A multicenter phase II trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine®) and gemcitabine in advanced non-small-cell lung cancer with pharmacokinetic evaluation using peripheral blood mononuclear cells
A multicenter phase II trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine®) and gemcitabine in advanced non-small-cell lung cancer with pharmacokinetic evaluation using peripheral blood mononuclear cells
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DOI：
10.1007/s10637-007-9085-0
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发表时间：
2008-04-01
影响因子：
3.4
通讯作者：
Mok, Tony
中科院分区：
文献类型：
--
作者：
Ma, Brigette;Goh, Boon Cher;Mok, Tony
背景：我们在一项II期研究中验证了3-氨基吡啶-2-羧基硫代氨基脲（3-AP, Triapine(R)）可能通过增强细胞内对吉西他滨的摄取来增强吉西他滨再治疗的应答。方法：既往接受吉西他滨作为晚期非小细胞肺癌（NSCLC）一线治疗的患者，每周输注3- ap和吉西他滨，持续3周，然后休息1周，每28天重复一次。收集血浆和外周血单个核细胞（PBMCs），评估3-AP对吉西他滨药代动力学和细胞内摄取的影响。结果：12例患者的治疗中位数为2个治疗周期，无客观反应，因此研究在中期分析时终止。4例患者病情稳定，到进展的中位时间为3个月（95%置信区间：1.7至9.1个月）。3级毒性包括中性粒细胞减少症（2例）、缺氧（3例）和呼吸困难（1例）。4例患者在3-AP输注期间出现可逆性症状性高铁血红蛋白血症，高铁血红蛋白水平轻度至中度升高，占总血红蛋白浓度的7.8 - 17.6%。有限的药代动力学数据未显示3-AP对吉西他滨有任何临床相关的药理学影响。结论：3-AP并没有增强先前接触过吉西他滨的晚期NSCLC患者对吉西他滨的临床反应。3-AP在肺癌中的进一步发展受到挑战，因为它可能导致高铁血红蛋白血症和缺氧，这在肺储备受损的患者中可能是一个问题。
Background: We tested the hypothesis that 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine(R)) may enhance response to re-treatment with gemcitabine by enhancing intracellular uptake of gemcitabine in a phase II study. Method: Patients who had prior exposure to gemcitabine as a first-line treatment of advanced non-small-cell lung cancer (NSCLC) were given weekly infusions of 3-AP and gemcitabine for 3 weeks followed by 1 week of rest, repeated every 28 days. Plasma and peripheral blood mononuclear cells (PBMCs) were collected to evaluate the effect of 3-AP on pharmacokinetics and intracellular uptake of gemcitabine. Result: Twelve patients were treated with a median of two treatment cycles without objective response, hence the study was terminated at interim analysis. Four patients had stable disease and the median time to progression was 3 months (95% confidence interval, CI: 1.7 to 9.1 months). Grade 3 toxicities included neutropenia (two patients), hypoxia (three patients) and dyspnea (one patient). Four patients developed reversible symptomatic methemoglobinemia during 3-AP infusion, with mild to moderately elevated methemoglobin levels that ranged from 7.8 to 17.6% of the total hemoglobin concentration. Limited pharmacokinetic data did not suggest any clinically relevant pharmacological influence of 3-AP on gemcitabine. Conclusion: 3-AP did not enhance clinical response to gemcitabine in this cohort of patients with prior exposure to gemcitabine for advanced NSCLC. Further development of 3-AP in lung cancer is challenged by its potential of causing methemoglobinemia and hypoxia, which could be problematic in patients with compromised pulmonary reserves.