Efficacy and safety of avatrombopag in combination with immunosuppressive therapy in treatment-naïve and relapsed/refractory severe aplastic anaemia: protocol for the DIAAMOND-Ava-FIRST and DIAAMOND-Ava-NEXT Bayesian Optimal Phase II trials
Stephane Heritier,
Alisa Higgins,
Piers Blombery,
Robin Filshie,
Paul Lacaze,
Kate Wilson,
William Stevenson,
Lauren Young,
Zoe McQuilten,
Jennifer Curnow,
Lucy Fox,
Vanessa Fox,
Ilona Cunningham,
Devendra K Hiwase,
Frank Firkin,
Kylie Mason,
Anthony K Mills,
Dominic Pepperell,
Sushrut Patil,
Jeff Szer,
Neil Waters,
Stephen Ting,
Erica Wood
Affiliations
Stephane Heritier
School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
Alisa Higgins
School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
Piers Blombery
Department of Clinical Haematology, Peter MacCallum Cancer Centre & The Royal Melbourne Hospital, Parkville, Victoria, Australia
Robin Filshie
Haematology Department, St Vincent’s Hospital, Melbourne, Victoria, Australia
Paul Lacaze
School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
Kate Wilson
University of Sydney, Sydney, New South Wales, Australia
William Stevenson
Department of Haematology, Royal North Shore Hospital, St Leonards, Sydney, Australia
Lauren Young
School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
Zoe McQuilten
Department of Haematology, Monash Health, Melbourne, Victoria, Australia
Jennifer Curnow
Department of Haematology, Westmead Hospital, Sydney, New South Wales, Australia
Lucy Fox
School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
Vanessa Fox
School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
Ilona Cunningham
Concord Repatriation General Hospital, Sydney, New South Wales, Australia
Devendra K Hiwase
Department of Haematology, Royal Adelaide Hospital, Adelaide, South Australia, Australia
Frank Firkin
Haematology Department, St Vincent’s Hospital, Melbourne, Victoria, Australia
Kylie Mason
Department of Clinical Haematology, Peter MacCallum Cancer Centre & The Royal Melbourne Hospital, Parkville, Victoria, Australia
Anthony K Mills
University of Queensland, Brisbane, Queensland, Australia
Dominic Pepperell
Department of Haematology, Fiona Stanley Hospital, Murdoch, Perth, Australia
Sushrut Patil
Department of Haematology, Alfred Hospital, Melbourne, Victoria, Australia
Jeff Szer
Department of Clinical Haematology, Peter MacCallum Cancer Centre & The Royal Melbourne Hospital, Parkville, Victoria, Australia
Neil Waters
School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
Stephen Ting
School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
Erica Wood
Department of Haematology, Monash Health, Melbourne, Victoria, Australia
Introduction Immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and ciclosporin is standard of care for patients with severe aplastic anaemia (sAA) not eligible or suitable for allogeneic stem cell transplant. While patients respond to IST, few achieve complete responses and a significant proportion are refractory or relapse. The addition of eltrombopag, a thrombopoietin-receptor agonist (TPO-A), to IST has been shown to improve haematological responses in sAA. Avatrombopag is a second-generation TPO-A with potential advantages over eltrombopag. However, to date avatrombopag has not been studied in sAA.Methods and analysis Investigator-initiated, single-arm registry-based Bayesian Optimal Phase II trial of avatrombopag conducted in two cohorts, patients with untreated sAA (FIRST cohort) and in patients with sAA that has relapsed or is refractory to IST (NEXT cohort). In the FIRST cohort, participants receive IST (equine ATG and ciclosporin) plus avatrombopag from day 1 until day 180 at 60 mg oral daily, with dose adjusted according to platelet count. Participants in the NEXT cohort receive avatrombopag at 60 mg oral daily from day 1 until day 180, with or without additional IST at the discretion of the treating clinician.For each cohort, two primary endpoints (haematological response and acquired clonal evolution) are jointly monitored and the trial reviewed at each interim analysis where a ‘go/no-go’ decision is made by evaluating the posterior probability of the events of interests.Ethics and dissemination The trial has received ethics approval (Monash Health RES-18-0000707A). The trial conduct will comply with ICH-GCP and all applicable regulatory requirements. The results of the trial will be submitted to a peer-review journal for publication.Trial registration number ACTRN12619001042134, ACTRN12619001043123.
