A phase I study of prolonged infusion of triapine in combination with fixed dose rate gemcitabine in patients with advanced solid tumors.
A phase I study of prolonged infusion of triapine in combination with fixed dose rate gemcitabine in patients with advanced solid tumors.
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DOI：
10.1007/s10637-012-9863-1
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发表时间：
2013-06
影响因子：
3.4
通讯作者：
Bekaii-Saab, Tanios
中科院分区：
文献类型：
--
作者：
Mortazavi, Amir;Ling, Yonghua;Martin, Ludmila Katherine;Wei, Lai;Phelps, Mitch A.;Liu, Zhongfa;Harper, Erica J.;Ivy, S. Percy;Wu, Xin;Zhou, Bing-Sen;Liu, Xiyong;Deam, Deidre;Monk, J. Paul;Hicks, William J.;Yen, Yun;Otterson, Gregory A.;Grever, Michael R.;Bekaii-Saab, Tanios
癌细胞长时间暴露于核糖核苷酸还原酶抑制剂三聚氰胺，随后暴露于吉西他滨，可增强吉西他滨的体外活性。与标准剂量相比，固定剂量率吉西他滨（FDR-G）的疗效有所改善。我们进行了一项I期试验，以确定最大耐受剂量（MTD），安全性，药代动力学（PK），药效学（PD），以及长期输注曲马多后FDR-G的初步疗效。曲安奈德以24小时输注给药，随后立即给予FDR-G（1000 mg/m2，100分钟）。最初，在21天周期的第1天和第8天给予该联合给药（A组，曲利司汀起始剂量120 mg）;但由于骨髓抑制，将其改为28天周期的第1天和第15天（B组，曲利司汀起始剂量75 mg）。测定甘油三酯稳态浓度（Css）和循环核糖核苷酸还原酶M2亚基（RRM 2）。36例患者入组。MTD确定为曲马多90 mg（24小时输注），紧接着吉西他滨1000 mg/m2（100分钟输注），每2周一次，4周为一个周期。DLT包括4级血小板减少症、白细胞减少症和中性粒细胞减少症。治疗耐受性良好，疲乏、恶心/呕吐、发热、转氨酶升高和血细胞减少是最常见的毒性。在30例可评价患者中，1例部分缓解，15例疾病稳定。与使用标准化至体表面积的剂量的既往研究相比，Trilycin PK相似，但变异性更大。RRM 2循环水平的稳定下降可能与结局相关。该联合用药耐受性良好，在该接受过大量预治疗的患者人群（包括既往吉西他滨治疗失败的患者）中显示初步活性证据。
Prolonged exposure of cancer cells to triapine, an inhibitor of ribonucleotide reductase, followed by gemcitabine enhances gemcitabine activity in vitro. Fixed-dose-rate gemcitabine (FDR-G) has improved efficacy compared to standard-dose. We conducted a phase I trial to determine the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of prolonged triapine infusion followed by FDR-G. Triapine was given as a 24-hour infusion, immediately followed by FDR-G (1000 mg/m2 over 100-minute). Initially, this combination was administered days 1 and 8 of a 21-day cycle (Arm A, triapine starting dose 120 mg); but because of myelosuppression, it was changed to days 1 and 15 of a 28-day cycle (Arm B, starting dose of triapine 75 mg). Triapine steady-state concentrations (Css) and circulating ribonucleotide reductase M2-subunit (RRM2) were measured. Thirty-six patients were enrolled. The MTD was determined to be triapine 90 mg (24-hour infusion) immediately followed by gemcitabine 1000 mg/m2 (100-minute infusion), every 2 weeks of a 4-week cycle. DLTs included grade 4 thrombocytopenia, leukopenia and neutropenia. The treatment was well tolerated with fatigue, nausea/vomiting, fever, transaminitis, and cytopenias being the most common toxicities. Among 30 evaluable patients, 1 had a partial response and 15 had stable disease. Triapine PK was similar, although more variable, compared to previous studies using doses normalized to body-surface-area. Steady decline in circulating levels of RRM2 may correlate with outcome. This combination was well tolerated and showed evidence of preliminary activity in this heavily pretreated patient population, including prior gemcitabine failure.
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影响因子：
3
作者：
Kolesar, Jill;Brundage, Richard C.;Pomplun, Marcia;Alberti, Dona;Holen, Kyle;Traynor, Anne;Ivy, Percy;Wilding, George
通讯作者：
Wilding, George
影响因子：
45.3
作者：
Bokemeyer, C;Gerl, A;Kanz, L
通讯作者：
Kanz, L
影响因子：
5.8
作者：
CORY, JG;CORY, AH;SARTORELLI, AC
通讯作者：
SARTORELLI, AC
影响因子：
5.8
作者：
KUBOTA, M;TAKIMOTO, T;MIKAWA, H
通讯作者：
MIKAWA, H
影响因子：
3
作者：
Feun, L;Modiano, M;MacDonald, S
通讯作者：
MacDonald, S