Light 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 macroglossia
Conditions
Sponsors
Prothena Therapeutics Limited
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 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
Exclusion criteria
Exclusion criteria: 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 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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 Component Score (PCS) of the Short Form-36 Version 2 (SF-36v2) • Change from baseline to 12 months of treatment in the 6MWT distance (meters) • NT-proBNP Slope over 12 months of treatment • Renal evaluable subjects: renal best response from baseline through 12 months of treatment • Peripheral neuropathy evaluable subjects: change from baseline to 12 months of treatment in NIS-LL total score • Hepatic evaluable subjects: hepatic best response from baseline through 12 months of treatment ;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
| Measure | Time frame |
|---|---|
| Secondary end point(s): - SF-36v2 - 6MWT -NT proBNP Slope - Renal best response - Peripheral neuropathy score - Hepatic Best Response ;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) •Change from baseline to 12 months of treatment in the 6MWT distance (meters) •NT proBNP Slope over 12 months of treatment •Renal evaluable subjects: renal best response from baseline through 12 months of treatment •Peripheral neuropathy evaluable subjects: change from baseline to 12 months of treatment in NIS-LL total score •Hepatic evaluable subjects: hepatic best response from baseline through 12 months of treatment | — |
Countries
Australia, Austria, France, Germany, Greece, Israel, Italy, Spain, United Kingdom, United States
Contacts
Public ContactJay Soto
Prothena Biosciences Inc
Outcome results
None listed