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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04512235
Recruitment Status : Recruiting
First Posted : August 13, 2020
Last Update Posted : September 17, 2020
Sponsor:
Collaborator:
IQVIA Biotech
Information provided by (Responsible Party):
Caelum Biosciences

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


Condition or disease Intervention/treatment Phase
AL Amyloidosis Drug: CAEL-101 Other: Placebo Drug: cyclophosphamide, bortezomib, and dexamethasone (CyBorD) Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Estimated 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 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.

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 : August 25, 2020
Estimated Primary Completion Date : August 2, 2022
Estimated Study Completion Date : February 24, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Amyloidosis

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 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.

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.




Primary Outcome Measures :
  1. Time from the first dose of study drug until death or end of study [ Time Frame: 50 weeks ]
  2. Number of patients with treatment emergent adverse events as assessed by CTCAE v5.0 [ Time Frame: 50 weeks ]

Secondary Outcome Measures :
  1. Change in distance walked (in meters) during a six-minute walk test [ Time Frame: 50 weeks ]
  2. 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. 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)

  3. 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.).

  4. 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.


Other Outcome Measures:
  1. Measure of N-terminal pro b-type natriuretic peptide (NT-proBNP) in blood samples [ Time Frame: 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 [ Time Frame: 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. Changes in Amyloid Load of the Heart, Liver and Spleen [ Time Frame: 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.

  4. Measure of aspartate aminotransferase (AST) [ Time Frame: 50 weeks ]
    For each subject, blood sample will be assayed for AST to determine effects on liver function relative to normal values.

  5. Measure of alanine aminotransferase (ALT) [ Time Frame: 50 weeks ]
    For each subject, blood sample will be assayed for ALT to determine effects on liver function relative to normal values.

  6. Measure of alkaline phosphatase (ALP) [ Time Frame: 50 weeks ]
    For each subject, blood sample will be assayed for ALP to determine effects on liver function relative to normal values.

  7. Measure of change in liver size [ Time Frame: 50 weeks ]
    For each subject, blood sample will be assayed to identify liver enzyme levels and viruses that are present and synonymous with an enlarged liver. Elevated liver enzyme levels often indicate inflammation in the liver.

  8. Measure of Kidney Glomeruli Filtration Rate [ Time Frame: 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.

  9. Measure of Serum Creatinine [ Time Frame: 50 weeks ]
    For each subject, blood sample will be assayed for creatinine to determine changes during treatment that reflect kidney function.

  10. 24-hour Urine Protein Measure [ Time Frame: 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.

  11. Quality of Life (QoL) by Short Form-36 (SF-36) v2 scaled domain scores [ 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.). Changes in the different domains can help assess the benefit or challenges of the disease and your treatment.

  12. EuroQual 5-dimension health survey (EQ-5D-5L™) [ Time Frame: 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.

  13. Measure of Plasma Levels of CAEL-101 [ Time Frame: 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.

  14. Determination of immunogenicity of CAEL-101 [ Time Frame: 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04512235


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

Locations
Show Show 30 study locations
Sponsors and Collaborators
Caelum Biosciences
IQVIA Biotech
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Responsible Party: Caelum Biosciences
ClinicalTrials.gov Identifier: NCT04512235    
Other Study ID Numbers: CAEL101-302
First Posted: August 13, 2020    Key Record Dates
Last Update Posted: September 17, 2020
Last Verified: August 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Each patient will be assigned a unique identifier after signing the Informed Consent Form (ICF). Patient numbers will not be reassigned. Any patient records or datasets transferred to the Sponsor must contain only the unique identifier and must not include patient names or any information which would make the patient identifiable. Patients will be informed that their personal study-related data will be used by the Sponsor in accordance with local data protection laws and that their medical records may be examined by representatives of the Sponsor, Institutional Review Board (IRB)/Independent Ethics Committee (IEC) members and by inspectors from regulatory authorities. Study monitors will inspect all documents and records that are required to be maintained by the Investigator for this study.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Caelum Biosciences:
Plasma Cell Dyscrasia
cyclophosphamide, bortezomib and dexamethasone (CyBorD)
AL Amyloidosis
Amyloid, Light chain Amyloidosis
treatment-naïve
Mayo Stage IIIa
Additional relevant MeSH terms:
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Immunoglobulin Light-chain Amyloidosis
Paraproteinemias
Amyloidosis
Proteostasis Deficiencies
Metabolic Diseases
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Blood Protein Disorders
Hematologic Diseases
Dexamethasone
Cyclophosphamide
Bortezomib
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Gastrointestinal Agents