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表皮生长因子受体 2 过表达乳腺癌患者接受 5 天间歇口服拉帕替尼治疗的 I 期剂量递增研究。

Phase I dose-escalation study of 5-day intermittent oral lapatinib therapy in patients with human epidermal growth factor receptor 2-overexpressing breast cancer.

机构信息

A. Jo Chien, Pamela N. Munster, Michelle E. Melisko, Hope S. Rugo, John W. Park, Andrei Goga, Glenna Auerback, Elham Khanafshar, and Mark M. Moasser, Helen Diller Family Comprehensive Cancer Center; A. Jo Chien, Pamela N. Munster, Michelle E. Melisko, Hope S. Rugo, John W. Park, Andrei Goga, Glenna Auerback, Elham Khanafshar, Karen Ordovas, and Mark M. Moasser, University of California San Francisco, San Francisco, CA; and Kevin M. Koch, GlaxoSmithKline, Research Triangle Park, NC.

出版信息

J Clin Oncol. 2014 May 10;32(14):1472-9. doi: 10.1200/JCO.2013.52.1161. Epub 2014 Apr 7.

Abstract

PURPOSE

The highly effective treatment of human epidermal growth factor receptor (HER) 2-amplified breast cancer has proven challenging because of a signal buffering capacity inherent in the functionally relevant HER2-HER3 target. HER2-HER3 signaling can be inactivated by doses of lapatinib that fully inactivate the HER2 kinase. In mouse models, such doses are not tolerable in continuous administration, but they are tolerable and highly effective in intermittent dosing. We pursued the clinical translation of this treatment hypothesis.

PATIENTS AND METHODS

We conducted a phase I dose-escalation study in women with advanced HER2-overexpressing breast cancer. Lapatinib was administered on days 1 through 5 of repeating 14-day cycles. Dose escalation was conducted using a 3+3 design with plasma lapatinib level monitoring.

RESULTS

Forty patients were evaluable for toxicity, and 34 patients were evaluable for dose-limiting toxicity (DLT). Lapatinib dose was escalated to 7,000 mg per day in twice-daily dosing with no DLTs; however, plasma lapatinib concentrations plateaued in this dose range. Additional cohorts evaluated strategies to increase lapatinib exposure, including the food effect, CYP3A4 inhibition, and dose fractionation. Of these, only ketoconazole was able to increase lapatinib exposure, despite highly variable lapatinib bioavailability. Intolerable exposure levels were not encountered. Eight patients (20%) experienced grade 3 diarrhea. Six patients achieved a response, and dramatic responses were seen in three patients with lapatinib concentrations approaching 10,000 ng/mL.

CONCLUSION

Lapatinib exposure can be safely and significantly increased through intermittent dosing but reaches a ceiling that currently impedes clinical translation of the treatment hypothesis. Preliminary efficacy data suggest that exposures approaching those seen in mouse models can result in highly significant tumor responses.

摘要

目的

由于功能相关的 HER2-HER3 靶标固有的信号缓冲能力,人表皮生长因子受体 (HER) 2 扩增型乳腺癌的高效治疗极具挑战性。HER2-HER3 信号可以被 lapatinib 剂量灭活,而 lapatinib 剂量完全灭活 HER2 激酶。在小鼠模型中,这种剂量在连续给药时无法耐受,但在间歇给药时是可耐受且高度有效的。我们追求这种治疗假设的临床转化。

患者和方法

我们对 HER2 过表达的晚期乳腺癌女性进行了 I 期剂量递增研究。拉帕替尼在重复的 14 天周期的第 1 天至第 5 天给药。使用 3+3 设计并监测血浆拉帕替尼水平进行剂量递增。

结果

40 名患者可评估毒性,34 名患者可评估剂量限制性毒性 (DLT)。在每日两次给药时,拉帕替尼剂量增加到每天 7000 毫克,没有 DLT;然而,在此剂量范围内,血浆拉帕替尼浓度达到平台期。额外的队列评估了增加拉帕替尼暴露的策略,包括食物效应、CYP3A4 抑制和剂量分割。其中,只有酮康唑能够增加拉帕替尼的暴露,尽管拉帕替尼的生物利用度变化很大。未出现无法耐受的暴露水平。8 名患者(20%)出现 3 级腹泻。6 名患者有反应,3 名患者拉帕替尼浓度接近 10000ng/ml 时出现明显反应。

结论

通过间歇给药可以安全且显著增加拉帕替尼的暴露,但目前达到了一个上限,这阻碍了治疗假设的临床转化。初步疗效数据表明,接近在小鼠模型中观察到的暴露水平可导致高度显著的肿瘤反应。

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