AMADEUS Reaches 50% Recruitment

Allogeneic stem cell transplantation (allo-SCT) increases survival rates in adult patients with high risk Acute Myeloid Leukemia (AML) and presents the only curative treatment option in Myelodysplastic Syndromes (MDS). However, despite improved outcomes, disease relapse remains the primary cause of treatment failure following allo-SCT.

One of the most promising strategies with the potential to reduce the risk of relapse after allo-SCT is the use of a post-transplant maintenance therapy. A prospective candidate for maintenance in this setting, azacitidine, demonstrates significant clinical activity in patients with emerging or overt disease relapse after allo-SCT, and may also reduce the risk of graft-versus-host disease (GvHD).

Oral azacitidine (CC-486), a recently developed oral formulation, provides a much more convenient route of administration and avoids the inconvenience and costs associated with frequent hospital visits, whilst facilitating easy dose modifications, and has been shown to demonstrate good tolerability.

AMADEUS is the first multicentre, prospective, double-blind, randomised phase III trial comparing the efficacy and safety of oral azacitidine versus placebo in AML or high risk MDS following allo-SCT.

THE AMADEUS TRIAL

Eligible patients for the study include adult patients (≥ 16 years) with a diagnosis of AML or high risk MDS and a planned allo-SCT from a matched sibling or matched unrelated donor using a myeloablative conditioning (MAC) or reduced intensity conditioning (RIC) regimen.

Patients commence trial therapy between 42 and 84 days post-transplant. Patients are randomised to receive placebo or oral azacitidine. Patients receive trial therapy once daily for the first 14 days of each 28-day cycle, for 12 months post-transplant or until relapse.

The primary objective of the study is the comparison of RFS. Secondary endpoints include OS, cumulative incidence of relapse, non-relapse mortality, incidence of acute and chronic GvHD, and GvHD-free relapse-free survival.

RECRUITMENT

AMADEUS is now open at 19 UK transplant centres. To date, 197 patients have been screened and 163 patients have been randomised to receive either oral azacitidine or placebo, meaning as of September 2021 over half of the required 324 patients have been recruited to AMADEUS.

Recruitment was briefly halted during the COVID-19 pandemic to ensure the safety of patients. However, owing to the clinical importance of the study, the resilience of sites, and continued PI engagement, all sites were re-opened by July 2020. In fact, over 80% of AMADEUS patients enrolled to date have been recruited since March 2020, when the pandemic first took hold in the UK.

Research sample collection in AMADEUS has exceeded targets with a return of 91.7% of expected samples to date. Blood and bone marrow samples are collected from patients participating in AMADEUS, in collaboration with three UK research laboratories: the Flow Cytometric MRD Lab in Birmingham, the Weatherall Institute of Molecular Medicine (WIMM) in Oxford and the Molecular MRD Lab in London.

In view of the COVID-19 pandemic, amendments were made to the study to collect COVID-19 data from patients, and to record how trial visits and assessments were impacted. In order to facilitate trial recruitment during these challenging circumstances, amendments were also made to permit some telephone consultations and allow defined protocol assessments to be performed locally.

FINAL THOUGHTS

AMADEUS is the first randomised trial of post-transplant CC-486 in patients allografted for AML or high-risk MDS. Recruitment to the trial has proved resilient despite the COVID-19 pandemic, confirming the value of delivering trials through an integrated national transplant trials network and the importance of this research question.

“AMADEUS remains the only randomised trial examining the clinical activity of CC-486 as maintenance in adults allografted for AML and high-risk MDS. The trial is relatively straight-forward to deliver and sites are recruiting well. We hope that the trial will contribute to a better understanding of how to improve patient outcomes post-transplant.” – Professor Charlie Craddock, AMADEUS Chief Investigator

Article written by Ellie Williams, AMADEUS Trial Coordinator