Abstract：
Sym013 contains six humanized monoclonal antibodies that bind to non-overlapping epitopes on three human epidermal growth factor receptors (HER1-3). Preclinical studies suggested Sym013 strongly suppresses growth of multiple epithelial tumors. This is a first-in-human study exploring safety and efficacy of Sym013 in patients with advanced epithelial malignancies.
Dose escalation used single-patient cohorts until the stopping rule was met, followed by 3 + 3 design. Dose levels planned were: 1, 2, 4, 6, 9, 12, 15, and 18 mg/kg. Treatment cycles were 28 days with imaging every eight weeks. Serum samples were collected at multiple time points for assessment of pharmacokinetics and development of anti-drug antibodies.
Thirty-two patients were enrolled with multiple solid tumors, most common being colorectal cancer (CRC; 10/32, 31%). Due to mucositis, rash, and diarrhea at 4 mg/kg once-weekly, dosing was changed to biweekly (Q2W). Mandatory prophylaxis was added due to Grade 3 infusion-related reaction and oral mucositis at 9 mg/kg Q2W. The 15 mg/kg Q2W cohort was enrolling when the study was terminated for business reasons. Most common adverse events were skin (81%) and gastrointestinal (75%) disorders, including dermatitis/rash, stomatitis, and diarrhea. One patient with CRC achieved a partial response; 12 patients with varied malignancies had stable disease.
During the conduct of the study, management of frequent infusion-related reactions, skin toxicities, and mucosal disorders, which are indicative of HER inhibition, necessitated multiple protocol amendments. The investigators, in concert with the Sponsor, agreed that achieving a tolerated regimen with acceptable target saturation was unlikely.
www.
gov ; NCT02906670 (September 20, 2016).
Dose escalation used single-patient cohorts until the stopping rule was met, followed by 3 + 3 design. Dose levels planned were: 1, 2, 4, 6, 9, 12, 15, and 18 mg/kg. Treatment cycles were 28 days with imaging every eight weeks. Serum samples were collected at multiple time points for assessment of pharmacokinetics and development of anti-drug antibodies.
Thirty-two patients were enrolled with multiple solid tumors, most common being colorectal cancer (CRC; 10/32, 31%). Due to mucositis, rash, and diarrhea at 4 mg/kg once-weekly, dosing was changed to biweekly (Q2W). Mandatory prophylaxis was added due to Grade 3 infusion-related reaction and oral mucositis at 9 mg/kg Q2W. The 15 mg/kg Q2W cohort was enrolling when the study was terminated for business reasons. Most common adverse events were skin (81%) and gastrointestinal (75%) disorders, including dermatitis/rash, stomatitis, and diarrhea. One patient with CRC achieved a partial response; 12 patients with varied malignancies had stable disease.
During the conduct of the study, management of frequent infusion-related reactions, skin toxicities, and mucosal disorders, which are indicative of HER inhibition, necessitated multiple protocol amendments. The investigators, in concert with the Sponsor, agreed that achieving a tolerated regimen with acceptable target saturation was unlikely.
www.
gov ; NCT02906670 (September 20, 2016).
摘要：
Sym013含有六种人源化单克隆抗体,其结合三种人表皮生长因子受体(HER1-3)上的非重叠表位。临床前研究表明Sym013强烈抑制多发性上皮肿瘤的生长。这是一项首次在人类研究中探索Sym013在晚期上皮恶性肿瘤患者中的安全性和有效性。
剂量递增使用单患者队列，直到满足停止规则，其次是3+3设计。计划的剂量水平为:1、2、4、6、9、12、15和18mg/kg。治疗周期为28天,每八周成像。在多个时间点收集血清样品以评估药代动力学和抗药物抗体的开发。
32例患者纳入多发性实体瘤，最常见的是结直肠癌（CRC；10/32，31%）。由于粘膜炎,皮疹,和腹泻4毫克/公斤，每周一次，剂量改为每两周一次（Q2W）。由于3级输注相关反应和9mg/kgQ2W的口腔粘膜炎，增加了强制性预防。当研究因商业原因终止时，15mg/kgQ2W队列正在注册。最常见的不良事件是皮肤（81％）和胃肠道（75％）疾病，包括皮炎/皮疹，口腔炎,和腹泻。1例CRC患者获得部分缓解；12例恶性肿瘤患者病情稳定。
在研究进行期间，频繁输液相关反应的管理，皮肤毒性，粘膜疾病，这表明了她的抑制作用，需要多个协议修正案。调查人员,与赞助商合作，一致认为不可能实现具有可接受的目标饱和度的耐受方案.
www.
gov；NCT02906670（2016年9月20日）。
剂量递增使用单患者队列，直到满足停止规则，其次是3+3设计。计划的剂量水平为:1、2、4、6、9、12、15和18mg/kg。治疗周期为28天,每八周成像。在多个时间点收集血清样品以评估药代动力学和抗药物抗体的开发。
32例患者纳入多发性实体瘤，最常见的是结直肠癌（CRC；10/32，31%）。由于粘膜炎,皮疹,和腹泻4毫克/公斤，每周一次，剂量改为每两周一次（Q2W）。由于3级输注相关反应和9mg/kgQ2W的口腔粘膜炎，增加了强制性预防。当研究因商业原因终止时，15mg/kgQ2W队列正在注册。最常见的不良事件是皮肤（81％）和胃肠道（75％）疾病，包括皮炎/皮疹，口腔炎,和腹泻。1例CRC患者获得部分缓解；12例恶性肿瘤患者病情稳定。
在研究进行期间，频繁输液相关反应的管理，皮肤毒性，粘膜疾病，这表明了她的抑制作用，需要多个协议修正案。调查人员,与赞助商合作，一致认为不可能实现具有可接受的目标饱和度的耐受方案.
www.
gov；NCT02906670（2016年9月20日）。
