今年ASCO年会ALNYLAM公司的一期临床试验的结果
报告摘要Phase I dose-escalation study of ALN-VSP02, a novel RNAi therapeutic for solid tumors with liver involvement.
Abstract:
Background: Malignancies involving the liver represent a significant unmet medical need. ALN-VSP02 is a novel RNA interference (RNAi) therapeutic comprised of lipid nanoparticle-formulated small interfering RNAs (siRNAs) targeting the expression of vascular endothelial growth factor (VEGF)-A and kinesin spindle protein (KSP).
Methods: A multicenter, open label, phase 1 dose escalation trial of ALN-VSP02 administered as a 15-minute iv infusion every two weeks was initiated in March 2009. Patients with advanced solid tumors are eligible if they have at least one measurable liver lesion and adequate liver function. The study uses a 3+3 design with 8 potential dose levels: 0.1, 0.2, 0.4, 0.7, 1.0, 1.25, 1.5, and 1.7 mg/kg. The primary objective is evaluation of safety and tolerability. Secondary objectives include assessment of PK and pharmacodynamic (PD) activity through DCE-MRI, biomarkers of angiogenesis, tumor biopsies, and response rate.
Results: As of December 2009, 12 patients (most with colorectal cancer) have been treated on the first 4 dose levels. Forty-one doses have been administered; 0.1-0.4 mg/kg ALN-VSP02 was well- tolerated, with no hepatotoxicity. The only significant adverse event (AE) was a grade 2 infusion reaction in one patient at 0.4 mg/kg that responded to slowing of the infusion. At 0.7 mg/kg, a patient with pancreatic neuroendocrine tumor extensively involving both lobes of the liver died of hepatic failure following the second dose; this was deemed possibly related to study drug. Two additional patients treated at 0.7 mg/kg did not exhibit hepatotoxicity or any other significant AEs. PK showed Cmax and AUC that were dose proportional with no accumulation. Serial DCE-MRI scans performed 2-9 days after the first dose on 8 of the 12 patients showed a ≥40% decline in Ktrans in 12 of 15 liver tumors (80%) evaluated. This decline in blood flow was associated with extensive tumor necrosis in the patient with the neuroendocrine tumor.
Conclusions: ALN-VSP02 was well-tolerated by the majority of patients across the first 4 dose levels. DCE-MRI results show preliminary evidence of an anti-VEGF effect. Accrual is continuing, and additional safety and PD data will be forthcoming.
好像说是剂量大于0.7毫克/公斤的对药物有响应的病人，大概50%有效，还是很失望，很像另一种多吉美，而不是能根治性的药物。
阿尔尼拉姆提交的给asco的报告，31个病人中，27个对药物有响应，其中12个剂量低于0.4的1人至少2个月稳定期SD,15个大于0.7的，6个人SD，一个人部分缓解。临床没显示药物毒性。
50%的比例已经不算低了，想易瑞沙，特罗凯，有效率只有百分之三四十，可还有很多人趋之若鹜。起码在研究报告里还是有有效的案例。最主要的是生物治疗几乎没有毒性，其他副作用不明显。对病人的损害较低。
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