Phase I Clinical Trial of ES-285. Homo sapiens

Phase I Safety, Pharmacokinetic and Pharmacogenomic Trial of ES-285, a Novel Marine Cytotoxic Agent Administered as an Infusion over 24 h Every 21 Days in Patients with Solid Tumors Purpose: A dose-escalation, phase I study evaluated the safety, pharmacokinetics, pharmacogenomics and efficacy of ES-285, a novel agent isolated from a marine mollusc, in adult cancer patients. Experimental design: Patients received a 24-hour i.v. infusion of ES-285 once every 3 weeks until disease progression or unacceptable toxicity. The starting dose was 4mg/m2. Dose escalation proceeded according to the worst toxicity observed in the previous cohort. Results: 28 patients were treated with 72 courses of ES-285 across 8 dose levels. No doselimiting toxicities (DLTs) were seen between 4mg/m2 and 128mg/m2. Two out of 4 patients treated at 256mg/m2 had dose-limiting reversible grade 3 transaminitis; one patient at 256mg/m2 also had transient grade 3 central neurotoxicity. One of 3 patients subsequently treated at 200mg/m2 died following drug-related central neurotoxicity. Pharmacokinetic studies indicated dose-proportionality with high volume of distribution (median Vss at 256mg/m2 was 2389L, range 1615-4051L) and long elimination half life (median t1/2 at 256mg/m2 was 29h, range 21-32h). The 3 patients with DLT had the highest drug exposure. Pharmacogenomic studies of paired surrogate tissue samples identified changes in gene expression following treatment that correlated with increasing dose. Pre-treatment 59- and 49-gene sets were identified in blood and skin respectively, that may predict DLT. Disease stabilisation for 6 to 18 weeks was recorded in 9 patients. Conclusion: Using this schedule, 128 mg/m2 was considered safe and feasible. At this dose, pharmacologically relevant concentrations of drug were safely achieved with pharmacogenomic studies indicating changes in the expression of genes of potential biological relevance. Keywords: dose response Overall design: 104 samples - Total RNA extracted from blood samples and skin biopsies, then amplified, labelled and hybridised to 22k cDNA gene expression microarrays. All samples were compared to Stratagene Human Reference RNA.

一项针对ES-285的I期安全性、药代动力学及药物基因组学试验：每21天输注24小时给药的新型海洋来源细胞毒性制剂用于实体瘤患者

研究目的：本项剂量递增型I期临床试验旨在评估从海洋软体动物中分离得到的新型制剂ES-285在成年癌症患者中的安全性、药代动力学、药物基因组学及抗肿瘤疗效。

试验设计：入组患者每3周接受一次24小时静脉输注ES-285，直至出现疾病进展或不可耐受的毒性反应。试验起始剂量为4mg/m²，剂量递增方案参照前一剂量组中观察到的最严重毒性反应制定。

试验结果：共28例患者接受了8个剂量水平下总计72个周期的ES-285治疗。在4mg/m²至128mg/m²剂量范围内未观察到剂量限制性毒性（dose-limiting toxicities, DLTs）。在256mg/m²剂量组的4例患者中，2例出现剂量限制性可逆性3级氨基转移酶升高；该组另有1例患者出现一过性3级中枢神经毒性。后续在200mg/m²剂量组接受治疗的3例患者中，1例因药物相关性中枢神经毒性死亡。药代动力学研究显示，ES-285呈剂量依赖性暴露，且分布容积较高（256mg/m²剂量组的稳态分布容积（volume of distribution at steady state, Vss）中位数为2389L，范围1615~4051L），消除半衰期（elimination half-life, t₁/₂）较长（256mg/m²剂量组的消除半衰期中位数为29h，范围21~32h）。出现DLTs的3例患者药物暴露量最高。针对配对替代组织样本的药物基因组学研究发现，治疗后基因表达变化与剂量升高呈正相关。分别在血液与皮肤样本中鉴定出预处理阶段的59基因与49基因特征集，或可用于预测DLTs。共9例患者实现了6至18周的疾病稳定。

研究结论：采用本给药方案时，128mg/m²被认为安全且可行。在该剂量下，可安全达到具有药理学相关性的药物浓度，且药物基因组学研究显示，潜在生物学相关基因的表达发生了变化。

关键词：剂量反应

试验整体设计：共104份样本——从血液样本与皮肤活检组织中提取总RNA，随后进行扩增、标记，并与22k cDNA基因表达微阵列进行杂交。所有样本均与Stratagene人类参考RNA进行比对。