Shapiro Geoffrey I, Vaishampayan Ulka N, LoRusso Patricia, Barton Jeremy, Hua Steven, Reich Steven D, Shazer Ronald, Taylor Carrie T, Xuan Dawei, Borghaei Hossein
Early Drug Development Center, Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Mayer 446, Boston, MA, 02215, USA.
Karmanos Cancer Institute, Detroit, MI, USA.
Invest New Drugs. 2017 Jun;35(3):315-323. doi: 10.1007/s10637-016-0419-7. Epub 2017 Jan 9.
Background The antibody-drug conjugate PF-06263507 targets the cell-surface, tumor-associated antigen 5T4 and consists of a humanized IgG1 conjugated to the microtubule-disrupting agent monomethylauristatin-F by a non-cleavable maleimidocaproyl linker. In this first-in-human, dose-finding trial (NCT01891669), we evaluated safety, pharmacokinetics, and preliminary antitumor activity of PF-06263507 in pretreated patients with advanced solid tumors, unselected for 5T4 expression. starting at 0.05 mg/kg, with 25, 56, and 95% dose increments, depending on observed dose-limiting toxicities (DLTs), applying a modified continual reassessment method. Results Twenty-six patients received PF-06263507 at 0.05 to 6.5 mg/kg. The first DLT, grade 3 photophobia, occurred at 4.34 mg/kg and two additional DLTs, grade 2 keratitis and grade 1 limbal stem cell deficiency (> 2-week dosing delay), at 6.5 mg/kg. The most common adverse events (AEs) were fatigue (38.5%), photophobia (26.9%), and decreased appetite, dry eye, nausea, and thrombocytopenia (23.1% each). No treatment-related grade 4-5 AEs were reported. Systemic exposure of PF-06263507 increased in a dose-related manner. At the maximum tolerated dose (MTD, 4.34 mg/kg), mean terminal half-life for PF-06263507 and unconjugated payload were ~6 and 3 days, respectively. Payload serum concentrations were substantially lower compared with PF-06263507. No objective responses were observed. Conclusions The MTD and recommended phase II dose were determined to be 4.34 mg/kg. Ocular toxicities accounted for the DLTs observed, as previously reported with monomethylauristatin-F payloads. Further studies are warranted to investigate clinical activity of this agent in patients with 5T4-expressing tumors.Trial registration ID: NCT01891669.
背景 抗体药物偶联物PF-06263507靶向细胞表面肿瘤相关抗原5T4，由人源化IgG1通过不可裂解的马来酰亚胺己酰接头与微管破坏剂单甲基澳瑞他汀-F偶联而成。在这项首次人体剂量探索试验（NCT01891669）中，我们评估了PF-06263507在未经选择5T4表达的晚期实体瘤预处理患者中的安全性、药代动力学和初步抗肿瘤活性。起始剂量为0.05mg/kg，根据观察到的剂量限制毒性（DLT），以25%、56%和95%的剂量递增，采用改良的连续重新评估方法。结果 26例患者接受了0.05至6.5mg/kg的PF-06263507治疗。首次DLT为3级畏光，发生在4.34mg/kg，另外两次DLT分别为2级角膜炎和1级角膜缘干细胞缺乏（给药延迟>2周），发生在6.5mg/kg。最常见的不良事件（AE）为疲劳（38.5%）、畏光（26.9%）以及食欲下降、干眼、恶心和血小板减少（各23.1%）。未报告与治疗相关的4-5级AE。PF-06263507的全身暴露呈剂量相关增加。在最大耐受剂量（MTD，4.34mg/kg）时，PF-06263507和未偶联的有效载荷的平均终末半衰期分别约为6天和3天。有效载荷血清浓度与PF-06263507相比显著较低。未观察到客观缓解。结论 MTD和推荐的II期剂量确定为4.34mg/kg。眼部毒性导致了观察到的DLT，如先前用单甲基澳瑞他汀-F有效载荷报道的那样。有必要进一步研究该药物在5T4表达肿瘤患者中的临床活性。试验注册号：NCT01891669。
