Newly diagnosed acute myeloid leukaemia (AML) Cancer
Conditions
Interventions
The ACT-AML-101 study is a prospective, multi-centre, open-label, Phase II, 1:1 randomized study comparing magrolimab, venetoclax and azacitidine combination therapy with the current standard of care
Sponsors
DIDACT Foundation
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. 18 to 70 years of age at the time of signing the Informed Consent Form (ICF) 2. Able to provide written informed consent for the study 3. Willing and able to adhere to the study visit schedule, treatment plan and other protocol requirements 4. Newly diagnosed acute myeloid leukaemia (AML) (previously untreated for AML) and morphological confirmation of AML fulfilling European LeukaemiaNet (ELN) 2022 criteria 5. Patients must be considered fit for intensive chemotherapy (IC) by the treating Investigator, using DA, DA+GO, CPX-351 (Vyxeos) or FLAG-Ida, and have either: 5.1. Adverse risk AML as defined by the ELN 2022 criteria and be 18 to 70 years of age; OR 5.2. Intermediate risk AML according to the ELN 2022 criteria and be 50 to 70 years of age 6. Genotype FLT3-ITD mutation-negative 7. ECOG performance status 0-2 8. Adequate renal function, as demonstrated by serum creatinine =1.5 x upper limit of normal (ULN) 9. Adequate liver function, as demonstrated by: 9.1. Aspartate aminotransferase (AST) =3 ULN 9.2. Alanine aminotransferase (ALT) =3 ULN 9.3. Total bilirubin =3 x ULN 10. Adequate cardiac function as demonstrated by left ventricular ejection fraction (LVEF) = 50% by echocardiogram (ECHO) 11. Patients must agree to use an adequate and medically accepted method of contraception throughout the study if they or their sexual partners are female-born of childbearing potential 11.1. Arm A patients: These measures must be in place during the study and for 3 months after the last dose of study treatment 11.2 Arm B female-born patients of childbearing potential: These measures must be in place during the study and for 6 months after the last dose of study treatment 11.3 Arm B non-sterilised male-born patients with female partners of childbearing potential: These measures must be in place during the study and for 3 months after the last dose of study treatment 11.4. Male-born patients should be advised to not father a child while receiving study treatment 11.5 Female-born patients of childbearing potential must agree to avoid becoming pregnant while on protocol treatment 12. Negative pregnancy test within 2 weeks prior to randomisation in female-born patients of childbearing potential 13. Pre-treatment blood cross-match completed
Exclusion criteria
Exclusion criteria: 1. Have received previous cytotoxic chemotherapy (intensive or non-intensive), targeted therapies, hypomethylating agents or venetoclax for AML or any other antecedent haematological condition, with the exception of hydroxycarbamide to control white blood cell (WBC) count or lenalidomide for treatment of myelodysplasia (MDS) 5q syndrome 2. Have received prior treatment with CD47 or signal regulatory protein alpha-targeting agents 3. Are in blastic transformation of chronic myeloid leukaemia (CML) 4. Clinical suspicion of active central nervous system (CNS) involvement with AML 5. Are not deemed fit for intensive chemotherapy (IC) on the basis of age or comorbidities 6. Have secondary malignancy, except MDS, treated basal cell carcinoma or localised squamous skin carcinomas, localised prostate cancer, or other malignancies for which patients are not on active anti-cancer therapies and have had no evidence of active malignancy for at least 1 year. Note: patients on maintenance therapy alone, who have no evidence of active malignancy for at least 1 year are eligible 7. Have acute promyelocytic leukaemia (APL) 8. Known newly diagnosed or uncontrolled human immunodeficiency virus (HIV), hepatitis B or hepatitis C infection. Patients with known chronic infections may enrol if the last two tests for viral load have been negative and their current therapy does not include a protease inhibitor or a non-nucleoside reverse-transcriptase inhibitor 9. Significant disease or medical conditions, as assessed by the Investigator, that would substantially increase the risk-benefit ratio of participating in the study. This includes, but is not limited to: 9.1. Acute myocardial infarction within 6 months of randomisation, 9.2. Unstable angina, cerebrovascular accident (CVA), transient ischemic attack (TIA), uncontrolled diabetes mellitus, significant active infections, and congestive heart failure New York Heart Association Class III to IV, within 3 months of randomisation. 10. History of Wilson’s disease or other copper-metabolism disorder 11. Pre-existing liver impairment with known cirrhosis 12. Judgement by the local Investigator that the patient should not participate in the study, if the patient is unlikely to comply with study procedures, restrictions and requirements 13. Concomitant use of: 13.1. Any strong or moderate CYP3A inhibitors, except posaconazole or voriconazole 13.2. Any strong or moderate CYP3A inducers 13.3. Preparations containing St John’s Wort 14. Known history, diagnosis or suspicion of haemophagocytic lymphohistiocytosis syndrome (HLH) 15. Pregnant and lactating patients 16. Female-born patients of childbearing potential, or male-born patients with female partners of childbearing potential, not willing to use adequate contraception during study and for the required contraceptive periods 17. Patients who are unable to swallow tablets whole 18. Unable to understand and therefore to give voluntary consent 19. Known hypersensitivity to any of the IMPs, the metabolites or formulation excipients 20. Current participation is another interventional clinical study. Patients in follow-up who have not received the interventional treatment within 4 weeks of randomisation may enrol. 21. Patients receiving any live vaccine within 4 weeks prior to initiation of study treatments 22. Patients known to require vaccination with a live vaccine during the treatment period or for 3 months after the end of study treatment 23. Known inherited or
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Superiority of the magrolimab, venetoclax and azacitidine combination therapy versus standard-of-care intensive chemotherapy as measured by event-free survival (EFS). EFS is defined as the time from randomisation to: 1. Treatment failure (failure to achieve complete remission (CR) or CR with incomplete haematologic recovery (CRi) after two cycles of therapy) 2. Confirmed relapse; or 3. Death from any cause whichever occurred earlier. The study will be analysed when 115 EFS events have occurred, or all patients have been followed for a minimum of 1 year, whichever is later. If 164 patients are recruited over 18 months, 5% of patients are lost to follow-up and the EFS hazard rate reduces by 90% after 12 months, it is estimated that the 115 events will occur approximately 1 year after the last patient is recruited. | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. Overall survival (OS) time. OS will be measured from date of randomisation to the date of death from any cause. 2. Complete response (CR). Defined by the proportion of patients with CR. 3. The composite CR and CR with incomplete haematologic recovery (CRi) rate. The proportion of patients with either CR or CRi will be assessed in patients on both arms based on peripheral blood count and bone marrow assessment. 4. The overall response rate. Defined as the proportion of patients with either CR, CRi or morphologic leukaemia-free state (MLFS). 5. Day 60 treatment-related mortality. Treatment-related mortality will be captured by the date of the first dose to survival data captured at day 60 and estimated from the OS Kaplan-Meier (KM) curve at Day 60. 6. The rate of measurable residual disease (MRD) negative CR (CRMRD-) defined by flow cytometry and or next-generation sequencing (NGS) pre-allo-SCT 7. Disease-free survival (DFS). DFS is defined for all patients achieving CR or CRi; measured from the date of achievement of remission until the earliest date of relapse or death. DFS assessment will be based on the results of bone marrow assessment obtained according to defined endpoints in the protocol. 8. Cumulative incidence of relapse (CIR). Defined for all patients achieving CR or CRi; measured from the date of achievement of a remission until the date of relapse. 9. Survival post allogeneic stem cell transplant (allo-SCT). Survival post-allo-SCT will be calculated from date of allo-SCT to the date of death and estimated from the corresponding KM curve. 10. Tolerability of magrolimab, venetoclax and azacitidine versus standard-of-care intensive chemotherapy. =CTCAE Grade 3 non-haematological adverse events (AEs) will be captured from the date of informed consent until 70 days from administration of the last dose of magrolimab/30 days from administration of any other study treatment (whichever is latest), or until the start of new anti-cancer therapy (including allo- | — |
Countries
United Kingdom
Outcome results
None listed