Phase II study of the efficacy and tolerability of two dosing regimens of the farnesyl transferase inhibitor, R115777, in advanced breast cancer
Phase II study of the efficacy and tolerability of two dosing regimens of the farnesyl transferase inhibitor, R115777, in advanced breast cancer
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DOI：
10.1200/jco.2003.10.064
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发表时间：
2003-07-01
影响因子：
45.3
通讯作者：
Howes, A
中科院分区：
文献类型：
--
作者：
Johnston, SRD;Hickish, T;Howes, A
目的：R115777是一种口服活性法尼基转移酶抑制剂，可特异性阻断参与生长因子依赖性细胞信号转导途径的法尼基化蛋白。我们在76名晚期乳腺癌患者中进行了一项II期研究。患者和方法：按顺序招募两组患者。第一组（n = 41）接受R115777连续给药[CD]方案，400或300 mg bid。第二组（n = 35）接受300 mg / bid的周期性治疗，治疗21天，休息7天（间歇给药[ID]）。结果：在CD队列中，4例患者（10%）有部分缓解（PR）， 6例患者（15%）在大于或等于24周（SD）时病情稳定。在ID队列中，5名患者（14%）有PR， 3名患者（9%）有延长的SD。前6名接受400mg / bid治疗的患者均出现3 - 4级中性粒细胞减少症，因此随后的35名患者接受300mg / bid治疗。ID组血液毒性发生率明显低于CD组（300 mg bid）： 3 ~ 4级中性粒细胞减少（14% vs 439/6, P = 0.016）和3 ~ 4级血小板减少（3% vs 26%, P = 0.013）。ID组中有1例患者出现2 - 3级神经毒性，而CD组中有15例患者出现2 - 3级神经毒性（3% vs 37%; P = 0.0004）。结论：法尼基转移酶抑制剂R115777在转移性乳腺癌患者中已显示出临床活性，且与CD方案相比，ID方案的治疗指标有显著提高。(C) 2003年由美国临床肿瘤学会出版。
Purpose : R115777 is an orally active farnesyl transferase inhibitor that specifically blocks farnesylation of proteins involved in growth-factor-dependent cell-signal-transduction pathways. We conducted a phase II study in 76 patients with advanced breast cancer.Patients and Methods: Two cohorts of patients were recruited sequentially. The first cohort (n = 41) received a continuous dosing [CD] regimen of R115777 400 or 300 mg bid. The second cohort (n = 35) received 300 mg bid in a cyclical regimen of 21 days of treatment followed by 7 days of rest (intermittent dosing [ID]).Results: In the CD cohort, four patients (10%) had a partial response (PR) and six patients (15%) had stable disease at greater than or equal to 24 weeks (SD). In the ID cohort, five patients (14%) had a PR and three patients (9%) had prolonged SD. The first six patients in the CD cohort treated at 400 mg bid all developed grade 3 to 4 neutropenia, so the subsequent 35 patients were treated at 300 mg bid. The incidence of hematologic toxicity was significantly lower in the ID than in the CD (300-mg bid) cohort: grade 3 to 4 neutropenia (14% v 439/6, P = .016) and grade 3 to 4 thrombocytopenia (3% v 26%, P = .013). One patient in the ID cohort developed grade 2 to 3 neurotoxicity compared with 15 patients in the CD cohort (3% v 37%; P = .0004).Conclusion: The farnesyl transferase inhibitor R115777 has demonstrated clinical activity in patients with metastatic breast cancer, and the ID regimen has a significantly improved therapeutic index compared with the CD regimen. (C) 2003 by American Society of Clinical Oncology.