This phase II clinical trial evaluates the efficacy and tolerability of the non-intensive treatment with venetoclax and the hypomethylating agent azacitidine as compared to the standard of care chemotherapy plus gemtuzumab ozogamicin in newly diagnosed NPM1 mutated AML patients fit for intensive chemotherapy.
A signed informed consent
Newly diagnosed CD33-positive AML with NPM1 mutation according to WHO criteria
Age 18-70 years
Fit for intensive chemotherapy, defined by
Activating FLT3 mutation
Relapsed or refractory AML
AML after antecedent myelodysplasia (MDS) with prior cytotoxic treatment
Prior history of malignancy, other than MDS, unless the subject has been free of the disease for ≥ 1 year prior to start of study treatment (exceptions are basal or squamous cell carcinoma of the skin, carcinoma in situ of the cervix or of the breast, incidental histologic finding of prostate cancer (T1a or T1b using the tumor, node, metastasis clinical staging system))
Parallel
Venetoclax plus Azacitidine
DrugInduction cycle 1: 100 mg venetoclax p.o. on day 1; 200 mg venetoclax p.o. on day 2; 400 mg venetoclax p.o. on days 3-28; 75 mg/m\^2 azacitidine s.c. on days 1-7 Induction cycles 2-3: 400 mg venetoclax p.o. on days 1-28; 75 mg/m\^2 azacitidine s.c. on days 1-7 Postremission cycles 1-9: 400 mg venetoclax p.o. on days 1-28; 75 mg/m\^2 azacitidine s.c. on days 1-7
standard of care chemotherapy plus gemtuzumab ozogamicin
DrugInduction cycle 1: 200 mg/m\^2 cytarabine cont inf i.v. on days 1-7; 60 mg/m\^2 daunorubicin i.v. on days 3-5; 3 mg/m\^2 (max 1 vial) gemtuzumab ozogamicin i.v. on days 1+4+7 Induction cycle 2 (patients not in remission, moderate or non-responders): 3000/1000 mg/m\^2 cytarabine i.v. BID on days 1-3; 10 mg/m\^2 mitoxantrone i.v. on days 3-5 Postremission cycles 1-3: 3000/1000 mg/m\^2 cytarabine i.v. BID on days 1-3
modified event-free survival (mEFS)
* Failure to achieve a CR/CRi/CRh after a maximum of two induction cycles in the control arm (SOC) or three induction cycles in the investigational arm (VEN+AZA), i.e. primary induction failure * Hematologic relapse after previous CR/CRi/CRh * Molecular failure, defined as either * Molecular progression, defined as confirmed ≥ 1 log10 increase of NPM1 MRD level in any two samples in a patient without prior MRD negativity or * Molecular relapse after previous MRD negativity, defined as confirmed ≥ 1 log10 between two consecutive positive samples in a patient who was previously tested as MRD negative * Death
Tolerability of treatment
cumulative occurence of CTCAE grade 3 and grade 4 adverse events
Remission (CR/CRi/CRh) rate
CR/CRi/CRh rate is defined as the proportion of patients, who achieved a CR or CRi or CRh during study participation.
molecular response rate
Proportion of patients with absence of detectable NPM1 mutant transcripts or with detectable NPM1 mutant transcripts who do not meet any of the definitions of molceular failure during study participation.
molecular persistence rate
Proportion of patients with detectable NPM1 mutant transcripts present after four cycles of treatment with less than a 4 log10 reduction from baseline.
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Technische Universität Dresden
Lead sponsor
AbbVie
Collaborator
University Hospital Heidelberg
Collaborator
