AMLM26 INTERCEPT: A multi-arm trial for patients with acute myeloid leukaemia investigating new treatments which target early relapse and changes in disease characteristics - The Master Protocol

The INTERCEPT study is a multi-domain, multi-arm, platform trial. This master protocol will govern the development and management of an adaptive clinical trial platform that will screen novel therapeutic combinations to demonstrate recurrent and sequential anti-leukaemic activity using MRD (minimal residual disease) technologies to provide proof of concept. This protocol allows patients to rotate from one treatment arm to another, when there is evidence of MRD progression. Patients enter the study in first or second morphologic remission(CR or CRi) with known and trackable MRD marker(s). The relevant MRD marker(s) will be monitored as per standard practice until evidence of MRD failure and/or morphological relapse. MRD monitoring could be performed every 1-3 months for approximately 2-3 years. For some MRD markers, it may be more appropriate to monitor bone marrow e.g. every 3 months for at least 12 months. Monitoring will occur as per standard practice at the site. They will then be allocated to the best available treatment option at the time. If there is more than one treatment option of equal value for the patient, they will be randomised to one option. As a platform trial, new treatment arms may be added, as well as the removal of futile therapeutic options. New targeted treatment domains may be created when there is sufficient evidence available to enable biomarker-driven enrichment cohorts to be accrued to more rapidly. In domains with a single treatment arm, proof of concept analyses of the primary efficacy endpoint will commence after the first 10 patients have had the required assessments or withdrawn earlier. In domains with more than one treatment arm and with a pre-planned comparison of the arms, the timing of the first analysis will be determined when these arms are added to the trial and information included in the specific treatment arm's linked ANZCTR entry. Treatment arms that commence with an EffTox design during a run-in period will have the timing of the first analysis and the frequency of subsequent analyses specified in the specific treatment arm's linked ANZCTR entry. Unless a domain or a treatment arm within a domain is stopped early for futility or overwhelming evidence of efficacy, the main analysis of the primary endpoint in a domain will usually occur when 50 patients have had the required assessments or have withdrawn early. Continuation of an efficacious treatment arm may be assessed if either new or rotated patients are likely to benefit from continued access to it. A treatment arm will close due to the following reasons- • Inadequate recruitment once a consistent accrual rate has been established • The treatment arm is determined by the Trial Management Committee(TMC) and Safety Data Monitoring Committee (SDMC) to be excessively toxic. • In treatment arms without a safety run-in and after at least 10 patients have commenced therapy in the treatment arm, greater than or equal to 33% incidence of adverse events that are either grade 3+ non-haematological toxicities considered drug related and not resolving to grade 2 within 14 days, or, grade 4 neutropenia and/or thrombocytopenia lasting greater than 21 days after drug cessation and not related to myeloid disease e.g. AML/MDS. If the pilot or phase 2/3 recruitment has been completed and there is a low likelihood that the experimental therapy will improve outcomes (futility) • If the pilot or phase 2/3 recruitment has been completed and there is evidence of overwhelming efficacy (superiority) • If the pilot or phase 2/3 recruitment has been completed and the pharmaceutical collaborator wishes to graduate the experimental therapy into an independent clinical trial • There is mutual agreement to close the study arm by the TMC and the pharmaceutical collaborator • Evidence becomes available during the accrual phase of the treatment arm, which clearly demonstrates that it is unethical to continue to treat patients on the trial arm. • There is evidence at interim analysis of inferiority of the treatment arm