Kantarjian Hagop M, Gandhi Varsha, Kozuch Peter, Faderl Stefan, Giles Francis, Cortes Jorge, O'Brien Susan, Ibrahim Nuhad, Khuri Fadlo, Du Min, Rios Mary Beth, Jeha Sima, McLaughlin Peter, Plunkett William, Keating Michael
Departments of Leukemia, Experimental Therapeutics, and Breast and Head and Neck, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
J Clin Oncol. 2003 Mar 15;21(6):1167-73. doi: 10.1200/JCO.2003.04.031.
To define the maximum-tolerated doses (MTDs) and dose-limiting toxicities (DLTs) of clofarabine, given as a 1-hour infusion daily for 5 days, in patients with solid tumors and with acute leukemia.
The initial part of the study defined the MTD and DLT in solid tumors. The second part of the study defined the MTD and DLT in acute leukemia.
The starting dose of clofarabine (15 mg/m(2)) was myelosuppressive, requiring several dose de-escalations to 2 mg/m(2), the dose suggested for phase II studies in solid tumors. Dose escalation in acute leukemia started at 7.5 mg/m(2), with several escalations to 55 mg/m(2). The DLT was reversible hepatotoxicity at 55 mg/m(2). The recommended dose for acute leukemia phase II studies was 40 mg/m(2). Among 32 treated patients with acute leukemia, two achieved a complete response and three had a marrow complete response without platelet recovery (hematologic improvement), for an overall response rate of 16%. At 40 mg/m(2), the median plasma clofarabine level was 1.5 micro mol/L (range, 0.42 to 3.2 micro mol/L; n = 7). Cellular and plasma pharmacokinetic studies suggested dose proportionality but showed a wide variation in intracellular concentrations of clofarabine triphosphate.
This phase I study defined the following two MTDs for clofarabine given as a 1-hour infusion daily for 5 days: 2 mg/m(2) for solid tumors, the DLT being myelosuppression; and 40 mg/m(2) for acute leukemia, the DLT being hepatotoxicity. Encouraging activity was observed in acute leukemia.
确定氯法拉滨对实体瘤和急性白血病患者的最大耐受剂量（MTD）和剂量限制性毒性（DLT），给药方式为每日1小时输注，共5天。
研究的第一部分确定实体瘤的MTD和DLT。研究的第二部分确定急性白血病的MTD和DLT。
氯法拉滨的起始剂量（15mg/m²）具有骨髓抑制作用，需要多次降低剂量至2mg/m²，这是实体瘤II期研究建议的剂量。急性白血病的剂量递增从7.5mg/m²开始，多次递增至55mg/m²。DLT为55mg/m²时出现的可逆性肝毒性。急性白血病II期研究的推荐剂量为40mg/m²。在32例接受治疗的急性白血病患者中，2例达到完全缓解，3例骨髓完全缓解但血小板未恢复（血液学改善），总缓解率为16%。在40mg/m²时，氯法拉滨的血浆中位水平为1.5微摩尔/升（范围为0.42至3.2微摩尔/升；n = 7）。细胞和血浆药代动力学研究表明剂量呈比例关系，但显示氯法拉滨三磷酸的细胞内浓度存在很大差异。
这项I期研究确定了氯法拉滨每日1小时输注、共5天给药时的以下两个MTD：实体瘤为2mg/m²，DLT为骨髓抑制；急性白血病为40mg/m²，DLT为肝毒性。在急性白血病中观察到了令人鼓舞的活性。
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