A trial comparing the effectiveness and safety of venetoclax to standard chemotherapy in acute myeloid leukaemia patients

INTERVENTION: VICTOR is a multicentre trial which will open in the UK, Denmark and New Zealand for patients with Acute Myeloid Leukaemia (AML) with NPM1 mutation. It is a randomised controlled trial and patients will be randomised to receive either standard of care intensive chemotherapy (with cytarabine, daunorubicin and gemtuzumab ozogamicin (DAGO)) or venetoclax combined with cytarabine (VEN+LDAC‐ the experimental combination). The primary aim of the study is to compare the two treatment arms in terms of molecular event free survival (mEFS), which is defined as failure to achieve complete remission (or complete remission without recovered blood counts) after two cycles of treatment, molecular persistence (the disease is not responding to treatment), progression or relapse resulting in a treatment change (this will be assessed via bone marrow samples), relapse or death. The two treatment arms will also be compared in terms of toxicity (side effects), overall survival, time to response or disease progression, quality of life and resource use (number of transfusions, days in hospital and use of anti‐infective medication). The aim is to demonstrate non‐inferiority in the experimental arm‐ therefore to show that this arm is at least equivalent to the current standard of care in terms of treatment outcome. It is expected that this arm will be associated with less severe side effects and economic cost compared to standard chemotherapy. Venetoclax is already widely used in the treatment of other blood cancers such as chronic lymphocytic leukaemia and research studies so far have demonstrated impressive outcomes in AML NPM1 mutated patients who have received venetoclax in combination with another chemotherapy drug‐ such as cytarabine. This is the first tria CONDITION: Acute myeloid leukaemia ; Cancer ; Malignant neoplasms, stated or presumed to be primary, of lymphoid, haematopoietic and related tissue PRIMARY OUTCOME: ; 1. Molecular event‐free survival time (mEFS) is calculated as the time from date of randomisation to the date of the first recorded event, where an event is defined as follows:; 1.1. Failure to achieve morphological CR or CRi after two cycles of therapy measured using blood and bone marrow tests; 1.1.1. Morphological complete remission (CR): <5% blasts in a cellular bone marrow with neutrophil count =1x109/L and platelet count =100 x 10(9)L; 1.1.2.Morphological complete remission with incomplete blood count recovery (CRi): <5% blasts but with neutropenia (neutrophil count <1x10(9)/L) or thrombocytopenia (platelet count <100 x 10(9)/L); 1.2. Molecular persistence, progression or relapse (i.e. molecular failure) requiring treatment change measured using blood and bone marrow tests; 1.2.1. Molecular persistence: Detectable NPM1 mutant transcripts present after completion of treatment, confirmed on a second consecutive sample. For the primary endpoint, molecular persistence is assessed at the end of the fourth cycle of primary treatment in both arms; 1.2.2. Molecular relapse: Detectable NPM1 mutant transcripts, confirmed on a second consecutive sample showing an increase of >1 log in a patient who previously tested negative in at least one technically adequate bone marrow sample (i.e. ABL Ct <26.5); 1.2.3. Molecular progression: An increase in NPM1 mutant transcript levels by >1 log, confirmed on a second sample; 1.3. Morphological relapse (=5% blasts in the blood or bone marrow in a patient with a previously documented CR, CRi or morphological leukaemia free state); 1.4. Death from any cause measured using patient records; SECONDARY OUTCOME: ; 1. Occurrence of morphological complete remission (CR) by the end of the second cycle of treatment is evaluated from the morphological response assessments taken at the end of cycles 1 and 2; 2. Death within 30 and 60 days from trial entry will include deaths from any cause and can only be evaluated in those patients who have been followed up for these periods of time; 3. Overall survival time is calculated as the time from date of randomisation to date of death from any cause; patients alive at the time of analysis will be censored at their date last seen alive; 4. Time to morphological relapse is calculated as the time from date of complete morphological remission to date when morphological relapse is first recorded; 5. Time to molecular relapse is calculated as the time from date of molecular remission to date when molecular relapse is first recorded; 6. Cumulative occurrence of grade 3 and 4 adverse events (AE) at 12 and 24 months is evaluated as the total number of grade 3 and 4 AE that are reported during these periods, from all AE that are reported and graded according to CTCAE criteria throughout the duration of the trial; 7. Prevalence of molecular complete remission at month 3, 6 and 12 is evaluated from the molecular response assessments taken at these approximate time points from trial entry; 8. Cumulative resource use at 12 and 24 months is calculated as total number of hospital admission days, total blood product usage and total number of days on intravenous antibiotics and antifungals that are reported for these periods of time from trial entry; 9. Health‐related quality of life (QoL) at month 3, 6, 12, 18 and 24 is evaluated from the EORTC QLQ‐C30 and EQ‐5D questionnaires completed by patients at clinic visits occurring at these approximate time points from trial entry; the questionnaires will yield 15 and 2 different measures of QoL respectively; 10. Performance status evaluated by clinical assessment according to the Eastern Cooperative Oncology Group classification (ECOG 0, 1, 2, 3 or 4) during clinic visits occurring at baseline and at month 3, 6, 12, 18 and 24; 11. Comprehensive Geriatric Assessment (CGA) comprises multiple measures of frailty that are evaluated during clinic visits at baseline and at month 12 and 24 and include: total number of medications prescribed, Hospital Anxiety and Depression score, Instrumental Activities of Daily Living score, Blessed Orientation Memory Concentration Test score, body mass index, weight, serum albumin level and timed get‐up and go measure; INCLUSION CRITERIA: 1. Diagnosis of CD33 positive acute myeloid leukaemia 2. Age >=60 years (prior to the interim analyses performed after enrolment of 50 and 100 patients) 3. Genotype NPM1mut FLT3 ITDneg (FLT3‐ Tyrosine Kinase Domain mutation, TKD, is permitted) 4. Eastern Cooperative Oncology Group (ECOG) performance status 0 ‐ 2 5. Serum creatinine <=1.5 x ULN (upper limit of normal) 6. Serum Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) <=2.5 ULN and bilirubin <=2 x ULN 7. Able to provide written informed consent 8. Considered fit for intensive chemotherapy with anthracyclines by treating physician