Tolcher Anthony W, Berlin Jordan D, Cosaert Jan, Kauh John, Chan Emily, Piha-Paul Sarina A, Amaya Alex, Tang Shande, Driscoll Kyla, Kimbung Richard, Kambhampati S R Prasad, Gueorguieva Ivelina, Hong David S
South Texas Accelerated Research Therapeutics LLC, San Antonio, TX, 78229, USA.
Vanderbilt-Ingram Cancer Center, Nashville, TN, 37232, USA.
Cancer Chemother Pharmacol. 2017 Apr;79(4):673-680. doi: 10.1007/s00280-017-3245-5. Epub 2017 Mar 9.
LY3022859 is an anti-TGFβRII IgG monoclonal antibody that inhibits receptor-mediated signaling activation. The primary objective of this phase I study was to determine a phase II dose in patients with advanced solid tumors. Secondary objectives were to assess safety and pharmacokinetics (PK).
LY3022859 was infused intravenously (IV) at 1.25 mg/kg over 1 h every 2 weeks (Q2W) (cohort 1A) and at flat doses of 12.5 mg (cohort 1B) and 25 mg (cohort 2) over 3 h Q2W.
Fourteen patients were enrolled in cohorts 1A (n = 2), 1B (n = 5), and 2 (n = 7). DLTs were experienced by both patients in cohort 1A (infusion-related reaction) and 2 patients in cohort 2 (cytokine release syndrome and infusion-related reaction). No MTD was determined. At the 25 mg dose level (cohort 2), after fifth infusion, LY3022859 had a short t (4.37-7.80 h) and rapid clearance (CL, 0.412 L/h). Exposure increased twofold (from 28.5 to 60.2 μg·h/mL) with increase in dose from 12.5 to 25 mg. No accumulation was observed after repeat administration.
The MTD for LY3022859 was not determined. Dose escalation beyond 25 mg was considered unsafe due to worsening symptoms (uncontrolled cytokine release) despite prophylaxis (corticosteroids and antihistamines).
clinicaltrials.gov Identifier: NCT01646203.
LY3022859是一种抗转化生长因子β受体II（TGFβRII）IgG单克隆抗体，可抑制受体介导的信号激活。这项I期研究的主要目的是确定晚期实体瘤患者的II期剂量。次要目的是评估安全性和药代动力学（PK）。
LY3022859每2周静脉输注1小时，剂量为1.25mg/kg（队列1A），每2周静脉输注3小时，固定剂量为12.5mg（队列1B）和25mg（队列2）。
共有14名患者入组，其中队列1A有2名，队列1B有5名，队列2有7名。队列1A的两名患者（输液相关反应）和队列2的两名患者（细胞因子释放综合征和输液相关反应）出现了剂量限制性毒性（DLT）。未确定最大耐受剂量（MTD）。在25mg剂量水平（队列2），第五次输注后，LY3022859的半衰期较短（4.37 - 7.80小时），清除速度较快（清除率CL为0.412L/h）。随着剂量从12.5mg增加到25mg，暴露量增加了两倍（从28.5μg·h/mL增加到60.2μg·h/mL）。重复给药后未观察到蓄积现象。
未确定LY3022859的MTD。尽管采取了预防措施（使用皮质类固醇和抗组胺药），但由于症状恶化（细胞因子释放失控），超过25mg的剂量递增被认为不安全。
clinicaltrials.gov标识符：NCT01646203。
