A Study to Evaluate the Efficacy and Safety of Daratumumab in Combination With Cyclophosphamide, Bortezomib and Dexamethasone (CyBorD) Compared to CyBorD Alone in Newly Diagnosed Systemic Amyloid Light-chain (AL) Amyloidosis

Phase 1

• Conditions: AL Amyloidosis (Newly Diagnosed Systemic AL Amyloidosis ); MedDRA version: 20.0Level: PTClassification code 10002022Term: AmyloidosisSystem Organ Class: 10021428 - Immune system disorders; Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2016-001737-27-ES
• Lead Sponsor: Janssen-Cilag International N.V.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2017-11-23
• Last Update Posted: 12 February 2018

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 370

Inclusion Criteria

1) 18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place) or older.
2) Histopathological diagnosis of amyloidosis based on detection by immunohistochemistry and polarizing light microscopy of green bi-refringent material in congo red stained tissue specimens (in an organ other than bone marrow) or characteristic electron microscopy appearance
Considerations for specific populations where other types of amyloidosis may be encountered:
- For male subjects 70 years of age or older who have cardiac involvement only, and subjects of African descent (black subjects), mass spectrometry typing of AL amyloid in a tissue biopsy is recommended to rule out other types of
amyloidosis such as age-related amyloidosis or hereditary amyloidosis (ATTR mutation)
3) Measurable disease of amyloid light chain amyloidosis as defined by at least ONE of the following:
-serum monoclonal protein =0.5 g/dL by protein electrophoresis (routine serum protein electrophoresis and immunofixation performed at central lab),
-serum free light chain =5.0 mg/dL with an abnormal kappa:lambda ratio or the difference between involved and uninvolved free light chains (dFLC) =5mg/ dL.
4) One or more organs impacted by AL amyloidosis according to consensus guidelines
5) Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0, 1 or 2
6)Pre-treatment clinical laboratory values meeting the following criteria during the Screening Phase:
a. Absolute neutrophil count =1.0 ×1000000000 /L;
b. Hemoglobin level =8.0 g/dL (=5 mmol/L); red blood cell transfusion allowed until 7 days before randomization
c. Platelet count =50 × 1000000000/L; Platelet transfusions are acceptable without restriction during the screening period
d. Alanine aminotransferase level (ALT) =2.5 times the ULN;
e. Aspartate aminotransferase (AST) =2.5 times the ULN
f. Total bilirubin level =1.5 × ULN except for subjects with Gilbert syndrome, in which case direct bilirubin =2 × ULN
g. Estimated glomerular filtration rate (eGFR) =20 mL/min/1.73m2. Please note the eGFR is measured by using the CKD-epi equation
7)Women of childbearing potential must commit to either abstain continuously from heterosexual sexual intercourse (if this is the preferred and usual lifestyle of the subject) or to use 2 methods of reliable birth control simultaneously. This includes one highly effective form of contraception (tubal ligation, intrauterine device, hormonal [birth control pills, injections, hormonal patches, vaginal rings or implants] or partner’s vasectomy) and one additional effective contraceptive method (male latex or synthetic condom, diaphragm, or cervical cap). Contraception must begin 4 weeks prior to dosing and continue for 1 year after discontinuation of cyclophosphamide or 3 months after discontinuation of daratumumab, whichever is longer. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy or bilateral oophorectomy.
8)During the study and for 1 year after stopping cyclophosphamide or 3 months after receiving the last dose of daratumumab, whichever is longer, a woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction.
9)A man who is sexually active with a woman of childbearing potential and has not had a vasectomy must agree to use a barrier method of birth control; eg, either condom with spermicidal foam/gel/film/cream/suppository or partner with

Exclusion Criteria

1.Prior therapy for AL amyloidosis or multiple myeloma including medications that target CD38, with the exception of 160 mg dexamethasone (or equivalent corticosteroid) maximum exposure prior to randomization
2.Previous or current diagnosis of symptomatic multiple myeloma, including the presence of lytic bone disease, plasmacytomas, =60% plasma cells in the bone marrow, or hypercalcemia
3.Evidence of significant cardiovascular conditions as specified below:
a.NT-ProBNP >8500 ng/L
b.New York Heart Association (NYHA) classification IIIB or IV heart failure
c.Heart failure that in the opinion of the investigator is on the basis of ischemic heart disease (eg prior myocardial infarction with documented history of cardiac enzyme elevation and ECG changes)or uncorrected valvular disease
and not primarily due to AL amyloid cardiomyopathy
d.Inpatient admission to a hospital for unstable angina or myocardial infarction within the last 6 months prior to first dose or percutaneous cardiac intervention with recent stent within 6 months or coronary artery bypass grafting within
6 months
e.For subjects with congestive heart failure, cardiovascular-related hospitalizations within 4 weeks prior to randomization
f.Subjects with a history of sustained ventricular tachycardia or aborted ventricular fibrillation or with a history of atrioventricular (AV) nodal or sinoatrial (SA) nodal dysfunction for which a pacemaker/ICD is indicated but not placed (Subjects who do have a pacemaker/ICD are allowed on study)
g.Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia’s formula (QTcF) >500 msec.Subjects who have a pacemaker may be included regardless of calculated QTc interval
h.Supine systolic blood pressure <90 mm Hg, or symptomatic orthostatic hypotension, defined as a decrease in systolic blood pressure upon standing of >20 mmHg despite medical management (eg, midodrine, fludrocortisones)in the absence of volume depletion
4.Planned stem cell transplant during the first 6 cycles of protocol therapy are excluded.Stem cell collection during the first 6 cycles of protocol therapy is permitted
5.History of malignancy (other than AL amyloidosis)within 3 years before the date of randomization (exceptions are squamous and basal cell carcinomas of the skin,carcinoma in situ of the cervix or breast, or other non-invasive lesion that in the opinion of the investigator, with concurrence with the sponsor's medical monitor, is considered cured with minimal risk of recurrence within 3 years)
6.Chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 second (FEV1) <50% of predicted normal.Note that FEV1 testing is required for subjects suspected of having COPD and subjects must be excluded if FEV1 <50% of predicted normal
7.Moderate or severe persistent asthma within the past 2 years,or currently has uncontrolled asthma of any classification.(Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study)
8.Seropositive for human immunodeficiency virus(HIV)
9.Known to have hepatitis B surface antigen positivity,or known to have a history of hepatitis C
10.Grade 2 sensory or Grade 1 painful peripheral neuropathy
11.Known hypersensitivity to bortezomib,boron or mannitol
12.Concurrent medical condition or disease (eg, active systemic infection)that is likely to interfere with study procedures or results,or that in the opinion of the investigator would constit

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified