Results of the first-in-human study of ABBV-075 (mivebresib), a pan-inhibitor of bromodomain (BD) and extra terminal (BET) proteins, in patients (pts) with relapsed/refractory (R/R) solid tumors.

Abstract

2510Background: BDs are protein domains that bind to acetylated histone tails, leading to upregulation of target genes driving oncogenesis. Inhibition of the BET family prevents assembly of the macromolecular complex and its transcriptional response. ABBV-075 is a pan-BET inhibitor that induces death in cell lines and tumor growth inhibition in xenograft models. This first-in-human, phase 1, two-part study (NCT02391480) assessed the safety and pharmacokinetics of ABBV-075 in pts with advanced tumors. Results from the dose escalation part in pts with solid tumors are reported. Methods: The dose escalation part of this open-label study enrolled adult pts with R/R solid tumors in a 3+3 fashion. Endpoints included maximum tolerated dose, recommended phase 2 dose (RP2D) at different ABBV-075 dosing schedules (daily, Monday/Wednesday/Friday [MWF], or 4 days on/3 off [4/7]), safety and preliminary efficacy. Results: As of Dec 2017, 72 pts with solid tumors enrolled in the dose escalation cohort. Most common tumors were: uveal/choroidal melanoma (n = 10); breast (n = 8); pancreatic (n = 6); head and neck (n = 5); and prostate (n = 3). Median age was 61.5 years (range 23–83); median treatment duration was 7.6 weeks (range 0.9–39.6). In total, 23, 27, and 22 pts entered the daily, MWF and 4/7 schedules. Overall, 71 pts (98.6\%) reported ≥1 treatment-emergent adverse events (TEAEs); thrombocytopenia (56.9\%), dysgeusia (48.6\%), fatigue (43.1\%) and nausea (34.7\%) were most common. Grade 3/4 TEAEs were reported in 52 pts (72.2\%); thrombocytopenia (30.6\%) and anemia (15.3\%) were most common; 11 pts died (none considered study drug related). Dose-limiting toxicities included thrombocytopenia, fatigue, aspartate aminotransferase elevation, gastrointestinal bleed and hypertension. The RP2D is 1.5 mg for the daily schedule, 2.5 mg for 4/7 and 3 mg for MWF. Of 65 evaluable pts, 25 pts (38.5\%) had stable disease and 40 pts (61.5\%) had progressive disease. Median progression-free survival was 1.8 months (95\% CI: 1.8, 1.9). Conclusions: ABBV-075 has a tolerable safety profile and led to stable disease in some pts with malignant solid tumors. Clinical trial information: NCT02391480.