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Abstract：
Vantictumab is a fully human monoclonal antibody that inhibits Wnt pathway signaling through binding FZD1, 2, 5, 7, and 8 receptors. This phase Ib study evaluated vantictumab in combination with nab-paclitaxel and gemcitabine in patients with untreated metastatic pancreatic adenocarcinoma. Patients received vantictumab at escalating doses in combination with standard dosing of nab-paclitaxel and gemcitabine according to a 3 + 3 design. A total of 31 patients were treated in 5 dosing cohorts. Fragility fractures attributed to vantictumab occurred in 2 patients in Cohort 2 (7 mg/kg every 2 weeks), and this maximum administered dose (MAD) on study was considered unsafe. The dosing schedule was revised to every 4 weeks for Cohorts 3 through 5, with additional bone safety parameters added. Sequential dosing of vantictumab followed by nab-paclitaxel and gemcitabine was also explored. No fragility fractures attributed to vantictumab occurred in these cohorts; pathologic fracture not attributed to vantictumab was documented in 2 patients. The study was ultimately terminated due to concerns around bone-related safety, and thus the maximum tolerated dose (MTD) of the combination was not determined. The MAD of vantictumab according to the revised dosing schedule was 5 mg/kg (n = 16).
摘要：
Vantictumab是一种完全的人单克隆抗体，通过结合FZD1、2、5、7和8受体来抑制Wnt途径信号传导。这项Ib期研究评估了vantictummab与nab-紫杉醇和吉西他滨联合治疗未经治疗的转移性胰腺癌患者。根据3+3设计，患者接受递增剂量的vantictummab与标准剂量的nab-紫杉醇和吉西他滨组合。总共31名患者在5个给药队列中接受治疗。由vantictummab引起的脆性骨折发生在第2组患者中（每2周7mg/kg），研究中的最大给药剂量（MAD）被认为是不安全的。对于队列3至5,将给药方案修改为每4周一次,增加了额外的骨安全参数。还探索了vantictummab随后nab-紫杉醇和吉西他滨的顺序给药。在这些队列中没有发生归因于vantictumab的脆性骨折；在2例患者中记录了非归因于vantictumab的病理性骨折。这项研究最终终止，因为担心骨骼相关的安全性，因此未确定组合的最大耐受剂量(MTD)。根据修订的给药方案,vantictummab的MAD为5mg/kg(n=16)。
