A Phase 3 Study to Evaluate the Efficacy and Safety of CAEL-101 in Plasma Cell Dyscrasia Treatment Naive Patients with Mayo Stage IIIb AL Amyloidosis

JRCT ID: jRCT2031200299

Registered date:15/01/2021

Basic Information

• Recruitment status: Not Recruiting
• Health condition(s) or Problem(s) studied: AL Amyloidosis
• Date of first enrollment: 15/01/2021
• Target sample size: 3
• Countries of recruitment: US,Japan,UK,Japan,Australia,Japan,Canada,Japan,France,Japan,Spain,Japan,Italy,Japan,Israel,Japan,Germany,Japan,Poland,Japan,Greece,Japan,Belgium,Japan,Russia,Japan
• Study type: Interventional

Intervention(s)

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 IIIb AL amyloidosis that have not received prior treatment. Patients randomized to receive CAEL-101 will receive 1000 mg/m2. 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. Approximately 111 patients will be enrolled using a 2:1 randomization ratio. A sample size re-estimation (SSR) procedure will be performed when approximately 50% 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.

Outcome(s)

Primary Outcome

-To determine if CAEL-101 and treatment for PCD improves overall survival in Mayo stage IIIb AL amyloidosis patients who are treatment naive compared to treatment for PCD alone
-To evaluate the safety and tolerability of CAEL-101 in combination with treatment for PCD

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: Not applicable
• Gender: Both

Include 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 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
4.Measurable hematologic disease at Screening as defined by at least one of the following:
a.Involved/Uninvolved Free Light Chain Difference (dFLC) > 4 mg/dL or
b.Involved Free Light Chain (iFLC) > 4 mg/dL with abnormal ratio or
c.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:
a.Immunohistochemistry or
b.Mass spectrometry or
c.Characteristic electron microscopy appearance
6.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 > 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:
a.Absolute neutrophil count >= 1.0 x 109/L
b.Platelet count >= 75 x 109/L
c.Hemoglobin >= 9 g/dL
d.Total direct bilirubin <= 2 times the upper limit of normal (x ULN) unless due to Gilbert's syndrome.
e.Aspartate aminotransferase (AST) <= 3 x ULN
f.Alanine aminotransferase (ALT) <= 3 x ULN
g.Alkaline phosphatase (ALP) <= 5 x ULN (except for patients with hepatomegaly and isozymes specific to liver, rather than bone)
h.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

Exclude 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:
a.First degree Atrioventricular (AV)-block
b.Second degree AV-block Type 1 (Mobitz Type 1/Wenckebach type)
c.Right or left bundle branch block
d.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:
a.Adequately treated basal cell carcinoma, squamous cell carcinoma, or in situ cervical cancer
b.Adequately treated stage I cancer from which the patient is currently in remission and has been in remission for > 2 years
c.Low-risk prostate cancer with Gleason score < 7 and prostate-specific antigen < 10 mg/mL
d.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. Hypersensitivity to the study drug
19. Have received a live vaccine within 4 weeks prior to first dose of CyBorD
20. Women who are breast feeding
21. 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.

Related Information

• Primary Sponsor: Caelum Medical Monitor
• Secondary ID(s): NCT04504825