Clinical trials

The “CAEL-101” monoclonal antibody trials for newly diagnosed AL Amyloidosis with cardiac involvement are now open in Australia!

All four AAN services, as well as the Royal Adelaide Hospital, are now recruiting patients to these studies!

CAEL101-301: A Phase 3, Double-Blind, Multicenter Study to Evaluate the Efficacy and Safety of CAEL-101 and Plasma Cell Dyscrasia Treatment Versus Placebo and Plasma Cell Dyscrasia Treatment in Plasma Cell Dyscrasia Treatment-Naïve Patients with Mayo Stage IIIb AL Amyloidosis

CAEL101-302: A Phase 3, Double-Blind, Multicenter Study to Evaluate the Efficacy and Safety of CAEL-101 and Plasma Cell Dyscrasia Treatment Versus Placebo and Plasma Cell Dyscrasia Treatment in Plasma Cell Dyscrasia Treatment-Naïve Patients with Mayo Stage IIIa AL Amyloidosis – A Study to Evaluate the Efficacy and Safety of AKCEA-TTR-LRx With Transthyretin Amyloidosis With Cardiomyopathy (ATTR Amyloidosis With Cardiomyopathy)

What is the drug in question?
CAEL-101 is a monoclonal antibody that attaches itself to part of the AL amyloid fibril in your tissues, and makes it easier for your own immune system to clear the amyloid deposits.

Who is eligible for the trial?
Patients with symptomatic newly diagnosed AL cardiac amyloidosis are eligible for these trials.
Patients who have already had treatment for their AL amyloidosis, or those without significant heart involvement are not eligible/
Does every patient receive the actual trial drug?
These are international Phase 3 prospective randomised placebo-controlled double-blinded studies.
All patients will receive the normal treatment for new diagnosed AL amyloidosis, that being bortezomib (Velcade), cyclophosphamide and dexamethasone.
In addition, patients will be randomized 2:1 to also receive either the CAEL-101 infusion delivered through an IV line into your vein (a “drip”) or the placebo (“dummy” drug) infusion. That means you have a 2 out of 3 chance of receiving the active drug. Neither you nor your doctor will know whether you are on the active drug or the placebo.

How is the drug administered?
CAEL-101 is administered as a intravenous (“a drip into a vein”) infusion. Patients will receive their injection weekly for four weeks then fortnightly.

How long does the trial go for?
At least 50 weeks (almost a year).

Anything else I need to know?
As part of the assessment for the trial, you will need to undergo several 6 minute walking tests, echocardiography (heart ultrasounds), and complete quality of life questionairres.

Key inclusion criteria:
Systemic AL (not ATTR) amyloidosis, involving the heart, as proven by

1. Biopsy proof for amyloid deposits (such as bone marrow, kidney or heart biopsy)
2. Cardiac MRI and/or echocardiography demonstrating signs of cardiac amyloidosis
3. Elevated serum free light chains >40mg/L.
4. NT-proBNP >650ng/L

Key exclusion criteria:

1. Patients who have received previous therapy for AL Amyloidosis
2. Patients whose systolic blood pressure if <90mmHg
3. Patients on dialysis, or taking high doses of prednisolone or doxycycline.

For more information, please check the five recruiting centres listed below and the Clinical Trials Gov website:

Sites

Queensland

Status:
Site:	Queensland Amyloidosis Centre, Princess Alexandra Hospital, Brisbane
Contact:	A/Prof Peter Mollee Email: amyloidosis@health.qld.gov.au

Victoria

Status:
Site:	Victorian and Tasmanian Amyloidosis Centre, Eastern Health, Melbourne
Contact:	Simon Gibbs simon.gibbs@monash.edu

South Australia

Status:
Site:	Royal Adelaide Hospital, Adelaide
Contact:	Dr Noemi Horvath Email:TBC

New South Wales

Status:
Site:	Westmead Hospital, Sydney
Contact:	Dr Fiona Kwok Email: WSLHD-TTRtrials@health.nsw.gov.au

Western Australia

Status:
Site:	Fiona Stanley Hospital, Perth
Contact:	Dr Hasib Sidiqi Email: coral.almeida@health.wa.gov.au Hasib.Sidiqi@health.wa.gov.au

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

Status:
Site:	St George’s Hospital, Sydney
Contact:	Dr Shir-Jing Ho and Lindy Williams Email: lindy.williams@health.nsw.gov.au

Victoria

Status:
Site:	Eastern Health, Melbourne
Contact:	Dr Simon Gibbs simon.gibbs@monash.edu

Queensland

Status:
Site:	Mater Medical Centre, 293 Vulture Street, South Brisbane
Contact:	Dr Kerri Taylor Email:TBC

Western Australia

Status:
Site:	Royal Perth Hospital
Contact:	Dr Michael Leahy Email: TBC

South Australia

Status:
Site:	Royal Adelaide Hospital
Contact:	Dr Noemi Horvath and Dr Angie Yong Email: CALHN.Amyloidtrials@sa.gov.au

A Phase II trial to evaluate the efficacy of Isatuximab plus Pomalidomide and Dexamethasone in patients with AL amyloidosis not in VGPR or better after any previous therapy

What is the drug in question?
Isatuximab is a monoclonal antibody that attacks the amyloid-forming plasma cells and helps your own immune system to kill these abnormal cells. It is very similar to daratumumab which is a highly effective treatment in AL amyloidosis.
Pomalidomide is an immunomodulatory drug which has been used for many years in myeloma, and has been shown to be effective and well tolerated in AL amyloidosis.
Dexamethasone is a steroid which also acts to suppress the production of the amyloid-forming plasma cells, and is usually combined with other treatments to improve their efficiency in destroying the amyloid-causing plasma cells and light chains.

Who is eligible for the trial?
Any patient with AL amyloidosis who have received at least one line of treatment with cyclophosphamide or melphalan and/or Velcade or ixazomib, and dexamethasone and not be in VGPR or better at the time of inclusion.

A “VGPR” stands for “Very Good Partial Response”, which is when the amyloid-making light chain is not more than 40mg/L greater than the other light chain. For instance, a patient with a lambda light chain of 55mg/L and a kappa light chain of 20mg/L would usually be consider in VGPR if the lambda light chains were the amyloid-causing light chains.

Does every patient receive the actual trial drug?
Yes, all patients receive isatuximab, pomalidomide and dexamethasone treatment.

How is the drug administered?
Pomalidomide and dexamethasone are oral tablets, while isatuximab is an intravenous (IV; through a “drip” in your arm) infusion.

Isatuximab will be given weekly for the first month then fortnightly for the remainder of the 12 month trial.

Pomalidomide is a tablet taken every day for 3 weeks then you have a week off. This is repeated every 4 weeks.
Dexamethasone is tablet taken once per week.

How long does the trial go for?
The trial will run for up to 12 months, but for those patients who achieve a complete 100% response to the treatment, the trial finishes after 9 months. However, patients will be followed up after the trial finishes every few months for up to 4 years.

Anything else I need to know?
Patients with myeloma bone disease and/or who have previously received daratumumab are not eligible for this study.

Key inclusion criteria:

1. Age: ≥18
2. Histologic diagnosis of AL amyloidosis
3. Patients should have received at least one line with an alkylating agent and/or a PI, and dexamethasone and not be in VGPR (or better) at the time of inclusion (patients who did not reach VGPR before, or patients in VGPR or better before but with a hematological relapse at the time of inclusion can be included)
4. Measurable hematologic disease: difference between involved and uninvolved FLC > 50 mg/L with an abnormal k/l ratio
5. Symptomatic organ involvement (heart, kidney, liver/GI tract, peripheral nervous system)
6. Wash-out period of at least 4 weeks from previous antitumor therapy or any investigational treatment or 5 half‐lives from previous antibodies, whichever is longer.
7. Adequate bone marrow function prior to 1st drug intake (C1D1), without transfusion or growth factor support within 5 days prior to 1st drug intake, defined as:
   – Absolute neutrophils count ≥ 1000/mm3,
   – Platelets ≥ 75000/mm3,
   – Hemoglobin ≥ 8.0 g/dL,
8. Adequate organ function defined as:
   – Serum ASAT or ALAT ≤ 3.0 X Upper Limit of the Normal range (ULN),
   – Serum total bilirubin level < 1.5 x ULN, unless for subjects with Gilbert’s syndrome where thedirect bilirubin should then be ≤ 2.0 x ULN.
9. ECOG status ≤ 2
10. Male participants must agree to use contraception during the intervention period and for at least 5 months after the last dose of IsaPd treatment and refrain from donating sperm during this period.
11. Female participants are eligible to participate if they are not pregnant, not breastfeeding, and at least one of the following conditions applies:
    – Not a Female of childbearing potential (FCBP), OR
    – a FCBP must have a negative serum or urine pregnancy test and must either commit to continue complete abstinence from heterosexual intercourse or apply two acceptable methods of birth control

Key exclusion criteria:

1. Presence of non-AL amyloidosis.
2. AL amyloidosis with isolated soft tissue involvement.
3. Bone marrow plasma cells > 30% and clinically symptomatic multiple myeloma with lytic bone lesions;
4. NT-proBNP > 8500 ng/L and hs-troponin I > 100 ng/L or hs-troponin T > 50 ng/L (cardiac stage IIIb patients);
5. Repetitive ventricular arrhythmias on 24h Holter ECG despite anti‐arrhythmic treatment sustained ventricular tachycardia, aborted ventricular fibrillation, atrioventricular nodal or sinoatrial nodal dysfunction with no pacemaker.
6. Chronic atrial fibrillation with uncontrolled heart rate.
   Significant cardiac dysfunction; myocardial infarction within 12 months; unstable poorly controlled angina pectoris;
7. Uncorrected valvular disease unrelated to AL amyloid cardiomyopathy,
   QT interval as corrected by Fridericia’s formula > 550 msec without pacemaker,
   Undergoing dialysis.
8. Ongoing toxicity (excluding alopecia and those listed in eligibility criteria) from any prior therapy > Grade 1 (NCI-CTCAE v5.0)
9. Supine systolic blood pressure < 90 mmHg, or symptomatic orthostatic hypotension, defined as a systolic blood pressure upon standing < 80 mmHg despite medical management (i.e. midodrine, fludrocortisones) in the absence of volume depletion.
10. Previous anti-CD38 therapy or pomalidomide therapy (if refractory to pomalidomide).
11. Hypersensitivity to IMiD® defined as any hypersensitivity reaction leading to stop IMiD® within the 2 first cycles or toxicity, which does meet intolerance definition
    History of malignancy within 3 years before the date of inclusion (exceptions are squamous and basal cell carcinomas of the skin, carcinoma of the skin, carcinoma in situ of the cervix or breast).
12. Active systemic infection and severe infections requiring treatment with a parenteral administration of antibiotics.
13. Received any investigational drug within 14 days or 5 half-lives of the investigational drug prior to initiation of study intervention, whichever is longer. In case of very aggressive disease delay could be shortened after agreement between sponsor and investigator, in absence of residual toxicities from previous therapy.
14. Known positive for HIV or active hepatitis A, B or C.
15. Pregnant of breast-feeding females.

ACCESS CLINICAL TRAILS DATABASE HERE

Sites

Victoria

Status:
Site:	Eastern Health, Melbourne
Contact:	Dr Simon Gibbs Email: simon.gibbs@monash.edu

Queensland

Status:
Site:	Princess Alexandra Hospital, Brisbane
Contact:	Associate Professor Peter Mollee Email: amyloidosis@health.qlg.gov.au

Western Australia

Status:
Site:	Fiona Stanley Hospital, Perth
Contact:	Associate Professor Hasib Sidiqi Email: hasib.sidiqi@wa.health.gov.au

South Australia

Status:
Site:	Royal Adelaide Hospital
Contact:	Dr Noemi Horvath Email: TBC

A Single-Arm, Open-Label, Phase 1/2 Study of ZN-d5 for the Treatment of Relapsed or Refractory Light Chain (AL) Amyloidosis

What is the drug in question?
This is a novel BCL-2 inhibitor, similar to venetoclax.

Inhibiting BCL-2 can lead to death in tumour cells dependent on BCL-2 activity, including multiple myeloma cells. Venetoclax has activity in relapsed and refractory AL amyloidosis.

This trial hopes to prove that ZN-d5 will be at least as effective as venetoclax in killing amyloid-forming plasma cells.

Who is eligible for the trial?
Patients with relapsed and refractory AL amyloidosis who have had disease relapse/progression or lack of response to 1 to 3 prior lines of therapy.

Does every patient receive the actual trial drug?
All patients will receive active drug. There is no placebo-arm to this study. ZN-d5 is not given with any other therapy.

How is the drug administered?
ZN-d5 is a oral tablet.

How long does the trial go for?
Up to 135 patients will be included in the trial. Subjects will remain on treatment until disease progression, adverse events, withdrawal of consent, death, or the end of the study.

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.

Key inclusion criteria:

1. A biopsy-confirmed diagnosis of AL amyloidosis based on one of the following: histopathology (positive Congo red-stained tissue confirmed by immunohistochemistry demonstrating light chain deposition without the presence of transthyretin), the presence of characteristic appearance on electron microscopy, or mass spectrometry typing of amyloid.
2. At least 1, and no more than 3, prior lines of therapy
3. Measurable disease defined by dFLC ≥ 20 mg/L.
4. History of organ involvement that included at least one of the following:
   • Renal: albuminuria or non-Bence Jones proteinuria > 0.5 g/day by 24-hour urine collection.
   • Cardiac: mean left ventricular wall thickness on echocardiogram more than 12 mm in the absence of a history of hypertension or valvular heart disease or unexplained low voltage (< 0.5 mV) on ECG; or NT-ProBNP > 332 ng/L (or BNP > 81-ng/L) in the absence of renal failure.
   • Hepatic: hepatomegaly on PE or ultrasound or alkaline phosphatase > 1.5 × the upper limit of normal (ULN).
   • Gastrointestinal: direct biopsy verification of amyloid deposition and gastrointestinal symptoms, such as gastrointestinal bleeding or diarrhea.
   • Neurologic: symmetrical lower extremity sensorimotor peripheral neuropathy or autonomic neuropathy, including gastric motility disorder, pseudo-obstruction, or voiding dysfunction unrelated to direct organ infiltration. Assessment of t(11;14) status by FISH on bone marrow sample.
5. Adequate time since prior therapy before initiation of treatment with ZN-d5 (at least 3 months from HSCT or the shorter of 60 days or 5 half-lives from previous drug or biologic therapy or any investigational treatment).
6. ECOG score of ≤ 2.
7. Adequate bone marrow function as follows:
   • Hemoglobin ≥ 80g/L, neutrophils ≥ 1.5 ×109/L, Platelets ≥ 50 × 109/L.
8. Adequate organ function as follows:
   • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN.
   • Alkaline phosphatase ≤ 5 × ULN.
   • Total bilirubin ≤ 1.5 × ULN except for subjects with Gilbert syndrome.
   • Serum albumin ≥ 2 g/dL (20 g/L).
   • eGFR ≥ 30 mL/min/1.73 m2

Key exclusion criteria:

1. Diagnosis of multiple myeloma according to the 2014 International Myeloma Working Group diagnostic criteria.
2. Mayo 2012 Stage IV disease, defined as follows:
   • NT-ProBNP ≥ 1800 ng/L, cTnT ≥ 0.025 ng/mL, dFLC ≥ 180 mg/L
3. Any of the following cardiac conditions:
   • New York Heart Association (NYHA) Class III or IV heart failure
   • History of sustained ventricular tachycardia or fibrillation, or ventricular arrhythmias
   • Corrected QT interval (QTc) > 500 msec
   • Second or third-degree atrioventricular block (Mobitz type I is permitted)
   • History of myocardial infarction, coronary stent placement, or coronary artery bypass grafting within 6 months of enrolment
   • Left ventricular ejection fraction (LVEF) by echocardiogram < 35%
   • Supine systolic blood pressure < 90 mm Hg or symptomatic orthostatic hypotension
4. Positive serum antibody tests for hepatitis B surface antigen or hepatitis C
5. Concurrent treatment with agents used to treat plasma cell disorders or AL amyloidosis, including experimental agents; such treatments should be discontinued the shorter of 60 days or 5 half-lives prior to first dose of ZN-d5
6. Prior treatment with ZN-d5, venetoclax, navitoclax, obatoclax or any other small molecule BCL-2 inhibitor
7. Any concurrent medical condition that would make a potential subject a poor candidate for this study, including uncontrolled serious infection, active malignancy other than non-melanoma skin cancer or carcinoma in situ of the cervix, uncontrolled pulmonary disease, severe diarrhea, cirrhosis, any condition likely to require systemic corticosteroids for more than 1 week during the course of this study, or major surgery within 28 days of enrolment.

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

Sites

New South Wales

Status:
Site:	Westmead Hospital
Contact:	Dr Fiona Kwok Email: WSLHD-TTRtrials@health.nsw.gov.au

Victoria

Status:
Site:	Eastern Health, Melbourne
Contact:	Dr Simon Gibbs Email: simon.gibbs@monash.edu

Queensland

Status:
Site:	Princess Alexandra Hospital
Contact:	Dr Emad Abro Email: amyloidosis@health.qld.org.au

Western Australia

Status:
Site:	Fiona Stanley Hospital
Contact:	Dr Hasib Sidiqi Email: coral.almeida@health.wa.gov.au hasib.Sidiqi@health.wa.gov.au

South Australia

Status:
Site:	Royal Adelaide Hospital
Contact:	Dr Noemi Horvath and Dr Angie Yong Email: CALHN.Amyloidtrials@sa.gov.au

A Phase Ib/II Open-Label Study of APG2575 in Combination with Novel Therapeutic Regimens in Subjects with Relapsed or Refractory Multiple Myeloma and Immunoglobulin Light Chain Amyloidosis

APG-2575 (varying doses) + pomalidomide and dexamethasone (Pd)

What is the drug in question?
Approximately 50% of patients with AL amyloidosis have a chromosomal (genetic) change involving part of chromosome 11 swapping with part of chromosome 14, referred to as “t(11;14)”. BCL-2 inhibitors target this mutation and can cause cell death of the plasma cells that make the amyloid. APG-2575 is a novel BCL-2 inhibitor.

In this study, APG-2575 is combined with pomalidomide, an immunomodulatory drug which has been used extensively in myeloma, and appears to be effective and well tolerated in AL amyloidosis too. Dexamethasone, a steroid, is also combined with APG-2575 and pomalidomide, to hopefully enhance the effect of the drug.
During the study, patients will be assigned different doses of APG-2575 to determine the highest dose that is the best tolerated.

Who is eligible for the trial?
Any patient with relapsed AL amyloidosis with organ involvement (eg. heart and/or kidneys), or a patient who has not achieved an excellent response to their first 3 cycles of front-line chemotherapy.

Does every patient receive the actual trial drug?
Yes, all patients receive APG-2575, pomalidomide and dexamethasone

How is the drug administered?
This is an all oral, tablet treatment

How long does the trial go for?
Patients will continue to receive treatment until disease progression, unacceptable toxicity, or withdrawal of consent.

Key inclusion criteria:
Systemic AL (not ATTR) amyloidosis, involving the heart, as proven by

1. ≥ 18 years of age.
2. Histochemical diagnosis based on detection by polarizing microscopy of green birefringent material in Congo red-stained tissue specimens, the type must have been confirmed unequivocally.
3. Symptomatic organ involvement.
4. At least one prior line of systemic therapy for AL. Patients who do not achieve at least a PR to frontline therapy in 3 months are eligible.
5. All MM/AL patients should have measurable disease as defined by at least ONE of the following:
   • Serum monoclonal protein 1.0 g/dl or more by protein electrophoresis.
   • >200 mg of monoclonal protein in the urine on 24-hour electrophoresis.
   • If both serum and urine monoclonal proteins are non-measurable:
   • Serum differential FLC concentration (dFLC) > 5 mg/dL; OR serum FLC of 7.5 mg/dL provided the κ/λ FLC ratio is abnormal
6. Eastern Cooperative Oncology Group (ECOG) ≤ 2.
7. Life expectancy ≥ 6 months.
8. Adequate hematologic function defined as:
   • ANC ≥1.0 x 109/L independent of growth factor support within 7 days of the first dose with study drug.
   • Haemoglobin ≥8 g/dL without transfusion or growth factor support within 7 days of the first dose of study drug.
   • Platelet count ≥ 100 x 109/L or ≥ 50 x 109/L if bone marrow involvement independent of transfusion support
9. Adequate hepatic and renal function defined as:
   • AST and ALT < 3 x upper limit of normal
   • Creatinine ≤3 mg/dL and CrCL ≥25 ml/min using the Cockcroft-Gault formula
   • Bilirubin< 1.5 x ULN (except if considered secondary to Gilbert’s syndrome and primarily indirect bilirubinemia)
10. PT/INR ≤2 x ULN and PTT (or aPTT) ≤2 x ULN.
11. Female subjects who are of non-reproductive potential. Female subjects of childbearing potential must have a negative serum pregnancy test upon study entry.
12. Male and female subjects who agree to use highly effective methods of birth control during the period of therapy and for 90 days after the last dose of study drug.
13. Ability to cooperate to complete neurological examinations if required

Key exclusion criteria:

1. AL amyloidosis patients who have not been treated with any systemic therapy
2. AL amyloidosis clinically overt multiple myeloma i.e. original CRAB criteria. Extent of marrow plasmacytosis is not prohibitive.
3. Subject has received antineoplastic therapy within 2 weeks before the date of initiating study treatment.
4. Subjects planning to undergo a stem cell transplant prior to progression of disease on this study, i.e., these subjects should not be enrolled in order to reduce disease burden prior to transplant.
5. Subject has peripheral neuropathy ≥grade 3 except caused by AL amyloidosis.
6. Active cardiovascular disease, such as uncontrolled arrhythmia (including Frederica corrected QT interval (QTc ≥470 msec) or Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction or unstable angina.
7. Major surgical procedure within ≤14 days prior to initiating study treatment, or anticipation of the need for major surgery during the course of the study treatment, radiotherapy ≤14 days prior to initiating study treatment, systemic treatment within 14 days before the first dose of APG2575.
8. Recent infection requiring systemic treatment that was completed ≤14 days before the first dose of study drug.
9. Subject has any concurrent or recent malignancy ≤ 1 year prior to registration with the exception of: basal or squamous cell skin cancer, any carcinoma in situ.

ACCESS CLINICAL TRAILS DATABASE HERE

Sites

Victoria

Status:
Site:	Epworth Freemasons, Melbourne
Contact:	Dr Simon Gibbs Email: simon.gibbs@monash.edu

A Study to Evaluate the Efficacy and Safety of AKCEA-TTR-LRx With Transthyretin Amyloidosis With Cardiomyopathy (ATTR Amyloidosis With Cardiomyopathy)

What is the drug in question?

AKCEA-TTR-LRx is a gene-silencing therapy, designed to reduce the production of TTR by the liver, and thus slow or stop the formation and progression of TTR amyloidosis.

Who is eligible for the trial?

Patients with symptomatic ATTR cardiac amyloidosis are eligible for this trial.

Both ATTRwt (wild-type) and ATTRv (hereditary) disease groups are included.

Does every patient receive the actual trial drug?

This is an international Phase 3 prospective randomised placebo-controlled double-blinded study.

Patients will be randomized 1:1 (50;50 chance) to receive either the AKCEA-TTR-LRx injection or the placebo (“dummy” drug) injection. Neither you nor your doctor will know whether you are on the active drug or the placebo.

How is the drug administered?

AKCEA-TTR-LRx is administered as a subcutaneous (“under the skin”) injection. Patients will receive their injection every four weeks

How long does the trial go for?

The TTRansform trial lasts 120 weeks (27 months).

Anything else I need to know?

Patients can also take EGCG and/or tafamidis during the study, but not diflunisal or doxycycline.

N.B. Neither EGCG nor Tafamidis will be supplied by the drug company, and tafamidis is currently not available on the PBS.

Key inclusion criteria:

1. “Symptomatic” heart failure defined as requiring hospitalisation or current/prior diuretic management.

2. NT-proBNP 600-6000 ng/L.

Key exclusion criteria:

1. Monoclonal gammopathy of undetermined significance (MGUS) unless fat, bone marrow, or heart biopsy confirms the absence of AL amyloid by mass spectrometry or immunoelectron microscopy.

2. eGFR <30mL/min/1.73 m²

3. Prior liver or heart transplant.

Access Clinical Trials Database

Sites

New South Wales

Status:
Site:	Liverpool Hospital, Sydney
Contact:	Study co-ordinator: Natalia Inness: natalia.inness@health.nsw.gov.au Principal Investigator: Gayathri.Kumarasinghe@health.nsw.gov.au Phone: (02) 8738 3078 Fax: (02) 8738 3054.

Status:
Site:	Westmead Hospital, Sydney
Contact:	Dr Mark Taylor
Email:	WSLHD-TTRtrials@health.nsw.gov.au

Victoria

Status:
Site:	The Victorian and Tasmanian Amyloidosis Service, Box Hill Hospital, Melbourne
Email:	simon.gibbs@monash.edu
Phone:	03 9094 9505

Tasmania

Status:
Site:	Royal Hobart Hospital
Contact:	Dr Dave Russell, Cardiologist,
Email:	Dave.russell@ths.tas.gov.au

Queensland

Status:
Site:	Princess Alexandra Hospital, Brisbane
Contact:	Cindy Hall, Study Co-ordinator
Phone:	07 3176 5145

Western Australia

Status:
Site:	Genesis Care, Perth
Contact:	Dr Peter Purnell
Email:	cardiology.research@genesiscare.com