improves the overall survival in Patients with cardiac AL Amyloidosis.

Condition

Eligibility

Eligible Ages
Over 18 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

Inclusion Criteria

  • Each patient must meet the following criteria to be enrolled in this study. 1. Provide written informed consent and be willing and able to comply with all study procedures 2. Adult, 18 years and older 3. AL amyloidosis Mayo stage IIIa based on the 2013 European Modification of the 2004 Standard Mayo Clinic Staging in patients with advanced cardiac involvement at the time of Screening 4. 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 ratio or 3. Serum Protein Electrophoresis (SPEP) m-spike > 0.5 g/dL 5. Histopathological diagnosis of amyloidosis AND confirmation of AL derived amyloid deposits by at least one of the following: 1. Immunohistochemistry or 2. Mass spectrometry or 3. Characteristic electron microscopy appearance 6. 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 > 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 7. Planned first-line treatment for plasma cell disorder is CyBorD administered as Standard of Care (SoC) 8. Adequate bone marrow reserve and hepatic and renal function as demonstrated by: 1. Absolute neutrophil count ≥ 1.0 x 109/L 2. Platelet count ≥ 75 x 109/L 3. Hemoglobin ≥ 9 g/dL 4. Total direct bilirubin ≤ 2 times the upper limit of normal (x ULN) unless due to Gilbert's syndrome. 5. Aspartate aminotransferase (AST) ≤ 3 x ULN 6. Alanine aminotransferase (ALT) ≤ 3 x ULN 7. Alkaline phosphatase (ALP) ≤ 5 x ULN (except for patients with hepatomegaly and isozymes specific to liver, rather than bone) 8. Estimated glomerular filtration rate (eGFR) ≥ 15 mL/min 9. Women of childbearing potential (WOCBP) must have a negative pregnancy test during Screening and must agree to use effective physician approved contraception from Screening to 90 days following the last study drug administration 10. Men must be surgically sterile or must agree to use effective physician approved contraception from Screening to 90 days following the last study drug administration

Exclusion Criteria

  • Patients who meet any of the following criteria will not be permitted entry to the study. 1. Have any other form of amyloidosis other than AL amyloidosis 2. Received prior therapy for AL amyloidosis or multiple myeloma. A maximum exposure of 160 mg dexamethasone (or equivalent corticosteroid) since diagnosis of AL amyloidosis and prior to randomization is allowed. 3. Meets the International Myeloma Working Group (IMWG) definition of multiple myeloma or POEMS syndrome 4. 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 5. Taking prednisone or its equivalent > 10 mg/day 6. Taking doxycycline 7. Receiving dialysis 8. Planned stem cell transplant during the first 6 months of protocol therapy. Stem cell collection during the protocol therapy is permitted. 9. 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 10. Left Ventricular Ejection Fraction (LVEF) is < 40% by echocardiogram at Screening 11. Have severe valvular stenosis (e.g., aortic or mitral stenosis with a valve area < 1.0 cm2) or severe congenital heart disease 12. 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.) 13. QT corrected by Fridericia (QTcF) is > 550 msec. Participants who have a pacemaker may be included regardless of calculated QTc interval. 14. There is evidence of acute ischemia or active conduction system abnormalities with the exception of any of the following: 1. First degree Atrioventricular (AV)-block 2. Second degree AV-block Type 1 (Mobitz Type 1/Wenckebach type) 3. Right or left bundle branch block 4. 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) 15. 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 16. There is active malignancy (including lymphoma) with the exception of any of the following: 1. Adequately treated basal cell carcinoma, squamous cell carcinoma, or in situ cervical cancer 2. Adequately treated stage I cancer from which the patient is currently in remission and has been in remission for > 2 years 3. Low-risk prostate cancer with Gleason score < 7 and prostate-specific antigen < 10 mg/mL 4. Other localized and/or low risk malignancies may be permitted with Medical Monitor approval. 17. Have received an investigational drug/device in another clinical investigational study within 60 days before Screening 18. Women who are breast feeding

Study Design

Phase
Phase 3
Study Type
Interventional
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 the SoC treatment for plasma cell dyscrasia (PCD) versus placebo combined with standard of care PCD treatment in patients with Mayo stage IIIa 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 267 patients will be enrolled using a 2:1 randomization ratio. A sample size re-estimation (SSR) procedure will be performed when approximately 40% of the expected deaths has been observed. Patients in both treatment groups will be followed from randomization until death from any cause or until the end of study.
Primary Purpose
Treatment
Masking
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description
This is a double-blind, randomized, multicenter international Phase 3 study.

Arm Groups

ArmDescriptionAssigned Intervention
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 77 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)
    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 77 deaths have been observed.
  • Other: Placebo
    Commercially available 0.9% Normal Saline will be used as the placebo.
  • Drug: cyclophosphamide, bortezomib, and dexamethasone (CyBorD)
    According to institutional standard of care.
Other
Concurrent Plasma Cell Dyscrasia Treatment
All patients will also receive concurrent treatment for Plasma Cell Dyscrasia (PCD) with CyBorD according to institutional SoC. Patients should initiate their CyBorD chemotherapy regimen within 7 days of receiving the first dose of study drug. It is the intent of this protocol that patients will receive CyBorD per institution SoC in the study, as long as they are tolerating it. However, after two cycles of CyBorD, if the patient is not benefiting from or tolerating CyBorD in the Investigator's judgement, the investigator may change the CyBorD regimen or stop it.
  • 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)
    According to institutional standard of care.

Recruiting Locations

Boston University Amyloidosis Center
Boston, Massachusetts 02118

More Details

Status
Recruiting
Sponsor
Caelum Biosciences

Study Contact

Caelum Medical Monitor
+1 609-337-3010
info@caelumbio.com

Detailed 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 IIIa 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 267 patients will be enrolled using a 2:1 randomization ratio of CAEL-101: placebo and will involve approximately 70 investigator sites. The primary objective of this study is to assess the effects of CAEL-101 versus placebo on all-cause mortality.

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.