The University of Texas MD Anderson Cancer Center, Houston, Texas.
HonorHealth Research Institute/TGen, Scottsdale, Arizona.
Clin Cancer Res. 2019 Nov 1;25(21):6309-6319. doi: 10.1158/1078-0432.CCR-19-0578. Epub 2019 Aug 16.
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 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.
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.
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).
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.
溴结构域和末端外结构域（BET）蛋白在与癌症发病机制相关的转录调控中发挥重要作用，BET 的治疗靶向/抑制会导致癌细胞凋亡。在首例泛 BET 抑制剂米维布司（ABBV-075）的人体研究中，在晚期实体瘤患者中确定了安全性概况、最大耐受剂量（MTD）和推荐的 II 期剂量（RP2D）。
不同米维布司给药方案（每日、周一/三/五（M-W-F）、4 天 ON/3 天 OFF（4/7））进行 3+3 剂量递增，随后在前列腺癌患者中进行剂量扩展。终点是安全性、耐受性、药代动力学和初步抗肿瘤活性。
72 名患有实体瘤的患者（14%葡萄膜黑色素瘤；11%结直肠癌；11%乳腺癌；8%胰腺癌；7%头颈部；49%其他）在剂量递增期间接受了米维布司治疗，12 名额外的前列腺癌患者在扩展队列中接受了治疗。与米维布司相关的最常见治疗相关不良事件（TEAE）是味觉障碍（49%）、血小板减少症（48%）、疲劳（26%）和恶心（25%）。与米维布司相关的最常见的 3/4 级 TEAE 是血小板减少症（35%）和贫血（6%）。剂量限制性毒性包括血小板减少症（每日 2 毫克；M-W-F 4.5 毫克）、胃肠道出血（每日 2 毫克）、高血压（4/7 的 2-3 毫克）、疲劳、食欲下降和天冬氨酸转氨酶升高（M-W-F 的 4 毫克）。在剂量递增中可评估的 61 名患者中，26 名（43%）病情稳定，35 名（57%）病情进展。中位无进展生存期为 1.8 个月（95%置信区间，1.8-1.9）。
基于安全性和耐受性，米维布司的 RP2D 为每日 1.5 毫克，4/7 为 2.5 毫克，M-W-F 为 3 毫克。米维布司具有可耐受的安全性特征，一些恶性实体瘤患者观察到病情稳定。
