A Phase 3, Randomized, Multicenter, Double-Blind, Placebo-Controlled, Efficacy and Safety Study of Birtamimab Plus Standard of Care vs. Placebo Plus Standard of Care in Mayo Stage IV Subjects with Light Chain (AL) Amyloidosis
- Conditions
- Mayo Stage IV Light Chain (AL) Amyloidosis10027476
- Registration Number
- NL-OMON54039
- Lead Sponsor
- Prothena Biosciences Limited
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Recruiting
- Sex
- Not specified
- Target Recruitment
- 11
Double-blind Phase:
1.Aged >=18 years and legal age of consent according to local regulations
2.Newly diagnosed and AL amyloidosis treatment naive
3.Bone marrow demonstrating clonal plasma cells
4.Confirmed diagnosis of AL amyloidosis by the following:
-Histochemical diagnosis of amyloidosis determined by polarizing light
microscopy of green birefringent material in Congo red-stained tissue specimens
OR characteristic electron microscopy appearance AND
-Confirmatory immunohistochemistry OR immunoelectron microscopy OR mass
spectroscopy of AL amyloidosis
5.If the subject meets any of the following:
-Is black or of African descent
-Is over 75 years of age
-Has a history of familial transthyretin amyloidosis
-No cardiac tissue is available for typing, THEN the subject must have gene
sequencing consistent with transthyretin (TTR) wild type (i.e., no TTR mutation
present) AND must score 0 in technetium-99m-3,3-diphosphono-1,2
propanodicarboxylic acid (99mTc DPD; Rapezzi 2011),
hydroxymethylenediphosphonate (99mTc HMDP; Galat 2015), OR pyrophosphate (99mTc
PYP; Bokhari 2013) scintigraphy
6.Cardiac involvement as defined by all of the following:
-Past documented or presently noted 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
-Either an endomyocardial biopsy demonstrating AL amyloidosis OR an
echocardiogram demonstrating a mean left ventricular wall thickness at diastole
>12 mm in the absence of other causes (e.g., severe hypertension, aortic
stenosis), which would adequately explain the degree of wall thickening OR
cardiovascular magnetic resonance imaging findings reported as characteristic
of amyloidosis
7.Confirmed Mayo Stage IV as defined by:
-NT-proBNP >=1800 pg/mL and
-Troponin-T >=0.025 ng/mL (mcg/L) or high sensitivity cardiac troponin T >=40
ng/L and
-Difference between involved and uninvolved free light chain >=18 mg/dL
8.Planned first-line chemotherapy contains bortezomib administered
subcutaneously weekly
9.Adequate bone marrow reserve, hepatic function, and renal function, as
demonstrated by:
-Absolute neutrophil count >=1.0 × 10e9/L
-Platelet count >=75 × 10e9/L
-Hemoglobin >=9 g/dL
-Total bilirubin <= 2 × the upper limit of normal (ULN) (except for subjects
with Gilbert*s syndrome, in which case direct bilirubin <=2 × ULN)
-Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase <=3 ×
ULN
-Alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase <=3 × ULN
-Alkaline phosphatase (ALP) <=5 × ULN
-Estimated glomerular filtration rate (eGFR) >=30 mL/min/1.73 m2 as estimated by
the Chronic Kidney Disease Epidemiology Collaboration equation
10.Seated systolic blood pressure (BP) 90 to 180 mmHg
11.Distance walked during each Screening 6MWT is >30 meters and <550 meters
12.Women of childbearing potential (WOCBP) must have 2 negative pregnancy tests
during Screening, the second within 24 hours prior to the first administration
of study drug, and must agree to use highly effective physician-approved
contraception from Screening to 90 days following the last study drug
administration
13. Male subjects must be surgically sterile or must agree to us
Double-blind Phase:
1. Non-AL amyloidosis
2. NT-proBNP >8500 pg/mL
3. Meets the International Myeloma Working Group (IMWG) definition of multiple
myeloma, except for malignancy biomarker of involved/uninvolved serum free
light chain ratio >=100 (Appendix 3)
4. Subject is eligible for and plans to undergo ASCT or organ transplant during
the study
5. Symptomatic orthostatic hypotension that in the medical judgment of the
Investigator would interfere with the subject*s ability to safely receive
treatment or complete study assessments
6. Myocardial infarction, uncontrolled angina, severe uncontrolled ventricular
arrhythmias, or electrocardiographic (ECG) evidence of acute ischemia, within 6
months prior to the Month 1-Day 1 Visit
7. Severe valvular stenosis (e.g., aortic or mitral stenosis with a valve area
<1.0 cm2) or severe congenital heart disease
8. ECG evidence of acute ischemia or active conduction system abnormalities
with the exception of any of the following:
• First degree AV-block
• Second degree AV-block Type 1 (Mobitz Type 1 / Wenckebach type)
• Right or left bundle branch block
• Atrial fibrillation with a controlled ventricular rate (uncontrolled [>110
bpm] ventricular rate is not allowed [determined by an average of 3 beats in
Lead II or 3 representative beats if Lead II is not representative of the
overall ECG])
9. Peripheral neuropathy assessed as National Cancer Institute Common
Terminology Criteria for Adverse Events (NCI CTCAE) Grade 2 with pain, Grade 3,
or Grade 4
10. Subject is receiving oral or intravenous antibiotics, antifungals, or
antivirals within 1 week of Month 1-Day 1 with the exception of prophylactic
agents
11. Prior treatment with hematopoietic growth factors, transfusions of blood or
blood products within 1 week of Month 1-Day 1
12. Prior radiotherapy within 4 weeks of Month 1-Day 1
13. Major surgery within 4 weeks of Month 1-Day 1 or planned major surgery
during the study
14. Active malignancy with the exception of any of the following:
• Adequately treated cutaneous basal cell carcinoma, squamous cell carcinoma,
or in situ cervical cancer
• Adequately treated Stage I cancer from which the subject is currently in
remission and has been in remission for 2 years
• Low-risk prostate cancer with Gleason score <7 prostate-specific antigen <10
ng/mL, and a stage of cancer at most cT2a, cN0, and CM0
• Any other cancer from which the subject has been disease-free for >=2 years
15. History of severe allergy to any of the components of birtamimab such as
histidine/L histidine hydrochloride monohydrate, trehalose dehydrate, or
polysorbate 20 or history of Grade >=3 infusion-related adverse events (AEs) or
hypersensitivity to another monoclonal antibody, or known hypersensitivity to
diphenhydramine (or an equivalent H1 antihistamine) or acetaminophen (or its
equivalent, paracetamol)
16. Known unresolved or active HIV, hepatitis B, hepatitis C, or SARS-CoV-2
infection
17. Prior treatment with plasma cell-directed chemotherapy, birtamimab,
daratumumab, 11-1F4, anti-serum amyloid P antibody, doxycycline for amyloid, or
other investigational treatment directed at amyloid
18. Treatment with another investigational agent within 30 days of Month 1-Day 1
19. Women who are pregnant or lactating
20. Any condition which could
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>• Time to all-cause mortality during the Double-blind Phase</p><br>
- Secondary Outcome Measures
Name Time Method <p>• Change from baseline to Month 9 of the Double-blind Phase in the 6-Minute<br /><br>Walk Test (6MWT) distance<br /><br>• Change from baseline to Month 9 of the Double-blind Phase in health related<br /><br>quality of life using the Short Form 36 questionnaire Version 2 (SF 36v2)</p><br>