Open AccessPF254 RESULTS FROM THE FIRST‐IN‐HUMAN STUDY OF MIVEBRESIB (ABBV‐075), A PAN‐INHIBITOR OF BROMODOMAIN AND EXTRA TERMINAL PROTEINS, IN PATIENTS WITH RELAPSED/REFRACTORY ACUTE MYELOID LEUKEMIA
Author(s) -
Borthakur G.,
Odenike O.,
Wolff J.E.,
Aldoss I.,
Rizzieri D.,
Prebet T.,
Hu B.,
Dinh M.H.,
Chen X.,
Modi D.A.,
Freise K.J.,
Jonas B.A.
Publication year - 2019
Publication title -
hemasphere
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.677
H-Index - 11
ISSN - 2572-9241
DOI - 10.1097/01.hs9.0000559228.65567.1b
Subject(s) - medicine , neutropenia , nausea , febrile neutropenia , adverse effect , gastroenterology , myeloid leukemia , anemia , myeloid , dysgeusia , refractory (planetary science) , surgery , toxicity , physics , astrobiology
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.