First-in-Human Trial of a Novel Anti-Trop-2 Antibody-SN-38 Conjugate, Sacituzumab Govitecan, for the Treatment of Diverse Metastatic Solid Tumors.
First-in-Human Trial of a Novel Anti-Trop-2 Antibody-SN-38 Conjugate, Sacituzumab Govitecan, for the Treatment of Diverse Metastatic Solid Tumors.
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DOI：
10.1158/1078-0432.ccr-14-3321
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发表时间：
2015-09-01
期刊：
影响因子：
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通讯作者：
Goldenberg DM
中科院分区：
文献类型：
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作者：
Starodub AN;Ocean AJ;Shah MA;Guarino MJ;Picozzi VJ Jr;Vahdat LT;Thomas SS;Govindan SV;Maliakal PP;Wegener WA;Hamburger SA;Sharkey RM;Goldenberg DM
Sacituzumab govitecan（IMMU-132）是一种靶向Trop-2（一种在许多上皮肿瘤上表达的表面糖蛋白）的抗体-药物偶联物（ADC），用于递送伊立替康的活性代谢产物SN-38。这项I期试验评估了这种ADC作为各种转移性实体癌预治疗患者的潜在治疗药物。在21天周期的第1天和第8天给予Sacituzumab govitecan，重复周期直至剂量限制性毒性或进展。剂量递增遵循标准的3 + 3方案，包括4个计划剂量水平，允许延迟给药或减量。25例患者（52-60岁，3种中位既往化疗方案）接受8（N=7）、10（N=6）、12（N=9）和18（N=3）mg/kg剂量水平治疗。中性粒细胞增多素具有剂量限制性，第1周期的最大耐受剂量为12 mg/kg，但重复周期毒性太大。较低剂量对于扩展治疗是可接受的，没有治疗相关的4级毒性，3级毒性限于疲劳（N=3）、中性粒细胞减少症（N=2）、腹泻（N=1）和白细胞减少症（N=1）。使用基于CT的RECIST 1.1，2例患者达到部分缓解（三阴性乳腺癌、结肠癌），另外16例患者的最佳缓解为疾病稳定。12例患者继续治疗16-36周，维持疾病控制; 6例存活15-20+个月。没有进行基于肿瘤Trop-2表达的患者预选。Sacituzumab govitecan在难治性癌症患者中具有可接受的毒性和令人鼓舞的治疗活性。II期研究选择8和10 mg/kg剂量。
Sacituzumab govitecan (IMMU-132) is an antibody-drug conjugate (ADC) targeting Trop-2, a surface glycoprotein expressed on many epithelial tumors, for delivery of SN-38, the active metabolite of irinotecan. This Phase I trial evaluated this ADC as a potential therapeutic for pretreated patients with a variety of metastatic solid cancers. Sacituzumab govitecan was administered on days 1 and 8 of 21-day cycles, with cycles repeated until dose-limiting toxicity or progression. Dose escalation followed a standard 3 + 3 scheme with 4 planned dose levels and dose delay or reduction allowed. Twenty-five patients (52-60 years old, 3 median prior chemotherapy regimens) were treated at dose levels of 8 (N=7), 10 (N=6), 12 (N=9), and 18 (N=3) mg/kg. Neutropenia was dose-limiting, with 12 mg/kg the maximum tolerated dose for cycle 1, but too toxic with repeated cycles. Lower doses were acceptable for extended treatment with no treatment-related grade 4 toxicities and grade 3 toxicities limited to fatigue (N=3), neutropenia (N=2), diarrhea (N=1), and leukopenia (N=1). Using CT-based RECIST 1.1, two patients achieved partial responses (triple-negative breast cancer, colon cancer) and 16 others had stable disease as best response. Twelve patients maintained disease control with continued treatment for 16-36 weeks; 6 survived 15-20+ months. No pre-selection of patients based on tumor Trop-2 expression was done. Sacituzumab govitecan had acceptable toxicity and encouraging therapeutic activity in patients with difficult-to-treat cancers. The 8 and 10 mg/kg doses were selected for Phase II studies.