First-in-human study of mivebresib (ABBV-075), an oral pan-inhibitor of bromodomain and extra terminal proteins, in patients with relapsed/refractory solid tumors

SA Piha-Paul, JC Sachdev, M Barve, P LoRusso… - Clinical Cancer …, 2019 - AACR
SA Piha-Paul, JC Sachdev, M Barve, P LoRusso, R Szmulewitz, SP Patel, PN Lara Jr…
Clinical Cancer Research, 2019AACR
Purpose: Bromodomain and extraterminal (BET) proteins play important roles in
transcriptional regulation relevant to cancer pathogenesis, and therapeutic
targeting/inhibition of BET causes apoptosis of cancer cells in vitro. In this first-in-human
study of the pan-BET inhibitor mivebresib (ABBV-075), the safety profile, MTD, and
recommended phase II dose (RP2D) were determined in patients with advanced solid
tumors. Patients and Methods: A 3+ 3 dose escalation for different mivebresib dosing …
Purpose
Bromodomain and extraterminal (BET) proteins play important roles in transcriptional regulation relevant to cancer pathogenesis, and therapeutic targeting/inhibition of BET causes apoptosis of cancer cells in vitro. In this first-in-human study of the pan-BET inhibitor mivebresib (ABBV-075), the safety profile, MTD, and recommended phase II dose (RP2D) were determined in patients with advanced solid tumors.
Patients and Methods
A 3 + 3 dose escalation for different mivebresib dosing schedules [daily, Monday/Wednesday/Friday (M-W-F), 4 days on/3 off (4/7)] was followed by dose expansion in patients with prostate cancer. Endpoints were safety, tolerability, pharmacokinetics, and preliminary antitumor activity.
Results
Seventy-two patients with solid tumors (14% uveal melanoma; 11% colorectal; 11% breast; 8% pancreatic; 7% head/neck; 49% others) were treated with mivebresib during dose escalation, and 12 additional patients with prostate cancer in expansion cohort. Most common treatment-emergent adverse events (TEAE) related to mivebresib were dysgeusia (49%), thrombocytopenia (48%), fatigue (26%), and nausea (25%). Most common grade 3/4 TEAEs related to mivebresib were thrombocytopenia (35%) and anemia (6%). Dose-limiting toxicities included thrombocytopenia (2 mg daily; 4.5 mg M-W-F), gastrointestinal bleed (2 mg daily), hypertension (2–3 mg 4/7), fatigue, decreased appetite, and aspartate aminotransferase elevation (4 mg M-W-F). Of 61 evaluable patients from dose escalation, 26 (43%) had stable disease and 35 (57%) had progressive disease. Median progression-free survival was 1.8 months (95% confidence interval, 1.8–1.9).
Conclusions
On the basis of safety and tolerability, mivebresib RP2D is 1.5 mg for the daily schedule, 2.5 mg for 4/7, and 3 mg for M-W-F. Mivebresib has a tolerable safety profile, and stable disease was observed in some patients with malignant solid tumors.
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