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
Interventions
Product Name: NEOD001
Product Code: NEOD001
Pharmaceutical Form: Powder for solution for infusion
INN or Proposed INN: N/A
CAS Number: N
Sponsors
Prothena Therapeutics Limited
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Subjects must meet all of the following criteria: 1. Aged = 18 years 2. Newly diagnosed and AL amyloidosis treatment naïve 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 mass spectroscopy of AL amyloidosis 5. Confirmed diagnosis of AL amyloidosis by mass spectrometry or immunoelectron microscopy of amyloid material in tissue biopsy if the subject meets any of the following: • is black or African American • is over 75 years of age with concurrent monoclonal gammopathy • has a history of familial amyloidosis and has concurrent monoclonal gammopathy OR • 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 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 • NT-proBNP = 650 pg/mL and = 8500 pg/mL 7. Planned first-line chemotherapy contains bortezomib administered weekly and SC 8. Adequate bone marrow reserve, hepatic function and renal function, as demonstrated by: absolute neutrophil count (ANC) = 1.0 x10^9/L • platelet count = 75 x 10^9/L • hemoglobin = 9 g/dL • total bilirubin = 2 times the upper limit of normal (x ULN) • aspartate aminotransferase (AST) / serum glutamic oxaloacetic transaminase (SGOT) = 3 x ULN • alanine aminotransferase (ALT) / serum glutamic pyruvic transaminase (SGPT) = 3 x ULN • alkaline phosphatase (ALP) = 5 x ULN (except for subjects with hepatomegaly and isozymes specific to liver, rather than bone) • estimated glomerular filtration rate (eGFR) = 30 mL/min/1.73 m^2 as estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation 9. Seated systolic blood pressure (BP) 90-180 mmHg 10. Distance walked during each Screening 6MWT is =30 meters and = 550 meters 11. Women of childbearing potenti
Exclusion criteria
Exclusion criteria: Subjects must meet none of the following criteria: 1. Non-AL amyloidosis 2. NT-proBNP 8,500 pg/mL 3. Meets the International Myeloma Working Group (IMWG) definition of Multiple Myeloma (see Appendix 5) *Note that subjects who meet the IMWG definition of symptomatic multiple myeloma with signs and/or symptoms attributable only to associated amyloidosis and who do not otherwise meet the criteria for diagnosis of smoldering myeloma are potentially eligible upon approval of the Sponsor. 4. Subject is eligible for and plans to undergo ASCT or organ transplant 5. 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 6. Myocardial infarction, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or 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 110 bpm] ventricular rate is not allowed [determined by an average of three beats in Lead II or three 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 IV antibiotics, antifungals or antivirals within 1 week of Month 1-Day 1 with the exception of prophylactic oral 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 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 and prostate-specific antigen < 10 mg/mL • 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 NEOD001 such as histidine/L histidine hydrochloride monohydrate, trehalose dehydrate, or polysorbate 20 or History of Grade = 3 infusion-related 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 or history of uncontrolled, active human immunodeficiency virus (HIV), Hepatiti
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the efficacy of NEOD001 plus standard of care vs. placebo plus standard of care when administered intravenously in subjects with AL amyloidosis by assessing time to all- cause mortality or cardiac hospitalization; Secondary Objective: In subjects with AL amyloidosis, comparing NEOD001 plus standard of care vs. placebo plus standard of care: • To evaluate the safety of NEOD001 • To evaluate the cardiac response rate as assessed by NT-proBNP • To evaluate health-related quality of life using the Short Form 36 questionnaire (SF-36) • To evaluate cardiac functional response using the 6 Minute Walk Test (6MWT) • To evaluate the renal response rate using established criteria • To evaluate peripheral neuropathy using the Neuropathy Impairment Scale – Lower Limbs (NIS-LL) • To evaluate the hepatic response rate according to consensus criteria • To evaluate cardiac-specific quality of life using the Kansas City Cardiomyopathy Questionnaire (KCCQ) • To evaluate time to cardiac mortality or cardiac hospitalization • To evaluate time to all-cause mortality ;Primary end point(s): Time to all-cause mortality or cardiac hospitalization;Timepoint(s) of evaluation of this end point: As adjudicated by the CEC | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • NT-proBNP best response from baseline to Month 9 • Change from baseline to Month 9 in the Physical Component Score of the SF-36 • Change from baseline to Month 9 in the 6MWT • For renal-evaluable subjects, renal best response from baseline to Month 9 • For subjects with peripheral neuropathy due to AL amyloidosis, change from baseline to Month 9 in the NIS-LL score • For hepatic-evaluable subjects, hepatic best response from baseline to Month 9 • Change from baseline to Month 9 in the KCCQ • Time to cardiac mortality or cardiac hospitalization as adjudicated by the CEC • Time to all-cause mortality ; Timepoint(s) of evaluation of this end point: • NT-proBNP best response from baseline to Month 9 • Change from baseline to Month 9 in the SF-36 • Change from baseline to Month 9 in the 6MWT • Renal best response from baseline to Month 9 (Palladini 2014) • Change from baseline to Month 9 in the NIS-LL score • Hepatic best response from baseline to Month 9 (Comenzo 2012) • Change from baseline to Month 9 in the KCCQ • Time to cardiac mortality or cardiac hospitalization as adjudicated by the CEC • Time to all-cause mortality | — |
Countries
Australia, Austria, Belgium, Canada, Denmark, France, Germany, Greece, Israel, Italy, Netherlands, Poland, Spain, United Kingdom, United States
Contacts
Public ContactJay Soto
Prothena Biosciences Inc
Outcome results
None listed