Phase I and pharmacokinetic study of weekly NV06 (Phenoxodiol™), a novel isoflav-3-ene, in patients with advanced cancer
Phase I and pharmacokinetic study of weekly NV06 (Phenoxodiol™), a novel isoflav-3-ene, in patients with advanced cancer
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DOI：
10.1007/s00280-006-0189-6
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发表时间：
2006-10-01
影响因子：
3
通讯作者：
Howes, LG
中科院分区：
文献类型：
--
作者：
de Souza, PL;Liauw, W;Howes, LG
背景资料：我们希望确定新的异黄-3-烯NV 06（Phenoxodiol（TM））的最大耐受剂量（MTD）、毒性和药代动力学，NV 06是一种具有与染料木素和flavopiridol化学和生物学相关的双酚结构的化合物。患者和方法：21名晚期癌症患者用每周静脉内施用递增剂量水平的NV 06治疗，每个剂量组1-4名患者。进行血浆采样以表征化合物的药代动力学（PK）特征。结果：毒性很小，9例患者发生无症状的3级淋巴细胞减少症。9例患者发生1级恶心，6例患者发生1级碱性磷酸酶升高，6例患者发生1级转氨酶升高。2例患者发生超敏反应。未达到MTD。大多数患者在治疗期间病情进展，但8例完成了12周的治疗，2例完成了24周的治疗。最佳缓解为疾病稳定6个月。总NV 06的血浆半衰期（T1/2）、清除率（Cl）和分布容积（V（D））分别为304（+/- 91）min、82（+/- 19）ml/min和32，663（+/-7，199）ml。结论：NV 06耐受性良好，可以安全地以至少30 mg/kg的剂量静脉输注1-2 h。
Background: We wished to define the maximum tolerated dose (MTD), toxicity, and pharmacokinetics of the novel isoflav-3-ene, NV06 (Phenoxodiol (TM)), a compound with a diphenolic structure related chemically and biologically to genistein and flavopiridol. Patients and Methods: Twenty-one patients with advanced cancers were treated with weekly intravenous administration of NV06 at escalating dose levels with 1-4 patients at each dose cohort. Plasma sampling was undertaken to characterize the pharmacokinetic (PK) profile of the compound. Results: Toxicity was minimal, with asymptomatic Grade 3 lymphocytopenia occurring in nine patients. Nine patients developed Grade 1 nausea, six patients developed Grade 1 increases in alkaline phosphatase, and six patients developed Grade 1 increases in transaminases. Two patients experienced hypersensitivity reactions. The MTD was not reached. Most patients had progressive disease on treatment but eight completed 12 weeks and two completed 24 weeks of treatment. The best response was stable disease of 6 months duration. The plasma half-life (T1/2), clearance (Cl), and volume of distribution (V (D)) were 304 (+/- 91) min, 82 (+/- 19) ml/min and 32,663 (+/- 7,199) ml, respectively, for total NV06. Conclusions: NV06 is well tolerated and can be given safely as an intravenous infusion over 1-2 h at a dose of at least 30 mg/kg.