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
- Conditions
- AL Amyloidosis (Newly Diagnosed Systemic AL Amyloidosis)MedDRA version: 20.0Level: PTClassification code 10002022Term: AmyloidosisSystem Organ Class: 10021428 - Immune system disordersTherapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2016-001737-27-IT
- Lead Sponsor
- JANSSEN CILAG INTERNATIONAL NV
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Authorised-recruitment may be ongoing or finished
- Sex
- All
- Target Recruitment
- 370
1) 18y(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 birefringent 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 70y or older who have cardiac involvement only, and subjects of African descent, MS typing of AL amyloid in a tissue biopsy is recommended to rule out other types of amyloidosis such as agerelated amyloidosis or ereditary amyloidosis (ATTR mutation)
3) Measurable disease of amyloid light chain amyloidosis as defined by at least ONE of the following:
-serum monoclonal protein major or =0.5 g/dL by PE (routine and immunofixation performed at central lab),
-serum free light chain major or =5.0 mg/L with an abnormal kappa:lambda or the difference between involved and uninvolved free light chains (dFLC) major or =50 mg/ L.
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 lab values meeting the following criteria during the Screening Phase:
a. Absolute neutrophil count major or =1.0 ×1000000000 /L;
b. Hemoglobin level major or =8.0 g/dL (major or =5 mmol/L); red blood cell transfusion allowed until 7 days before randomization
c. Platelet count major or =50 × 1000000000/L;
d. ALT minor or =2.5 times the ULN;
e. AST minor or =2.5 times the ULN
f. Total bilirubin level minor or =1.5 × ULN except for subjects with Gilbert syndrome, in which case direct bilirubin minor or =2 × ULN
g. Estimated glomerular filtration rate (eGFR) minor or =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 or to use 2 methods of reliable birth control simultaneously. This includes one highly effective form of contraception and one additional effective contraceptive method. Contraception must begin 4 w prior to dosing and continue for 1y after discontinuation of cyclophosphamide or 3m 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 occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository during and up to 4 months after discontinuation of cyclophosphamide or 3 months after discontinuation of daratumumab, whichever is longer. All men must also not donate sperm during the study and for 4 months after discontinuation of cyclophosphamide or 3 months after discontinuation of daratumumab, whichever is longer.
10) A woman of childbearing potential must have a negat
1. Prior therapy for AL or MMY including medications that target CD38, except 160mg dexamethasone or equiv corticosteroid maximum exposure prior to random
2.Previous or current diagnosis of symptomatic MMY, including lytic bone disease, plasmacytomas,=60% plasma cells in the bone marrow, or hypercalcemia
3.significant cardiovascular conditions as below:
a.NT-ProBNP >8500 ng/L
b.NYHA classif. IIIB or IV heart failure
c.Heart failure that in the opinion of the investigator is ischemic heart disease (prior myocardial infarction with documented history of cardiac enzyme elevation and ECG hanges)or uncorrected valvular disease and not primarily due to AL cardiomyopathy
d.Inpatient admission to a H for unstable angina or infarction within the last 6m prior to first dose or percutaneous intervention with recent stent within 6m or coronary bypass within 6m
e.congestive heart failure, cardiovascular-related hospitalizations within 4w prior to random
f.history of sustained ventricular tachycardia or aborted ventricular fibrillation or AV nodal or SA nodal dysfunction for which a pacemaker/ICD is indicated but not placed (Subjects who do have a pacemaker/ICD are allowed)
g.Screening 12-lead ECG showing a baseline QT as corrected by Fridericia's formula (QTcF) >500 msec.Subjects who have a pacemaker may be included regardless of calculated QTc
h.Supine SBP <90 mm Hg, or symptomatic orthostatic hypotension, defined as a decrease in systolic blood pressure upon standing of >20 mmHg despite medical mngment (midodrine, fludrocortisones)in the absence of volume depletion
4.Planned stem cell transplant in the first 6 cycles of therapy excluded.Stem cell collection in the 1st 6 cycles of protocol therapy is permitted
5.History of malignancy (other than AL amyloidosis)within 3y before the date of random;
6.COPD with a FEV in 1 sec (FEV1) <50% of predicted normal.FEV1 testing is required for subjects suspected of having COPD and subjects must be excluded if FEV1 <50% of redicted normal
7.Moderate/severe persistent asthma in the past 2y,currently has uncontrolled asthma of any classification.(subjects who currently have controlled intermittent asthma or controlled mild persistent asthma allowed)
8.HIV+
9.Any of the following: seropositive HBV or known seropositive HCV
10.G2 sensory or G1 painful peripheral neuropathy
11.Known hypersensitivity to bortezomib,boron or mannitol
12.Concurrent medical condition or disease that is likely to interfere with procedures or results,or that in the opinion of the PI would constitute a hazard for particip
13.Any form of non-AL,including wild type or mutated amyloidosis
14.Known allergies,hypersensitivity,or intolerance to monoclonal antibodies or hum proteins,or their excip, or known sensitivity to ammalian-derived products
15.Known or suspected of not being able to comply with protocol(alcoholism,drug dependency)or the subject has any condition for which,in the opinion of the PI, participation would not be in the interest of the subject or that could prevent, limit,or confound the protocol
16. Woman pregnant or breast-feeding or planning to be pregnant while enrolled in this study or within 1y after discontinuation of cyclophosphamide or 3m following discontinuation of daratumumab,whichever is longer
17.Received an invest drug (including invest vaccines) or used an invasive invest med device within 4w before Cycle1,Day 1
18. Major surgery within 2w before Cycle1,Day1,or will not have fully recovered from surgery,or h
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method