A Phase I/II Open-Label Cohort Evaluating the Safety and Efficacy of a Tagraxofusp, Venetoclax, Cladribine, Cytarabine Induction Regimen, leading into a Randomised Open-label Cohort Evaluating Safety and Efficacy of a Tagraxofusp, Venetoclax, Cladribine, Cytarabine Induction Regimen Compared with Intensive Chemotherapy in Fit Adults with Newly Diagnosed Acute Myeloid Leukaemia

Research summary

The current standard of care in fit adults with newly diagnosed AML consists of induction chemotherapy with either DA,DA+GO,CPX351 (Vyxeos) or FLAG-Ida,depending on patient fitness and disease biology. Patients who achieve a blast clearance will then proceed to either consolidation chemotherapy or an allo-SCT dependent on both their predicted risk of relapse if treated with chemotherapy alone and their ability to proceed to transplant. In patients with a predicted risk of disease relapse greater than 40%,allo-SCT is widely recognised as a key component of the treatment algorithm for patients in CR1,providing a suitable donor is available and the patient is deemed fit enough for allo-SCT. Patients deemed ineligible for allo-SCT either because of a predicted low risk of relapse or on the grounds of patient fitness,receive further consolidation chemotherapy followed in selected patients by CC-486 (an orally administrated formulation of azacitidine) maintenance. Increased donor availability coupled with the advent of better tolerated reduced intensity conditioning (RIC) regimens has led to a substantial rise in the number of patients with AML in CR1 who proceed to allo-SCT. Two major factors currently limit allo-SCT access and represent major barriers to the delivery of a potentially curative allograft. Firstly,a significant number of adults with either adverse risk AML or older patients with intermediate risk AML do not achieve blast clearance with current induction chemotherapy regimens. Secondly,induction chemotherapy is associated with increased treatment related mortality in both these groups,which can preclude safe delivery of a subsequent allo-SCT. Taken together with the fact that the presence of high levels of pre-allo-SCT MRD is associated with an increased risk of relapse post-allo-SCT,and the fact that the toxicity of induction chemotherapy can increase allo-SCT related mortality,there is therefore an urgent requirement for the development of improved induction regimens in fit adults with allo-mandatory AML. Such innovative induction strategies should have the ability to increase the CR rate and at the same time reduce treatment related mortality. The recent development of the Bcl-2 inhibitor venetoclax (VEN) is transforming the management of unfit and,increasingly fit,adults with newly diagnosed AML. The VIALE-A trial established a VEN/HMA combination as standard of care in older,unfit patients which results in complete (CR) and partial remission (CRi) rates in the region of 50-70%. Currently a VEN/HMA combination is being explored as an alternative to intensive chemotherapy in fit adults with newly diagnosed AML in a large randomised trial. More recently,cladribine (CLAD) in combination with VEN and low dose cytarabine (LDAC),(CLAD/VEN/LDAC) has been shown to result in CR/CRi rates 93% with a 2%,day 28 mortality in fit adults with newly diagnosed AML. A recent update in an expansion cohort of 124 newly diagnosed adults with a median age of 68 confirmed these encouraging results reporting a CR/CRi rate of 85% (Separately important data has demonstrated that the addition of tagraxofusp (TAG) a first in class CD123 targeting agent,to a VEN/AZA regimen in older patients with newly diagnosed AML is well tolerated and associated with particularly encouraging response rates,and high CR (MRDneg) rates) particularly in patients with a TP53 mutation. Taken together there is therefore now a compelling rationale to examine the clinical activity and tolerability of a TAG/CLAD/VEN/LDAC induction regimen in allo-mandatory fit adults with newly diagnosed high-risk AML. We therefore wish to test this hypothesis in this phase I/II,randomised,superiority study which will examine clinical outcomes in fit adults with newly diagnosed adverse risk AML (age ≥18 to ≤70 years),or older adults with newly diagnosed intermediate risk AML (age ≥50 to ≤70 years) who are treated with the tagraxofusp,venetoclax,cytarabine and cladribine,combination compared with standard of care induction chemotherapy regimens.

Principal Investigator

Connor Sweeney

Contact us

Email: Latephasehaematology@ouh.nhs.uk

IRAS number

1012553