Phase 2 study of daratumumab monotherapy in previously untreated patients with stage 3B light chain (AL) amyloidosis

Phase 1

• Conditions: Patients with newly diagnosed stage 3B AL amyloidosis; MedDRA version: 20.0Level: PTClassification code 10002022Term: AmyloidosisSystem Organ Class: 10021428 - Immune system disorders; Therapeutic area: Diseases [C] - Immune System Diseases [C20]

• Registration Number: EUCTR2018-004333-33-FR
• Lead Sponsor: European Myeloma Network

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2019-12-02
• Last Update Posted: 3 August 2020

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 40

Inclusion Criteria

1. Men or women 18 years of age or older.
2. Diagnosis of amyloidosis, AL type, based on:
a. Histopathological diagnosis of amyloidosis based on detection by immunohistochemistry and polarizing light microscopy of green bi-refringent material in Congo Red stained tissue specimens (excluding bone marrow) or characteristic electron microscopy appearance
AND
b. 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 local lab)
- serum free light chain (FLC) =2.0 mg/dL (20 mg/L) with an abnormal kappa:lambda ratio or the difference between involved and uninvolved free light chains (dFLC) =2mg/dL (20 mg/L). Serum FLCs will be measured using the Freelite assay at a central laboratory.
- Note: Measurable disease by Urine Bence-Jones Proteinuria is not sufficient for study enrolment.
AND
c. Cardiac involvement by AL amyloidosis according to consensus guidelines (See ATTACHMENT 3)
3. Mayo Stage 3B disease, defined as both A. increased cardiac troponin (hsTnT >54 pg/ml) AND B. increased NT-proBNP = 8500 pg/ml
4. For subjects with congestive heart failure, symptoms should be optimally managed and clinically stable with no cardiovascular-related hospitalizations within 2 weeks prior to Cycle 1 Day 1, as assessed by the Principal Investigator. [See also exclusion criteria 3]
5. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0, 1,2 or 3 (ATTACHMENT 1)
6. Subject must have pre-treatment clinical laboratory values meeting the following criteria during the Screening Phase:
a. Absolute neutrophil count =1.0 × 109/L;
b. Hemoglobin level =10.0 g/dL (=5 mmol/L)
c. Platelet count =75 × 109/L; platelet transfusions are NOT acceptable
d. Alanine aminotransferase level (ALT) =2.5 x ULN;
e. Aspartate aminotransferase (AST) =2.5 x ULN
f. Total bilirubin level =1.5 × ULN, except for subjects with history of Gilbert Syndrome, in which case direct bilirubin = 2 × ULN
g. Estimated Glomerular Filtration Rate (eGFR) =20 mL/min; Please note that 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 prior to dosing and continue for 3 months after discontinuation of daratumumab. 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 3 months after receiving the last dose of daratumumab, female subjects 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, e.g. either condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/

Exclusion Criteria

1.Prior therapy for AL amyloidosis or multiple myeloma with the exception of 160 mg dexamethasone (or equivalent steroid) maximum exposure prior to Cycle 1 Day 1.
2.Previous or current diagnosis of symptomatic multiple myeloma including the presence of lytic bone disease, plasmacytomas, = 60% plasma cells in the bone marrow, and/or hypercalcemia.
3.Evidence of significant cardiovascular conditions as specified below:
a. New York Heart Association (NYHA) classification of heart failure, stages IIIB or IV
b. Heart failure that in the opinion of the investigator due to ischemic heart disease or uncorrected valvular disease, and not due to AL amyloid cardiomyopathy.
c. Hospitalization for unstable angina or myocardial infarction or percutaneous cardiac intervention with recent stent or coronary artery bypass grafting, all within the last 6 months prior to the first dose
d. 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 will not be placed (subjects who do have a pacemaker/ICD are allowed in the study)
e. Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia’s formula (QTcF) >500 msec. Subjects who have pacemaker may be included regardless of calculated QTc interval.
f. Supine systolic blood pressure <90 mmHg, or symptomatic orthostatic hypotension, defined as a decrease in systolic blood pressure upon standing of >20 mmHg despite medical management in the absence of volume depletion
4. Subjects planning to undergo a 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. Diagnosed or treated for malignancy other than AL, except:
a. Malignancy treated with curative intent and with no known active disease present for =24 months before Cycle 1 Day 1
b. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
c. Adequately treated carcinoma in situ (e.g. cervical, breast) with no evidence of disease
6. Subject has known 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. Subject has known 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. Subject is known to be seropositive for human immunodeficiency virus (HIV). HIV positive subjects who are stable on highly active antiretroviral therapy (HAART) with no opportunistic infections within the last 6 months are eligible.
9. Subjects known:
a. to be seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (ie, subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded.
b. seropositive for hepatitis C
10. Subject has

Study & Design

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