一项针对晚期实体瘤患者的间歇性高剂量吉非替尼与固定剂量多西他赛的I期试验。

A phase I trial of intermittent high-dose gefitinib and fixed-dose docetaxel in patients with advanced solid tumors.

作者信息

Fury Matthew G, Solit David B, Su Yungpo Bernard, Rosen Neal, Sirotnak F M, Smith Robert P, Azzoli Christopher G, Gomez Jorge E, Miller Vincent A, Kris Mark G, Pizzo Barbara A, Henry Roxanne, Pfister David G, Rizvi Naiyer A

机构信息

Division of Solid Tumor Oncology, Head and Neck Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center and Weill Medical College of Cornell University, New York, NY 10021, USA.

出版信息

Cancer Chemother Pharmacol. 2007 Mar;59(4):467-75. doi: 10.1007/s00280-006-0286-6. Epub 2006 Aug 1.

DOI:10.1007/s00280-006-0286-6

PMID:16896930

Abstract

PURPOSE

Based on our mouse xenograft model demonstrating that intermittent high-dose gefitinib sensitizes tumors to subsequent treatment with taxanes, we initiated this phase I trial to explore docetaxel in combination with escalating doses of intermittent gefitinib (Iressa) given prior to docetaxel.

METHODS

This was a phase I study where patients with advanced cancer were treated with escalating doses of gefitinib (1,000, 1,500, 2,250, 3,000 mg) on days 1 and 2 followed by docetaxel (75 mg/m2) on day 3 of a 21 day cycle. Gefitinib pharmacokinetic data were obtained on days 1, 2, and 3 of cycles 1 and 2 at each dose level.

RESULTS

18 patients were enrolled in this study with the most frequent tumor types being non-small cell lung cancer and head and neck squamous cell cancer. The dose-limiting toxicity was neutropenia (n=1 at dose level 2, n=2 at dose level 4). Rash, diarrhea, and fatigue were the most common grade 1-2 toxicities. Pharmacokinetic data indicated no accumulation of gefitinib between cycles 1 and 2 and no clear correlation between gefitinib plasma levels and toxicity. Partial responses were observed in one patient with head and neck squamous cell carcinoma and one patient with anaplastic thyroid cancer.

CONCLUSION

The recommended dose for phase II studies is gefitinib 2,250 mg on days 1 and 2, followed by docetaxel 75 mg/m2 on day 3.

摘要

目的

基于我们的小鼠异种移植模型显示间歇性高剂量吉非替尼可使肿瘤对随后的紫杉烷类治疗敏感，我们启动了这项I期试验，以探索多西他赛联合递增剂量的间歇性吉非替尼（易瑞沙），吉非替尼在多西他赛之前给药。

方法

这是一项I期研究，晚期癌症患者在第1天和第2天接受递增剂量的吉非替尼（1000、1500、2250、3000毫克）治疗，然后在21天周期的第3天接受多西他赛（75毫克/平方米）治疗。在每个剂量水平的第1、2和3周期的第1、2和3天获取吉非替尼的药代动力学数据。

结果

18名患者参加了本研究，最常见的肿瘤类型是非小细胞肺癌和头颈部鳞状细胞癌。剂量限制性毒性是中性粒细胞减少（剂量水平2时n = 1，剂量水平4时n = 2）。皮疹、腹泻和疲劳是最常见的1-2级毒性。药代动力学数据表明第1周期和第2周期之间吉非替尼无蓄积，且吉非替尼血浆水平与毒性之间无明显相关性。在1名头颈部鳞状细胞癌患者和1名间变性甲状腺癌患者中观察到部分缓解。