AL Amyloidosis trials

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There are currently five major AL Amyloidosis trials taking place at the NAC:

  1. The ALchemy trial–a study of chemotherapy in AL Amyloidosis patients
  2. Tourmaline AL1 — a phase 3 AL Amyloidosis trial for patients with relapsed disease
  3. Plasma studies — an analysis of the bone marrow of AL Amyloidosis patients.
  4. Targeted radiotherapy for AL Amyloidosis (TRALA)
  5. The Vital Amyloidosis Study

For detailed information about the disease itself, please see the AL Amyloidosis section.

 

ALchemy

The ALchemy (AL amyloidosis chemotherapy) study is a large, on-going, ‘real world’ study of chemotherapy in systemic AL amyloidosis, funded by a grant from the charity Myeloma UK.

The NAC started this study in 2009 in order to address several unanswered questions relating to patients with AL amyloidosis.

An unmet need

Prior to ALchemy, there had been no large systematic studies following and monitoring patients with systemic AL amyloidosis from the time of diagnosis (prospective studies).  Studies that had been carried out were small and usually did not include patients with severe disease.  Many patients were lost to follow up after their initial visits to the NAC.  It was therefore hard to assess accurately exactly which chemotherapy treatments patients around the country were receiving, what side effects they experienced and how the disease and treatment impacted on their quality of life.

ALchemy aimed to fill these gaps in our knowledge and to help us to improve our clinical practice accordingly.

Our goal was to gain a ‘real world’ picture of the disease by close monitoring of all patients with systemic AL amyloidosis regardless of age or disease severity.

Who is eligible for ALchemy?

All patients diagnosed with systemic AL amyloidosis in need of treatment are eligible for enrolment in ALchemy if they are able and willing to give informed consent and have had no (or minimal) prior therapy.

ALchemy monitoring

Patients enrolled in the study are monitored closely by NAC clinical research nurses.

  • Before ALchemy started, our standard follow up protocol involved an NAC assessment at diagnosis then every 6 months.
  • The ALchemy protocol involves:
    • Evaluation of patients’ response to treatment after 3 months, after just 3 cycles of treatment.
    • Requesting that the patients’ local treating physicians and nurses supply us with data regarding chemotherapy and other treatments and side effects after every cycle (every month).
    • Requesting that patients send us blood samples after every cycle (every month) so we can check free light chain (FLC) concentrations and serum protein electrophoresis (SPE).  We provide the blood sample tubes and pre-addressed padded envelopes and patients can go to their GP or local hospital clinic to have the blood drawn.

We wanted to assess the feasibility of this intensive, early monitoring approach.  We also wanted to evaluate whether such early assessments could lead to better treatment outcomes.

ALchemy has already led to improved patient care

Soon after the ALchemy study began, it became clear that patients were benefiting from the more intensive monitoring with the extra appointment after the first 3 cycles of chemotherapy, monthly blood samples and treatment forms from the local doctors.

As a result, we have incorporated all of these into our standard clinical practice for all patients.

Tourmaline AL 1

The trial

This is an international randomised phase 3 trial of a new drug – MLN9708, in patients with AL amyloidosis with relapsed or refractory disease.  MLN9708 belongs to the drug class called proteasome inhibitors.  This drug class also includes bortezomib, a drug which is often effective treatment for AL amyloidosis.

Patients with relapsed disease have responded to a chemotherapy treatment regime in the past, but after a while the AL amyloidosis has worsened again despite continued treatment.

Refractory disease means that patients have not responded to the treatment regime they received.

This trial aims to find out if patients with relapsed and refractory AL amyloidosis respond better to treatment with MLN9708 plus dexamethasone than to other chemotherapy regimes.

What the trial involves for patients

In order to compare the effects of MLN9708 plus dexamethasone to the effects of other chemotherapy regimes that doctors usually select for patients with relapsed or refractory AL amyloidosis, each patient taking part in the trial is randomly assigned to one of the following two groups:

  • Experimental: MLN9708 plus dexamethasone

Patients will receive MLN9708 (4.0 mg) orally (PO) on Days 1, 8, and 15 plus dexamethasone 20 mg/day PO weekly on Days 1, 8, 15, and 22 of each 28-day cycle; dexamethasone may be increased up to 40 mg/day after 4 weeks, if tolerated

  • Active comparator: doctor’s choice

Patients will receive one of the following regimes as selected by their doctor:

  • Dexamethasone: 20 mg/day orally (PO) on Days 1-4, 9-12 & 17- 20 of each 28-day cycle
  • Dexamethasone + melphalan: dexamethasone 20 mg/day PO on Days 1-4 of each 28-day; plus melphalan 0.22 mg/kg PO on Days 1-4 every 28 days.
  • Dexamethasone + cyclophosphamide: dexamethasone 20 mg/day PO weekly on Days 1, 8, 15 & 22 of each 28-day cycle; plus cyclophosphamide 500 mg PO Days 1, 8 & 15 every 28 days.
  • Dexamethasone + thalidomide: dexamethasone 20 mg/day PO weekly Days 1, 8, 15 & 22 of each 28-day cycle; plus thalidomide total dose up to 200 mg/day PO
  • Dexamethasone + lenalidomide: dexamethasone 20 mg/day PO weekly on Days 1, 8, 15 & 22 of each 28-day cycle; plus lenalidomide 15 mg/day for 21 days every 28 days

Who can take part in the trial

Patients with systemic AL amyloidosis affecting the heart and/or kidneys who have received one or two previous lines of treatment are eligible for participation in this trial.

Outcomes

The following outcomes will be assessed in this trial:

  • Overall response rate (ORR) – this will include estimation of what proportion of patients have complete response (CR), a very good partial response (VGPR) or a partial response (PR) to treatment.  Response is assessed with the blood test which measures the free light chain (FLC) concentration.  The better the response to treatment, the greater the drop in FLC concentration.
  • Hospitalisation rates for heart failure or progression to end stage kidney disease or death after 2 years.

In addition, the overall survival (OS), progression free survival (PFS), the safety and the number of patients with heart and/or kidney response will be assessed.

Timing

This study is open for recruitment at the NAC in London and in Oxford, Birmingham and Manchester.

 

A study of genotype and phenotype in plasma cells in patients with AL amyloidosis

The study

This study will assess the characteristics of abnormal bone marrow plasma cells in patients with AL amyloidosis.

Background

Treatment of AL amyloidosis is chemotherapy targeting abnormal bone marrow plasma cells.  The characteristics of these cells determines the treatment outcomes.  This study seeks to characterise in detail the abnormal plasma cells by flow cytometry, DNA analysis and exome sequencing.

What the trial involves for patients

All patients with AL amyloidosis need a bone marrow test as a part of the diagnostic work up for amyloidosis and for response assessment at the end of treatment.  This study seeks an additional bone marrow sample as well as the usual diagnostic sample.

Who can take part in the trial

Patients with systemic AL amyloidosis may participate in this trial, starting either at the time of diagnosis or after completion of treatment.

Outcomes

It is hoped that the detailed analysis of genetic and other characteristics of abnormal plasma cells in patients with AL amyloidosis will improve understanding of development of disease and response to treatment.

Timing

This study is open for recruitment at the NAC.

The Vital Amyloidosis Study

The trial

This is an international randomised phase 3 efficacy and safety trial of a new drug – NEOD001, in patients with newly diagnosed AL amyloidosis.  NEOD001 is a monoclonal antibody developed for the treatment of AL amyloidosis.

NEOD001 was granted orphan drug designation by the European Medicines Agency in 2013 and by the FDA in 2012.

What the trial involves for patients

In order to compare the effects of NEOD001 to the effects of placebo, each patient taking part in the trial is randomly assigned to one of the following two groups:

  • Experimental: NEOD001

Patients will receive NEOD001 (24 mg/kg, maximum dose of 2500mg) as a 60-120 minute intravenous infusion once every 28 days

  • Placebo:

Patients will receive a 250ml mag of normal saline by intravenous infusion once every 28 days.

All patients will also receive standard chemotherapy as selected by their doctor. First line chemotherapy must be a proteasome inhibitor containing regimen, with the proteasome inhibitor administered weekly. Subsequent chemotherapy regimens may be prescribed at the doctor’s discretion.

Who can take part in the trial

Patients with newly diagnosed, treatment naïve, systemic AL amyloidosis affecting the heart, for whom the planned first line chemotherapy regimen contains a proteasome inhibiting agent administered weekly.

Patients with multiple myeloma and patients in whom autologous stem cell transplantation is planned are not eligible to take part in this trial.

Outcomes

The primary outcome assessed in this trial will be the time to death from any cause or hospitalization because of heart disease.

Other outcomes assessed (secondary outcomes) from baseline to 9 months will include:

  • NT-proBNP best response
  • Change in 6 minute walk test
  • Change in scores on standardised questionnaires assessing general health and cardiomyopathy
  • Renal and hepatic functions

Timing

This study is open for recruitment at the NAC.

 

Targeted radiotherapy for AL Amyloidosis (TRALA)

Background

The most effective treatment available for AL amyloidosis is high dose chemotherapy which kills the abnormal cells in the bone marrow.  This treatment is also toxic to the normal bone marrow cells, so patients who receive high dose chemotherapy need to undergo autologous stem cell transplantation, where normal bone marrow cells are collected from the patient before chemotherapy then reinfused after chemotherapy.

This treatment can be very effective, but the high dose chemotherapy may be associated with serious adverse effects.

The TRALA study will investigate the use of targeted radiotherapy to destroy the bone marrow cells instead of high dose chemotherapy. Patients will undergo stem cell transplantation, as with high dose chemotherapy.

It is hoped that the targeted radiotherapy will be as effective as high dose chemotherapy in destroying the abnormal bone marrow cells that cause AL amyloidosis, with less severe side effects.

Targeted radiotherapy means that the radiation is given directly to the bone marrow using a radiolabelled antibody.  This avoids exposure of healthy organs to radiation.

The trial

This is a phase 1/2a study to assess the use of targeted radiotherapy with [90Y] –labelled anti-CD 66 (anti CD66 antibody radiolabelled with Yttrium 90) as the sole conditioning prior to autologous stem cell transplant in patients with AL amyloidosis.

What the trial involves for patients

In order to assess the safety and toxicity associated with use of [90Y] –labelled anti-CD 66 to treat AL amyloidosis, and to determine the optimal radiation dose that can be delivered safely to patients with AL amyloidosis, patients will undergo:

  • An initial dosimetry and imaging hospital visit to determine the radiation dose that will be given. This visit will involve administration of a different radiolabelled drug (CD66 radiolabelled with Indium-111), followed by scans 1, 3 and 4 days later.
  • About 1 week later, harvesting of the patient’s stem cells followed by administration of the study treatment with [90Y] –labelled anti-CD 66, then subsequent re-infusion of the patient’s stem cells (autologous stem cell transplantation).
  • Examination and testing by the study doctors 30 days and 100 days after stem cell transplantation.

There will be three treatment levels with step-wise increase of the infused [90Y]-labelled anti-CD66 radiation activity which will be given prior to autologous stem cell transplantation .

The total number of participants planned is between 12-18.

Who can take part in the trial

Patients with systemic AL amyloidosis with an indication for treatment who satisfy all standard autologous stem cell transplantation inclusion criteria (good organ function, no significant heart involvement, good performance status).

Outcomes

The primary outcomes assessed in this trial will be the safety and toxicity associated with the use of [90Y]-labelled anti-CD66 and establishment of the maximum tolerated radiation dose (MTD) over three infused radiation activity levels.

Other outcomes assessed (secondary outcomes) will include assessment of clonal response, disease response, cardiac recovery, time to progression and overall survival.

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