A study to evaluate whether NEOD001 is safe and effective in subjects with light chain AL amyloidosis affecting the heart.
- Conditions
- ight chain (AL) amyloidosis involves a hematologic disorder caused by clonal plasma cells that produce misfolded immunoglobulin light chains. Overproduction of misfolded light chains results in both soluble, aggregated forms of light chains and insoluble,fibrillar deposits of abnormal AL protein (amyloid),in the tissues and organs. This can cause a range of symptoms and organ dysfunction including cardiac,renal,and hepatic dysfunction,gastrointestinal involvement and neuropathy and macroglossiaMedDRA version: 20.0Level: PTClassification code 10036673Term: Primary amyloidosisSystem Organ Class: 10021428 - Immune system disordersTherapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]
- Registration Number
- EUCTR2015-004318-14-AT
- Lead Sponsor
- Prothena Therapeutics Limited
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 129
1. Age =18 years
2. Confirmed diagnosis of systemic AL amyloidosis by the following:
o 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
o Confirmatory electron microscopy OR immunohistochemistry OR mass spectrometry of AL amyloidosis
3. If the subject meets any of the following criteria, confirm diagnosis of AL amyloidosis by mass spectrometry OR immunoelectron microscopy of amyloid material in tissue biopsy:
o Is black or African American
o Is over 75 years of age (at time of diagnosis) with concurrent monoclonal gammopathy
o Has a history of familial amyloidosis and has concurrent monoclonal gammopathy
OR
o If the subject meets any of the above 3 conditions and has echocardiographic evidence of amyloidosis, biopsy-proven amyloidosis with a monoclonal gammopathy and no tissue is available for mass spectrometry or immunoelectron microscopy, the subject must have gene sequencing consistent with transthyretin (TTR) wild type (e.g., no TTR mutation present) AND must score 0 in technetium-99m-3,3-diphosphono-1,2 propanodicarboxylic acid (99mTc DPD; Rapezzi et al, 2011), hydroxymethylenediphosphonate (99mTc HMDP; Galat et al, 2015), or pyrophosphate (99mTc PYP; Bokhari et al, 2013) scintigraphy
4. Cardiac involvement as defined by BOTH of the following:
o 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
o 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
5. NT-proBNP =650 pg/mL and =5000 pg/mL (i.e., =76.7 pmol/L and =590 pmol/L)
6. Received at least one prior systemic chemotherapeutic regimen, which may include stem cell transplant, for AL amyloidosis
7. Achieved at least a partial hematologic response to a first-line therapy resulting in a stable hematologic condition not currently requiring additional active treatment against the plasma cell dyscrasia component of their AL disease
8. Adequate bone marrow reserve, hepatic and renal function, as demonstrated by:
o Absolute neutrophil count (ANC) =1.0 × 109/L
o Platelet count =75 × 109/L
o Hemoglobin =9 g/dL
o Total bilirubin =2 × upper limit of normal (ULN)
o Aspartate aminotransferase (AST) =3 × ULN
o Alanine aminotransferase (ALT) =3 × ULN
o Alkaline phosphatase (ALP) =5 × ULN (except for subjects with hepatomegaly and isozymes specific to liver, rather than bone)
o Estimated glomerular filtration rate (eGFR) =30 mL/min/1.73 m2 as estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation
9. Systolic blood pressure 90-180 mmHg
10. Distance walked during each of the two Screening 6-minute walk tests (6MWTs) is >100 meters and <600 meters
11. 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
12. Male subjects must be surgica
Subjects must not meet any of the following criteria:
1. Diagnosis of non-AL amyloidosis
2. Meets the International Myeloma Working Group (IMWG) definition of Multiple Myeloma
3. Symptomatic orthostatic hypotension that in the medical judgment of the Investigator would interfere with subject's ability to safely receive treatment or complete study assessments
4. Myocardial infarction, uncontrolled angina, uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia, within 6 months prior to the Month 1-Day 1 Visit
5. Severe valvular stenosis (e.g. aortic or mitral stenosis with a valve area <1.0 cm2) or severe congenital heart disease
6. ECG evidence of acute ischemia or active conduction system abnormalities with the exception of any of the following:
o First degree atrioventricular (AV) block
o Second degree AV block Type 1 (Mobitz Type 1/Wenckebach type)
o Right or left bundle branch block
o Atrial fibrillation with a controlled ventricular rate (uncontrolled [i.e., >110 bpm] ventricular rate is not allowed [determined by an average of three beats in Lead II or 3 representative beats if Lead II is not representative of the overall ECG])
7. Has not recovered (i.e., equivalent to a Common Terminology Criteria for Adverse Events [CTCAE] =Grade 2) from the clinically significant toxic effects of prior anticancer therapy. Exception: subjects with prior bortezomib treatment may have CTCAE Grade 2 neuropathy.
8. Received any of the following within the specified time frame prior to the Month 1-Day 1 Visit:
o Oral or intravenous antibiotics, antifungals, or antivirals within 1 week, with the exception of prophylactic oral agents. Note: In the event that a subject requires the chronic use of antivirals, Medical Monitor permission is required for entry into the study.
o Hematopoietic growth factors, transfusions of blood or blood products within 1 week
o Chemotherapy, radiotherapy, or other plasma cell directed therapy within 6 months
o ASCT within 12 months
o Major surgery within 4 weeks
o Planned major surgery or organ transplant during the study
o Any other investigational agent within 4 weeks
o Prior treatment with NEOD001, 11-1F4, anti-serum amyloid P (SAP) antibody (exception: allowed as part of established diagnostic procedures such as SAP scintigraphy), or other investigational treatment directed at amyloid
o Doxycycline within 6 weeks
9. Active malignancy with the exception of any of the following:
o Adequately treated basal cell carcinoma, squamous cell carcinoma, or in situ cervical cancer
o Adequately treated Stage I cancer from which the subject is currently in remission and has been in remission for =2 years
o Low-risk prostate cancer with Gleason score <7 and prostate-specific antigen <10 mg/mL
o Any other cancer from which the subject has been disease-free for =2 years
10. History of Grade =3 infusion-related adverse events (AEs) or hypersensitivity to another monoclonal antibody
11. History of severe allergy to any of the components of NEOD001 such as histidine/L-histidine hydrochloride monohydrate, trehalose dehydrate, or polysorbate 20
12. Currently known uncontrolled bacterial, viral, fungal, HIV, hepatitis B, or hepatitis C infection
13. Women who are breastfeeding
14. Any condition which could interfere with, or the treatment for which might interfere with, the conduct of the study or which would, in the opinion of the Investigator, unacceptably increase the subject’s risk by p
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: The objective of this study is to determine the efficacy and safety of NEOD001 versus placebo in subjects with AL amyloidosis who have persistent cardiac dysfunction.;Secondary Objective: •Change from baseline to 12 months of treatment in the Physical<br>Component Score (PCS) of the Short Form-36 Version 2 (SF-36v2)<br>•Change from baseline to 12 months of treatment in the 6MWT distance<br>(meters)<br>•NT-Pro BNP Slope over 12 months of treatment<br>•Renal evaluable subjects: renal best response from baseline through<br>12 months of treatment<br>•Peripheral neuropathy evaluable subjects: change from baseline to 12<br>months of treatment in NIS-LL total score<br>•Hepatic evaluable subjects: hepatic best response from baseline<br>through 12 months of treatment<br>;Primary end point(s): NT-proBNP best response;Timepoint(s) of evaluation of this end point: NT-proBNP best response from baseline through 12 months of treatment
- Secondary Outcome Measures
Name Time Method Secondary end point(s): - SF-36v2<br>- 6MWT<br>- NT-ProBNP Slope<br>- Renal best response<br>- Peripheral neuropathy score<br>- Hepatic Best Response<br>;Timepoint(s) of evaluation of this end point: •Change from baseline to 12 months of treatment in the Physical Component Score (PCS) of the Short Form-36 Version 2 (SF-36v2)<br>•Change from baseline to 12 months of treatment in the 6MWT distance (meters)<br>•NT-Pro BNP Slope over 12 months of treatment<br>•Renal evaluable subjects: renal best response from baseline through 12 months of treatment<br>•Peripheral neuropathy evaluable subjects: change from baseline to 12 months of treatment in NIS-LL total score<br>•Hepatic evaluable subjects: hepatic best response from baseline through 12 months of treatment<br>