A randomized, phase II, dose-finding study of the pan-ErbB receptor tyrosine-kinase inhibitor CI-1033 in patients with pretreated metastatic breast cancer
A randomized, phase II, dose-finding study of the pan-ErbB receptor tyrosine-kinase inhibitor CI-1033 in patients with pretreated metastatic breast cancer
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DOI：
10.1007/s00280-009-0975-z
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发表时间：
2009-11-01
影响因子：
3
通讯作者：
Rugo, Hope S.
中科院分区：
文献类型：
--
作者：
Rixe, Olivier;Franco, Sandra X.;Rugo, Hope S.
为了评估泛ErbB受体酪氨酸激酶抑制剂CI-1033在转移性乳腺癌（MBC）中的有效性和安全性，将原发肿瘤表达千分之一的ErbB受体的可测量的、进行性或复发性MBC患者随机分配至以下CI-1033方案：50 mg（A组）或150 mg（B组）每日一次，无停药期，或450 mg/天× 14天，每21天一次（C组）。主要终点为1年无进展生存期（PFS），共有194例患者接受治疗。A组、B组和C组的1年PFS估计值分别为3.8%、2.0%和4.6%;中位PFS分别为61天、56天和58天;评估者评估的总体缓解率分别为1.5%、1.5%和7.3%。反应持续时间为110-419天。在C组中，HER 2阳性肿瘤患者的缓解率（18.8 vs. 2.6%）和1年总生存率（86.7 vs. 47.5%）高于HER 2阴性肿瘤患者。3/4级不良事件（AE）的发生率呈剂量依赖性，分别影响A、B和C组10.3%、48.6%和80.4%的患者。最常见的3/4级治疗相关AE为腹泻、虚弱和口腔炎。由于3/4级AE的高频率，C组的招募被提前中止。单药CI-1033在表达千分之一日元1 ErbB受体的MBC患者中未显示出有临床意义的活性。在C组HER 2阳性肿瘤患者中观察到抗肿瘤活性。然而，只有50 mg剂量耐受性良好，最高剂量达到不可接受的毒性水平。
To evaluate the efficacy and safety of the pan-ErbB receptor tyrosine-kinase inhibitor CI-1033 in metastatic breast cancer (MBC).Patients with measurable, progressive, or recurrent MBC whose primary tumor expressed a parts per thousand yen1 ErbB receptor were randomized to the following CI-1033 regimens: 50 mg (arm A) or 150 mg (arm B) daily without rest period, or 450 mg/day x 14 days every 21 days (arm C). The primary endpoint was 1-year progression-free survival (PFS).Overall, 194 patients were treated. One-year PFS estimates were 3.8, 2.0, and 4.6%; median PFS was 61, 56, and 58 days; and investigator-assessed overall response rates were 1.5, 1.5, and 7.3%, in arms A, B, and C, respectively. Response duration was 110-419 days. In arm C, response (18.8 vs. 2.6%) and 1-year overall survival rates (86.7 vs. 47.5%) were greater in patients with HER2-positive versus HER2-negative tumors. The incidence of grade 3/4 adverse events (AEs) was dose-dependent, affecting 10.3, 48.6, and 80.4% of patients in arms A, B and C, respectively. The most common grade 3/4, treatment-related AEs were diarrhea, asthenia, and stomatitis. Arm C enrollment was prematurely discontinued due to a high frequency of grade 3/4 AEs.Single-agent CI-1033 did not show clinically meaningful activity in heavily pretreated patients with MBC expressing a parts per thousand yen1 ErbB receptor. Antitumor activity was observed in arm C patients with HER2-positive tumors. However, only the 50 mg dose was well tolerated, and the highest dose reached unacceptable levels of toxicity.