Holstein Sarah A, Bigelow James C, Olson Richard D, Vestal Robert E, Walsh Gerald M, Hohl Raymond J
Department of Medicine, Roswell Park Cancer Institute, Elm & Carlton Sts, Buffalo, NY, 14263, USA,
Invest New Drugs. 2015 Jun;33(3):594-602. doi: 10.1007/s10637-015-0220-z. Epub 2015 Feb 21.
5-imino-13-deoxydoxorubicin (DIDOX; GPX-150) is a doxorubicin analog modified in two locations to prevent formation of cardiotoxic metabolites and reactive oxygen species. Preclinical studies have demonstrated anti-cancer activity without cardiotoxicity. A phase I study was performed in order to determine the maximum-tolerated dose (MTD) of GPX-150 in patients with metastatic solid tumors.
GPX-150 was administered as an intravenous infusion every 21 days for up to 8 cycles. An accelerated dose escalation was used for the first three treatment groups. The dosing groups were (A) 14 mg/m(2), (B) 28 mg/m(2), (C), 56 mg/m(2), (D) 84 mg/m(2), (E) 112 mg/m(2), (F) 150 mg/m(2), (G) 200 mg/m(2), and (H) 265 mg/m(2). Pharmacokinetic samples were drawn during the first 72 h of cycle 1.
The MTD was considered to be reached at the highest dosing level of 265 mg/m(2) since dose reduction was required in 5 of 6 patients for neutropenia. The most frequent adverse events were neutropenia, anemia, fatigue, and nausea. No patients experienced cardiotoxicity while on the study. The best overall response was stable disease in four (20 %) patients. Pharmacokinetic analysis revealed an AUC of 8.0 (±2.6) μg · h/mL, a clearance of 607 (±210) mL/min/m(2) and a t1/2β of 13.8 (±4.6) hours.
GPX-150 administered every 21 days has an acceptable side effect profile and no cardiotoxicity was observed. Further investigation is needed to determine the efficacy of GPX-150 in anthracycline-sensitive malignancies.
5-亚氨基-13-脱氧多柔比星（DIDOX；GPX-150）是一种在两个位点进行修饰的多柔比星类似物，可防止心脏毒性代谢物和活性氧的形成。临床前研究已证明其具有抗癌活性且无心脏毒性。开展了一项I期研究，以确定GPX-150在转移性实体瘤患者中的最大耐受剂量（MTD）。
GPX-150每21天静脉输注一次，最多8个周期。前三个治疗组采用加速剂量递增法。给药组分别为（A）14mg/m²、（B）28mg/m²、（C）56mg/m²、（D）84mg/m²、（E）112mg/m²、（F）150mg/m²、（G）200mg/m²和（H）265mg/m²。在第1周期的前72小时采集药代动力学样本。
由于6例患者中有5例因中性粒细胞减少需要降低剂量，因此认为在最高给药水平265mg/m²时达到了MTD。最常见的不良事件是中性粒细胞减少、贫血、疲劳和恶心。在研究期间，没有患者出现心脏毒性。最佳总体反应是4例（20%）患者病情稳定。药代动力学分析显示，曲线下面积（AUC）为8.0（±2.6）μg·h/mL，清除率为607（±210）mL/min/m²，β半衰期（t1/2β）为13.8（±4.6）小时。
每21天给药一次的GPX-150具有可接受的副作用，且未观察到心脏毒性。需要进一步研究以确定GPX-150在对蒽环类药物敏感的恶性肿瘤中的疗效。
