Uziely B, Jeffers S, Isacson R, Kutsch K, Wei-Tsao D, Yehoshua Z, Libson E, Muggia F M, Gabizon A
Norris Cancer Center, University of Southern California, Los Angeles, USA.
J Clin Oncol. 1995 Jul;13(7):1777-85. doi: 10.1200/JCO.1995.13.7.1777.
The purpose of our studies was to define the maximal-tolerated dose of liposomal doxorubicin (DOX-SL; Liposome Technology Inc, Menlo Park, CA), a doxorubicin formulation of polyethyleneglycol-coated liposomes, characterize the toxicities associated with this formulation, and evaluate any indication of antitumor activity within a phase I setting.
Two separate phase I studies were conducted following the initial human pharmacokinetic testing at one of the sites (Hadassah). The starting dose of 20 mg/m2 at the University of Southern California was just below the dose without toxicity in the pharmacokinetic study. At Hadassah, the phase I starting dose was just above their earlier safe single doses, 60 mg/m2. Both studies involved cohorts of at least three patients and redosing every 3 to 4 weeks. To determine the recommended dose for phase II trials, an additional level of 50 mg/m2 every 3 weeks was explored, and the level of 60 mg/m2 every 4 weeks was expanded.
A total of 56 patients receiving 281 courses of DOX-SL was accrued and evaluated for toxicity. Hand-foot (H-F) syndrome and stomatitis are the two main dose-limiting factors of DOX-SL. Stomatitis was dose-limiting for high single doses of DOX-SL greater than 70 mg/m2. Skin toxicity manifested primarily as H-F syndrome was dose-limiting for repetitive dosing, but acceptable at either 50 mg/m2 every 3 weeks or 60 mg/m2 every 4 weeks. Attenuation of acute subjective symptoms and lack of alopecia were generally observed. Patients with carcinomas of the breast, ovary, prostate, and head and neck were among those showing objective antitumor responses or improvement based, in part, on blood levels of tumor markers.
The toxicity profile of DOX-SL differs prominently from that of the free drug administered by bolus or rapid infusion and with some differences, resembles that of prolonged continuous infusion. This finding, as well as the antitumor activity observed, supports wide phase II testing of DOX-SL in solid tumors.
我们研究的目的是确定聚乙二醇包被脂质体阿霉素（DOX-SL；脂质体技术公司，加利福尼亚州门洛帕克）的最大耐受剂量，该制剂为阿霉素的脂质体制剂，描述与此制剂相关的毒性，并在I期试验中评估任何抗肿瘤活性迹象。
在其中一个研究地点（哈达萨）进行初始人体药代动力学测试后，开展了两项独立的I期研究。南加州大学的起始剂量为20mg/m²，略低于药代动力学研究中无毒性的剂量。在哈达萨，I期起始剂量略高于他们之前的安全单剂量，即60mg/m²。两项研究均纳入至少三名患者的队列，每3至4周重新给药一次。为确定II期试验的推荐剂量，探索了每3周额外增加50mg/m²剂量水平，并扩大了每4周60mg/m²剂量水平。
共纳入56例接受281疗程DOX-SL治疗的患者，并对其毒性进行评估。手足综合征和口腔炎是DOX-SL的两个主要剂量限制因素。口腔炎是大于70mg/m²的高单次剂量DOX-SL的剂量限制因素。主要表现为手足综合征的皮肤毒性是重复给药的剂量限制因素，但每3周50mg/m²或每4周60mg/m²时可接受。一般观察到急性主观症状减轻且无脱发。乳腺癌、卵巢癌、前列腺癌和头颈癌患者出现了客观抗肿瘤反应或病情改善，部分基于肿瘤标志物的血液水平。
DOX-SL的毒性特征与推注或快速输注的游离药物显著不同，且在某些方面与延长持续输注相似。这一发现以及观察到的抗肿瘤活性支持对DOX-SL在实体瘤中进行广泛的II期试验。
