A phase II clinical and pharmacokinetic study of intravenous exatecan mesylate (DX-8951f) in patients with untreated metastatic gastric cancer
A phase II clinical and pharmacokinetic study of intravenous exatecan mesylate (DX-8951f) in patients with untreated metastatic gastric cancer
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DOI：
10.1007/s10637-005-2907-z
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发表时间：
2005-10-01
影响因子：
3.4
通讯作者：
De Jager, R
中科院分区：
文献类型：
--
作者：
Ajani, JA;Takimoto, C;De Jager, R
目的：确定DX-8951 f在既往未经治疗的转移性胃癌患者中每天输注30分钟持续5天每3周一次的抗肿瘤活性，并评价DX-8951 f在该患者人群中的毒性和药代动力学（PK）。患者和方法：入组了41例患者。所有患者既往均患有未经治疗的转移性胃癌。给予DX-8951 f直至疾病进展或出现不可接受的毒性。每2个疗程后使用RECIST标准评估反应。结果：39例患者可评价。2例患者获得部分缓解（PR），18例患者获得疾病稳定（SD），包括5例未经证实的PR患者。共提供了141个疗程（中位数3，范围1-10）。最常见的药物相关毒性是中性粒细胞减少症。非血液学毒性多为轻度至中度;最常见的是恶心、呕吐和厌食。使用线性2室PK模型充分描述了DX-8951（DX-8951 f的无水形式）的血浆浓度。所有浓度和剂量事件均同时建模，并通过群体PK模型进行解释。在给药的5天内，没有证据表明DX-8951清除的消除PK、自抑制或诱导存在非线性。结论：DX-8951 f对转移性胃癌有一定的抗肿瘤活性，其药代动力学与剂量成正比。毒性特征是可预测且可管理的。这种药剂的进一步开发是必要的。
Purpose: To determine the anti-tumor activity DX-8951f when administered as a 30-minute infusion daily for 5 days every 3 weeks to patients with previously untreated metastatic gastric cancer, and to evaluate toxicities and pharmacokinetics (PK) of DX-8951f in this patient population. Patients and methods: Forty-one patients were enrolled. All had previously untreated metastatic gastric cancer. DX-8951f was administered until disease progression or unacceptable toxicity. Responses were assessed after every 2 courses using RECIST criteria. Results: Thirty-nine patients were evaluable. Two patients achieved a partial response (PR) and 18 achieved stable disease (SD), including five patients with unconfirmed PR. A total of 141 courses of therapy were delivered (median 3, range 1-10). The most common drug-related toxicity was neutropenia. Non-hematologic toxicities were mostly mild to moderate; the most common were nausea, vomiting and anorexia. Plasma concentrations of DX-8951 (the anhydrous form of DX-8951f) were well described using a linear 2-compartment PK model. All concentrations and dose events were simultaneously modeled and explained by the population PK model. There was no evidence of non-linearity in the elimination PK, auto-inhibition or induction of DX-8951 clearance over the five days of administration. Conclusions: DX-8951f had modest activity against metastatic gastric cancer and its PK was dose-proportional. The toxicity profile was predictable and manageable. Further development of this agent is warranted.