Tourmaline AL 1

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 on days 1, 8 & 15 every 28 days.
  • Dexamethasone + thalidomide: dexamethasone 20 mg/day PO weekly on 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 state 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, 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.