Publication | Closed Access
First-in-human study of ABBV-075 (mivebresib), a pan-inhibitor of bromodomain and extra terminal (BET) proteins, in patients (pts) with relapsed/refractory (RR) acute myeloid leukemia (AML): Preliminary data.
13
Citations
0
References
2018
Year
ImmunologyPathologyFirst-in-human StudyTumor BiologyMyeloid NeoplasiaHematological MalignancyOncologyRr AmlHematologyNovel TherapyMolecular OncologyCancer ResearchPart 1Myeloid LeukemiaCancer TreatmentPart 2Adult T-cell Leukemia-lymphomaMedicineExtra Terminal
7019 Background: Pts with RR AML have a poor prognosis. BET proteins bind acetylated histone tails, leading to the upregulation of oncogenic target genes; their inhibition can block aberrant transcription in tumor models. ABBV-075 is a pan-BET inhibitor with antitumor activity in vitro and in xenograft models of AML. This 2-part first-in-human study assesses the safety and PK of ABBV-075 at various monotherapy or combination dosing schedules (NCT02391480). In part 1, the recommended phase 2 dose for ABBV-075 monotherapy in pts with solid tumors was identified. Here, we report preliminary data from part 2 in pts with RR AML. Methods: Adult pts with RR AML received daily ABBV-075 as monotherapy (ABBV075-mono) or combined with venetoclax (ABBV075-VEN). The dose-limiting toxicity (DLT) period was 28 d (ABBV075-mono) or 21 d (ABBV075-VEN). Thrombocytopenia was not considered a DLT. Results: As of 1 Jan 2018, 19 pts (median age: 65 y [range, 30–78]; 14 pts had ≥3 prior therapies) were enrolled: 12 pts in ABBV075-mono, 7 in ABBV075-VEN cohorts. Median time on treatment was 39 d (range, 3–213). There were no DLTs; 16 pts experienced AEs. AEs irrespective of causality in > 3 pts were: anemia (11), fatigue (11), dysgeusia (10), nausea (9), diarrhea (7), decreased appetite (7), febrile neutropenia (6), thrombocytopenia (6), and dry mouth, vomiting, contusion, decreased platelet count, decreased weight, hyponatremia, and hemoptysis (4 each). 15 pts had grade ≥3 AEs (anemia [11]); 13 pts had serious AEs (febrile neutropenia [4]). 10 pts died of causes unrelated to ABBV-075, 5/10 pts due to AML progression. In ABBV075-mono cohorts, bone marrow blast count was ≤50% of baseline in 4/11 evaluable pts. 1 pt (female; normal cytogenetics; STAG2 mut) reached complete remission with incomplete hematologic recovery (thrombocytopenia) in cycle 5, still maintained at 8 m from treatment start. At cutoff date, the median overall survival for all pts was 3.2 m, and 4 pts were still in treatment without progression for 1, 6, 20, and 24 w. Enrollment is ongoing. Conclusions: ABBV-075 was well tolerated and showed antileukemic effects in pts with RR AML. Clinical trial information: NCT02391480.