Abstract
Background:Bromodomain and extra‐terminal (BET) proteins bind to acetyllysines and upregulate oncogenic target genes. Mivebresib (ABBV‐075) is a pan‐BET inhibitor with antitumor activity in vitro and xenograft models of AML. This 2‐part phase 1 study evaluates the safety and pharmacokinetics of mivebresib at monotherapy or combination dosing schedules in patients with solid tumors (part 1) and acute myeloid leukemia (AML; part 2) (NCT02391480).Aims:Here, we report preliminary data from part 2 in patients with relapsed/refractory (RR) AML.Methods:Mivebresib monotherapy (MIV‐mono), or combined with venetoclax (MIV‐VEN), were administered daily to adult patients with AML. The dose‐limiting toxicity (DLT) period was 28 d.Results:As of Dec 2018, 41 patients (median age: 69 y [range, 29–84]; 19 patients had >2 prior therapies) were enrolled: 19 in MIV‐mono (5 of whom switched to MIV‐combo) and 22 who began treatment in MIV‐VEN cohorts. 23 patients had high cytogenetic risk. Median time on treatment was 28 d (range, 8–562). There were no DLTs. All patients experienced a treatment‐emergent adverse event (AE), most commonly (≥40% patient incidence), fatigue (56%), dysgeusia (46%), decreased appetite (44%), diarrhoea (42%), nausea (42%), vomiting (42%). 40 patients had grade ≥3 AEs (febrile neutropenia (37%), anemia (34%) and thrombocytopenia (32%). 33 patients had serious AEs, most commonly febrile neutropenia (19%). 25 deaths were reported; 15 patients died of causes unrelated to mivebresib and 10 patients due to AML progression. The median best % bone marrow blast change for 26 evaluable patients was −20% (range, −98% to +300%). Gene expression analysis in pre‐ and post‐treatment peripheral blood samples showed that HEXIM1, DCXR and CD93 genes were reliable PD biomarkers of ABBV‐075 which were consistently modulated in a dose‐dependent manner. At the cutoff date, median overall survival for all patients was 2.6 m.Summary/Conclusion:Mivebresib was well tolerated and showed antileukemic effects in patients with RR AML.
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