University of Colorado Cancer Center, Aurora, CO, USA.
University of Washington Seattle Cancer Care Alliance, Seattle, WA, USA.
Invest New Drugs. 2018 Oct;36(5):836-847. doi: 10.1007/s10637-018-0560-6. Epub 2018 Jan 15.
Purpose and Methods Trop-2 is a glycoprotein over-expressed in many solid tumors but at low levels in normal human tissue, providing a potential therapeutic target. We conducted a phase 1 dose-finding study of PF-06664178, an antibody-drug conjugate that targets Trop-2 for the selective delivery of the cytotoxic payload Aur0101. The primary objective was to determine the maximum tolerated dose and recommended phase 2 dose. Secondary objectives included further characterization of the safety profile, pharmacokinetics and antitumor activity. Eligible patients were enrolled and received multiple escalating doses of PF-06664178 in an open-label and unblinded manner based on a modified continual reassessment method. Results Thirty-one patients with advanced or metastatic solid tumors were treated with escalating doses of PF-06664178 given intravenously every 21 days. Doses explored ranged from 0.15 mg/kg to 4.8 mg/kg. Seven patients experienced at least one dose limiting toxicity (DLT), either neutropenia or rash. Doses of 3.60 mg/kg, 4.2 mg/kg and 4.8 mg/kg were considered intolerable due to DLTs in skin rash, mucosa and neutropenia. Best overall response was stable disease in 11 patients (37.9%). None of the patients had a partial or complete response. Systemic exposure of PF-06664178 increased in a dose-related manner. Serum concentrations of free Aur0101 were substantially lower than those of PF-06664178 and total antibody. No correlation of Trop-2 expression and objective response was observed, although Trop-2 overexpression was not required for study entry. The intermediate dose of 2.4 mg/kg appeared to be the highest tolerated dose, but this was not fully explored as the study was terminated early due to excess toxicity. Conclusion PF-06664178 showed toxicity at high dose levels with modest antitumor activity. Neutropenia, skin rash and mucosal inflammation were dose limiting toxicities. Findings from this study may potentially aid in future antibody drug conjugate design and trials.
目的和方法 Trop-2 是一种在许多实体瘤中过度表达的糖蛋白，但在正常人体组织中低表达，为潜在的治疗靶点。我们进行了 PF-06664178 的 I 期剂量探索研究，PF-06664178 是一种靶向 Trop-2 的抗体药物偶联物，用于选择性递送细胞毒性有效载荷 Aur0101。主要目的是确定最大耐受剂量和推荐的 II 期剂量。次要目标包括进一步确定安全性特征、药代动力学和抗肿瘤活性。合格的患者以开放标签和非盲法的方式根据改良的连续再评估方法，按递增剂量接受 PF-06664178 治疗。结果 31 名患有晚期或转移性实体瘤的患者接受了静脉注射每 21 天一次的递增剂量的 PF-06664178 治疗。探索的剂量范围从 0.15mg/kg 到 4.8mg/kg。7 名患者经历了至少一次剂量限制性毒性（DLT），即中性粒细胞减少或皮疹。由于皮肤皮疹、粘膜和中性粒细胞减少的 DLT，3.60mg/kg、4.2mg/kg 和 4.8mg/kg 的剂量被认为是不可耐受的。11 名患者（37.9%）的最佳总体反应为疾病稳定。没有患者有部分或完全缓解。PF-06664178 的全身暴露呈剂量相关性增加。游离 Aur0101 的血清浓度明显低于 PF-06664178 和总抗体。虽然 Trop-2 过表达不是入组研究的必要条件，但未观察到 Trop-2 表达与客观缓解之间的相关性。中间剂量 2.4mg/kg 似乎是可耐受的最高剂量，但由于毒性过高，研究提前终止，因此尚未完全探索。结论 PF-06664178 在高剂量水平下显示出毒性，抗肿瘤活性适中。中性粒细胞减少、皮疹和粘膜炎症是剂量限制性毒性。这项研究的结果可能有助于未来的抗体药物偶联物设计和试验。
