Department of Internal Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, United States; Department of Internal Medicine, Weill Medical College at Cornell University, New York, NY, United States.
Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, United States.
J Hepatol. 2014 Feb;60(2):319-24. doi: 10.1016/j.jhep.2013.09.008. Epub 2013 Sep 14.
BACKGROUND & AIMS: IGF-IR is implicated in hepatic carcinogenesis. This and preliminary evidence of biological activity of anti-IGF-1R monoclonal antibody cixutumumab in phase I trials prompted this phase II study.
Patients with advanced HCC, Child-Pugh A-B8, received cixutumumab 6mg/kg weekly, in a Simon two-stage design study, with the primary endpoints being 4-month PFS and RECIST-defined response rate. Tissue and circulating markers plus different HCC scoring systems were evaluated for correlation with PFS and OS.
As a result of pre-specified futility criteria, only stage 1 was accrued: N=24: median age 67.5 years (range 49-83), KPS 80% (70-90%), 20 males (83%), 9 stage III (37%)/15 stage IV (63%), 18 Child-Pugh A (75%), 11 HBV (46%)/10 HCV (42%)/11 alcoholic cirrhosis (46%)/2 NASH (8%), 11 (46%) diabetic. Median number of doses: 7 (range 1-140). Grade 3/4 toxicities >10% included: diabetes, elevated liver function tests, hyponatremia, and lymphopenia. Four-month PFS was 30% (95% CI 13-48), and there were no objective responses. Median overall survival was 8 months (95% CI 5.8-14). IGF-R1 staining did not correlate with outcome. Elevated IGFBP-1 correlated with improved PFS (1.2 [95% CI 1-1.4]; p 0.009) and OS (1.2 [95% CI 1.1-1.4]; p 0.003).
Cixutumumab monotherapy did not have clinically meaningful activity in this unselected HCC population. Grade 3-4 hyperglycemia occurred in 46% of patients. Elevated IGFBP-1 correlated with improved PFS and OS.
IGF-IR 参与了肝肿瘤的发生。这一发现以及抗 IGF-1R 单克隆抗体 cixutumumab 在 I 期试验中的初步生物学活性证据促使我们进行了这项 II 期研究。
Child-Pugh A-B8 级的晚期 HCC 患者接受每周 6mg/kg 的 cixutumumab 治疗，采用 Simon 两阶段设计研究，主要终点为 4 个月 PFS 和 RECIST 定义的反应率。组织和循环标志物以及不同的 HCC 评分系统被评估与 PFS 和 OS 的相关性。
由于预先设定的无效标准，仅招募了第一阶段：N=24：中位年龄 67.5 岁（范围 49-83），KPS 80%（70-90%），20 名男性（83%），20 名 stage III（37%）/15 名 stage IV（63%），18 名 Child-Pugh A（75%），11 名 HBV（46%）/10 名 HCV（42%）/11 名酒精性肝硬化（46%）/2 名 NASH（8%），11 名（46%）糖尿病患者。中位剂量数：7（范围 1-140）。>10%的 3/4 级毒性包括：糖尿病、肝功能检查升高、低钠血症和淋巴细胞减少症。4 个月 PFS 为 30%（95%CI 13-48），无客观反应。中位总生存期为 8 个月（95%CI 5.8-14）。IGF-R1 染色与结局无关。IGFBP-1 升高与 PFS（1.2[95%CI 1-1.4]；p=0.009）和 OS（1.2[95%CI 1-1.4]；p=0.003）的改善相关。
在未选择的 HCC 人群中，cixutumumab 单药治疗没有临床意义上的活性。46%的患者出现 3-4 级高血糖。IGFBP-1 升高与 PFS 和 OS 的改善相关。
