Clinical trials

AFFIRM-AL (NEOD001-301): A Phase 3 Randomized, MultI-Centre Double-Blind, Placebo-Controlled, Efficacy and Safety Study of Birtamimab Plus Standard of Care vs Placebo Plus Standard of Care in Newly Diagnosed Mayo Stage IV Subjects with Light Chain AL Amyloidosis

What is the drug in question?
Birtamimab – this is a monoclonal antibody that attaches to the amyloid deposits and hopefully this promotes your own immune system to clear the amyloid deposits in your body. This is combined with the typical standard treatment, usually “VCD” chemotherapy.

Who is eligible for the trial?
Newly diagnosed patients with systemic AL amyloidosis with advanced disease in the heart.

Does every patient receive the actual trial drug?
Two out of every three patients will receive birtamimab and one out of three will receive a placebo (“dummy”) drug. Neither you nor your treating team will know which drug you are on.

How is the drug administered?
Birtamimab is given through an IV (drip into the vein) every 28 days

How long does the trial go for?
Once 135 patients have received at least 9 months of treatment, the data will be analysed, and a decision of whether to stop the trial or continue will be made then.

Anything else I need to know?
This trial has been previously performed in patients with newly diagnosed AL amyloidosis but only those with advanced heart disease appeared to possibly benefit. This current trial called “AFFIRM” is looking to see whether a benefit can be proven in more advanced heart disease when a larger number of patients are analysed.rres.

Key inclusion criteria:

1. Newly diagnosed, treatment naive systemic AL amyloidosis with:
   1. Bone marrow demonstrating clonal plasma cells
   2. Confirmed diagnosis of AL amyloidosis by the following:
      1. 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
      2. Confirmatory immunohistochemistry OR mass spectroscopy of AL amyloidosis
2. 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 due to 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
3. Confirmed Mayo Stage IV as defined by:
   • NT-proBNP ≥1800 pg/mL and
   • Troponin-T >0.03 ng/mL and
   • dFLC ≥18 mg/dL
4. Planned first-line chemotherapy contains bortezomib administered subcutaneously weekly
5. Adequate bone marrow reserve, hepatic function, and renal function, as demonstrated by:
   • Absolute neutrophil count ≥1.0 × 109/L
   • Platelet count ≥75 × 109/L
   • Hemoglobin ≥9 g/dL
   • Total bilirubin ≤ 2 × the upper limit of normal (ULN)
   • Aspartate aminotransferase (AST)≤3 × ULN
   • Alanine aminotransferase (ALT) ≤3 × ULN
   • Alkaline phosphatase (ALP) ≤5 × ULN
   • Estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2
6. Seated systolic blood pressure (BP) 90 to 180 mmHg
7. Distance walked during Screening 6MWT is >30 meters and <550 meters

Key exclusion criteria:

Subjects must meet none of the following criteria:

1. Non-AL amyloidosis
2. NT-proBNP >8500 pg/mL
3. Meets the International Myeloma Working Group (IMWG) definition of multiple myeloma (Appendix 3)
   *Note that subjects who meet the IMWG definition of symptomatic multiple myeloma with signs and/or symptoms attributable only to associated amyloidosis are potentially eligible upon approval of the Sponsor.
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 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 A V-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 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 ng/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 birtamimab 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. 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
17. History of epilepsy or seizure disorder with the exception of childhood febrile seizures
18. Waldenström’s macroglobulinemia and/or immunoglobulin M monoclonal gammopathy

For more information, please contact one of the five recruiting centres in
Australia, or use this link.

Sites

New South Wales

Victoria

Queensland

Western Australia

South Australia