AMLM26/T1 INTERCEPT: A multi-arm trial for patients with acute myeloid leukaemia investigating new treatments which target early relapse and changes in disease characteristics - Gilteritinib+ Venetoclax

The ALLG AMLM26 INTERCEPT trial is an adaptive trial allowing the testing of multiple new therapeutic options targeting various AML biomarkers in a staged manner. The Master Protocol outlines the overall study structure (this is detailed in ANZCTR entry ACTRN12621000439842). There will be separate domains for each AML biomarker being investigated. Each domain will have at least one investigational agent. Each investigational agent may be used on its own and/or in combination with other agents. Each option will be a different treatment arm within a domain. Separate Therapy-Specific Protocol Appendices will include treatment-specific information for each investigational agent including all of the treatment arms specific to that investigational agent. Each treatment arm may be targeted to a specific AML biomarker (domain) and/or may be used when patients have no targetable option available. This entry is for gilteritinib in combination with venetoclax . Gilteritinib in tablet form will be administered orally with or without food. Venetoclax also in tablet form will be administered orally after food. A pilot safety run-in phase will be undertaken to verify the tolerability of gilteritinib in combination with venetoclax and to identify the appropriate dose for expansion of the proof-of-concept phase in patients. The first dose level explored will be level 4, if this is not tolerable lower dose levels will be studied. The dose levels explored will be, Level 4: Gilteritinib 120mg daily. Administered days 1-28 of a 28-day cycle for 12 cycles. If the patient is in morphological remission, Venetoclax 400mg daily. Administered days 2-28 inclusive. No dose ramp-up is required. Venetoclax continues at 400mg daily on days 1- 28 from cycle 2 onwards. If the bone marrow blasts at screening > 5%, a 3-day dose ramp-up is required for cycle 1. Venetoclax 100mg on day 2, then 200mg on day 3, then 400mg daily on days 4-28. Venetoclax continues at 400mg daily on days 1-28 from cycle 2 onwards. Level 3: Gilteritinib 120mg daily. Administered days 1-28 of a 28-day cycle for 12 cycles. If in morphological remission, venetoclax will be dosed at 400mg daily days 2-21 inclusive. No dose ramp-up is required. Venetoclax continues at 400mg daily on days 1- 21 from cycle 2 onwards. If bone marrow blasts at screening >5%, a 3-day dose ramp-up is required. Venetoclax 100mg on day 2, then 200mg on day 3, then 400mg daily on days 4-21. Venetoclax continues daily at 400mg on days 1- 21 from cycle 2 onwards. Level 2: Gilteritinib 120mg daily. Administered days 1-28 of a 28-day cycle for 12 cycles. If in morphological remission, venetoclax will be dosed at 400mg daily days 2-14 inclusive. No dose ramp-up is required. Venetoclax continues at 400mg on days 1-14 from cycle 2 onwards. If bone marrow blasts at screening >5%, a 2-day dose ramp-up is required. Venetoclax 100mg on day 2, then 200mg on day 3, then 400mg daily on days 4-14. Venetoclax continues at 400mg on days 1-14 from cycle 2 onwards. Level 1: Gilteritinib 80mg daily. Administered days 1-28 of a 28-day cycle for 12 cycles. If in morphological remission, venetoclax will be dosed at 200mg daily days 2-14 inclusive. No dose ramp-up is required. Venetoclax continues at 200mg on days 1-14 from cycle 2 onwards. If bone marrow blasts at screening >5%, a 2-day dose ramp-up is required. Venetoclax 100mg on day 2, then 200mg on days 3-14. Venetoclax continues at 200mg on days 1-14 from cycle 2 onwards. Once the optimal dose is determined in the safety run-in phase enrolment onto a proof-of-concept phase will commence using the dose level deemed tolerable. Patients will be asked to complete a dose diary to confirm the tablets were taken. In order to monitor adherence to the interventions patients will be asked to return the gilteritinib and venetoclax containers (with unused tablets or empty containers) to the hospital.