AL Amyloidosis trials

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There are currently six major AL Amyloidosis trials taking place at the NAC or UCL:

  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. Dose Escalation Study of Carfilzomib Taken With Thalidomide and Dexamethasone in Relapsed AL Amyloidosis (CATALYST)  – a phase 1 trial in patients with relapsed or refractory AL amyloidosis
  6. A Study to Evaluate the Efficacy and Safety of Daratumumab in Combination With Cyclophosphamide, Bortezomib and Dexamethasone (CyBorD) Compared to CyBorD Alone in Newly Diagnosed Systemic Amyloid Light-chain (AL) Amyloidosis –a phase 3 trial of a new targeted therapy in combination with standard chemotherapy in patients with newly diagnosed AL amyloidosis

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

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, and who have not received bortezomib first line, 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 ongoing 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 ongoing 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.

Timing

This study is open for recruitment at the NAC.

Dose Escalation Study of Carfilzomib Taken With Thalidomide and Dexamethasone in Relapsed AL Amyloidosis (CATALYST)

Background

The most effective treatment available for AL amyloidosis is high dose chemotherapy followed by autologous stem cell transplantation (ASCT). However this treatment is only appropriate for patients with limited organ involvement, younger age and good functional status.

The majority of patients with AL amyloidosis are not candidates for ASCT and are treated with combination chemotherapy, often including bortezomib, a proteasome inhibitor. Bortezomib is particularly effective in AL amyloidosis but may have severe side effects.

Carfilzomib, a different drug from the proteasome inhibitor class, appears to be better tolerated than bortezomib, with fewer side effects. However information on carfilzomib in AL amyloidosis treatment is limited.

The CATALYST study will investigate safety, efficacy and dosing of carfilzomib in patients with AL amyloidosis.

The trial

This is a phase 1/1a dose escalation study to investigate safety and efficacy of carfilzomib in combination with thalidomide and dexamethasone, in patients with relapsed or refractory AL amyloidosis.

The trial starts with a dose escalation phase to determine maximum tolerated and recommended dose. There will then be an expansion phase to assess efficacy.

What the trial involves for patients

Participants in the escalation phase will receive up to six cycles of treatment with carfilzomib thalidomide and dexamethasone in combination.  Carfilzomib will be administered on Day 1, 8, and 15, with four groups of patients each receiving different doses of carfilzomib.

Following determination of the maximum tolerated dose and recommended dose, the trial will be opened to an expansion phase where participants will receive the recommended dose of carfilzomib, along with thalidomide and dexamethasone.

Patients will initially undergo screening assessments at the National Amyloidosis Centre, including a physical examination, laboratory tests, a pregnancy test, an echocardiogram, a 24 hour Holter monitor test, a bone marrow examination (if the doctors think this is necessary), and an assessment of medical history.  They will then be referred to their local participating hospital, where some of these assessments will be repeated.

If the patient can go on to the trial, they will need to visit their local participating hospital on Days 1, 8, and 15 of each 28-day cycle for up to 6 cycles of treatment.  At every treatment visit, patients will have blood tests, and at the end of cycle 2, another echocardiogram. In the course of the study, patients will also undergo further assessment sessions at the National Amyloidosis Centre.

Who can take part in the trial

Patients with systemic AL amyloidosis with relapsed or refractory disease after chemotherapy or ASCT.

Outcomes

The primary outcome measures are:

  • assessment of dose-limiting toxicities to establish the maximum tolerated dose of carfilzomib
  • determination of proportion of patients receiving carfilzomib who experience severe (Grade ¾) toxicity

Secondary outcome measures include clonal response rates after 3 and 6 months and organ response rate.

Timing

The study is ongoing at the NAC.

A Study to Evaluate the Efficacy and Safety of Daratumumab in Combination With Cyclophosphamide, Bortezomib and Dexamethasone (CyBorD) Compared to CyBorD Alone in Newly Diagnosed Systemic Amyloid Light-chain (AL) Amyloidosis

Background

Cyclophosphamide, Bortezomib and Dexamethasone (CyBorD) is standard therapy received by many patients with newly diagnosed systemic AL amyloidosis.

Daratumumab is an approved agent for treating multiple myeloma via intravenous infusion.  It is not a chemotherapy drug; it belongs to the relatively new class of drugs called targeted therapy.  It is an antibody targeting a cell surface protein called CD38, which is found on the abnormal plasma cells that cause myeloma and AL amyloidosis.  Daratumumab treatment, in combination with standard chemotherapy, has shown good efficacy in treating myeloma, and preliminary trials in AL amyloidosis have also been encouraging.

Daratumumab is usually given intravenously, which may be challenging for patients with AL amyloidosis whose hearts may be adversely affected by receiving fluids intravenously.  In this trial, daratumumab is administered in a novel way- by subcutaneous injection, which is hoped to be safer and more effective for patients with AL amyloidosis.

The trial aims to compare outcomes in newly diagnosed patients with AL amyloidosis treated with CyBorD alone to those treated with CyBorD and Daratumumab.  The study is designed to allow stem cell collection after the first 6 months of therapy so that stem cell transplantation may be considered in the future.

The trial

This is a phase 3 trial, to test the primary hypothesis that daratumumab in combination with CyBorD will improve the overall haematological response rate compared to CyBorD alone in patients with AL amyloidosis.  Participants are expected to be involved in the trial for around 8 years, which will include a screening phase, treatment phase, post-treatment observation phase and long-term follow up phase.

What the trial involves for patients

The screening phase will involve complete clinical evaluation.

In the treatment phase, participants in the experimental group will receive dexamethasone followed by subcutaneous daratumumab, followed by cyclophosphamide and bortezomib on weekly treatment days  in every 28 day cycle for a maximum of 6 cycles. Daratumumab will be administered weekly for the first 8 weeks, then every two weeks for 4 cycles then every 4 weeks till disease progression or subsequent therapy for a maximum of 2 years.

Participants in the active comparator arm will receive the same treatment with CyBorD but without daratumumab.

During the treatment phase, adverse events and clinical response will be monitored, during the post treatment observation phase disease evaluations will be performed and during the long term follow up phase subsequent treatment, treatment response, and clinical status will be followed.

Who can take part in the trial

Patients with newly diagnosed systemic AL amyloidosis.

For a full list of exclusion criteria, see the www.clinicaltrials.gov website.

Outcomes

The primary outcome measure is – percentage of participants with overall complete haematological response.

Secondary outcome measures include progression free survival, organ response rate, overall survival, change in cancer quality of life questionnaire scores.

Timing

The study is ongoing at UCL.

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