Combination of azacitidine (AZA) for 7 days every 28 days with a continuous daily exposure to Venetoclax (VEN), an oral bcl-2 inhibitor, is now approved for the treatment of acute myeloid leukemia (AML) in patients ineligible for intensive chemotherapy due to age (\>75 years) or comorbidities. VEN+AZA showed significant overall response rate and survival benefit but combination carries a risk of considerable toxicity (such as profound/prolonged cytopenia and infections) before but also after remission. These toxicities make it difficult to apply the recommended treatment regimen, in particular the continuous daily intake of VEN. Recent reports suggest that reducing VEN duration per cycle seems safe and feasible. We propose to investigate a reduced-intensity VEN regimen (7-day dosing/28) versus the standard continuous VEN therapy (28-day dosing/28), combined with AZA, with the primary goal of maintaining efficacy while reducing associated toxicity.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
262
Venetoclax 400 mg orally once Daily
75 mg/m2 Subcutaneous (SC) or intravenous (IV) Daily with a continuous 7-day scheme or on a 5-on/2-off \[weekend\]/2-on schedule (5-0-2) in 28-day cycle
Gustave Roussy
Villejuif, France
Proportion of subjects with complete remission or complete remission with incomplete marrow recovery (CR/CRi)
This proportion will be calculated based on current IWG criteria for AML
Time frame: at any time point during the study (at 30 days, 60 days, 3 years)
Overall survival (OS)
Time frame: at 30 days, 60 days, 1, 2 and 3 years
Event-Free Survival (EFS)
Defined as the number of days from the date of randomization to the date of treatment failure, hematologic relapse from CR/CRh/CRi or death from any cause, whichever occurs first.
Time frame: at 30 days, 60 days, 1, 2 and 3 years
Early mortality rate
Time frame: At day 60
Time to first response
Defined as the number of days from the date of randomization to the date of earliest CR or CRi
Time frame: at 30 days, 60 days, 1, 2 and 3 years
Time to best response
Defined as the number of days from the date of randomization to the date of CR (or CRi if patients never reached CR).
Time frame: at 30 days, 60 days, 1, 2 and 3 years
Duration of response (DoR)
Among subjects who achieved CR and CRi, duration of response (DOR) will be calculated as the date of the first response to the date of first documented disease relapse, disease progression, treatment failure, or death.
Time frame: at 30 days, 60 days, 1, 2 and 3 years
Venetoclax (VEN) scheme modification (dosing schedule modification, delays >2 days or discontinuation)
Defined as the proportion of CR/CRi patients that presented treatment modification not authorized by protocol as VEN schedule modification (dose, duration), delay \>2 days from the initial Day of the subsequent cycle and/or temporary/definitive VEN discontinuation.
Time frame: until the last cycle of treatment (up to 3 years)
Platelet transfusion requirement
measured by the number of platelet concentrates received by patient during each cycle from cycle 1 day 1 to relapse or last day of cycle 6.
Time frame: At 24 weeks
Febrile neutropenia or severe infection (grade III/IV) incidence
measured by the number of episodes of febrile neutropenia or severe infection (grade III/IV) by patient during each cycle from cycle 1 day 1 to relapse or last day of cycle 6.
Time frame: At 24 weeks
Hospitalization requirement and length stay
Hospitalization requirement will be defined as number of all hospitalization longer than 24h during each cycle from Cycle 1 Day 1 to relapse or last day of Cycle 6. Hospitalization length stay will be defined by the addition of number of days of each hospitalization longer than 24h during each cycle from cycle 1 day 1 to relapse or last day of cycle 6.
Time frame: At 24 weeks
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