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首页> 外文期刊>Anticancer Research: International Journal of Cancer Research and Treatment >A phase I study to determine the safety and pharmacokinetics of intravenous administration of TAS-106 once per week for three consecutive weeks every 28 days in patients with solid tumors
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A phase I study to determine the safety and pharmacokinetics of intravenous administration of TAS-106 once per week for three consecutive weeks every 28 days in patients with solid tumors

机译：一项I期研究，用于确定实体瘤患者中TAS-106每周一次，连续28周，连续28周，每周一次静脉内施用TAS-106的安全性和药代动力学

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Background: The nucleoside 3′-c-ethynylcytidine (TAS-106) was designed to inhibit RNA synthesis which occurs throughout the cell cycle except for the M phase. TAS-106 is incorporated into cells, is rapidly phosphorylated to a monophosphate form, and is preferentially distributed into malignant cells. Preclinical studies showed that TAS-106 has a wide antitumor spectrum against human cancer xenografts. This phase I study was conducted in order to determine the recommended phase II dose of TAS-106 administered once per week for three consecutive weeks, every 28 days in patients with solid tumors. Patients and Methods: Patients were enrolled in cohorts of three, starting at 0.22 mg/m 2/dose. Patients received at least two doses in order to be evaluable in each dose cohort. Dose escalation was stopped if two or more patients experienced dose limiting toxicity at any dose level. Results: In 20 evaluable patients, TAS-106 was given at the following dose levels (mg/m2/dose): 0.22 (3 pts), 0.33 (3 pts), 0.66 (3 pts), 0.99 (1 pt), 1.32 (3 pts), 2.64 (3 pts) and 3.96 (1 pt). Three additional patients were evaluated at 2.64 mg/m 2/dose for further characterization of toxicity and safety. A total of 16 patients completed courses 1 and 2. All 21 patients enrolled experienced at least one adverse event. The AE attributed to the study drug was grade 2 peripheral neuropathy characterized by peripheral sensory neuropathy, numbness, tremor, pain, and hyperesthesia involving the fingers, hands, toes, and feet. Conclusion: Due to neurotoxicity the MTD was the 2.64 mg/m 2/dose for the study schedule. No suggested phase II dose was determined. However, at the 1.32 mg/m 2/dose level, no patients experienced DLTs during course 1 or 2. This could be further studied to determine its viability as a potential phase II dosage.
机译：背景：核苷3'-c-乙炔基胞苷（TAS-106）设计用于抑制RNA合成，除了M期外，RNA合成贯穿整个细胞周期。 TAS-106掺入细胞，迅速磷酸化为单磷酸形式，并优先分布到恶性细胞中。临床前研究表明，TAS-106对人类癌症异种移植物具有广泛的抗肿瘤谱。进行这一I期研究是为了确定实体瘤患者中TAS-106的II期推荐剂量，每周两次，连续三周，每28天一次。患者和方法：患者入组三组，起始剂量为0.22 mg / m 2 /剂量。患者接受至少两次剂量，以便在每个剂量组中进行评估。如果两个或两个以上患者在任何剂量水平均经历剂量限制性毒性，则停止剂量递增。结果：在20例可评估的患者中，以以下剂量水平（mg / m2 /剂量）给予TAS-106：0.22（3 pts），0.33（3 pts），0.66（3 pts），0.99（1 pt），1.32 （3分），2.64（3分）和3.96（1分）。对另外三名患者进行了2.64 mg / m 2 /剂量的评估，以进一步表征毒性和安全性。共有16名患者完成了课程1和2。所有入组的21位患者都经历了至少一项不良事件。归因于该研究药物的AE是2级周围神经病，其特征是周围感觉神经病，麻木，震颤，疼痛和感觉亢进，涉及手指，手，脚趾和脚。结论：由于神经毒性，研究计划的MTD为2.64 mg / m 2 /剂量。未确定建议的II期剂量。但是，在1.32 mg / m 2 /剂量水平下，没有患者在1或2疗程中经历过DLT。可以进一步研究以确定其作为II期潜在剂量的可行性。

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