Phase I trial of the oral PARP inhibitor olaparib in combination with paclitaxel for first- or second-line treatment of patients with metastatic triple-negative breast cancer.
Phase I trial of the oral PARP inhibitor olaparib in combination with paclitaxel for first- or second-line treatment of patients with metastatic triple-negative breast cancer.
复制标题
DOI：
10.1186/bcr3484
复制
发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Carmichael J
中科院分区：
文献类型：
--
作者：
Dent RA;Lindeman GJ;Clemons M;Wildiers H;Chan A;McCarthy NJ;Singer CF;Lowe ES;Watkins CL;Carmichael J
这项I期研究评估了奥拉帕尼（olaparib）联合紫杉醇治疗转移性三阴性乳腺癌（mTNBC）患者的安全性、耐受性和有效性。奥拉帕尼是一种有效的口服聚（adp -核糖）聚合酶（PARP）抑制剂。既往接受过≤1次细胞毒方案治疗mTNBC的符合条件的患者使用奥拉帕尼200 mg bid连续加紫杉醇90 mg/m2，每4周周期治疗3周。由于中性粒细胞减少，很大一部分患者的剂量改变导致第二组患者的入组，如果他们在第1周期出现≥2级中性粒细胞减少，则接受粒细胞集落刺激因子治疗，并在随后的周期中继续预防性治疗。所有患者均有可测量的疾病；根据RECIST（1.0版）评估肿瘤反应。19例患者（队列1，n = 9；队列2，n = 10）接受治疗；15例既往接受紫杉烷化疗。最常见的不良事件是腹泻（n = 12, 63%）、恶心（n = 11, 58%）和中性粒细胞减少（n = 11, 58%）。队列1中报告了7例中性粒细胞减少事件（4例级别≥3），队列2中报告了4例（2例级别≥3，包括一例发热性中性粒细胞减少事件）。在队列1中，紫杉醇的中位（范围）剂量强度为57%(26 - 100%)，在队列2中为73%（29 - 100%）。7名患者（37%）证实部分缓解；1例患者继续接受奥拉帕尼单药治疗，无进展。奥拉帕尼和每周紫杉醇联合治疗伴有显著的临床相互作用，尽管进行了二级预防，但中性粒细胞减少的发生率高于预期。鉴于令人鼓舞的应答率，应该考虑替代的计划和给药策略（由阿斯利康资助；ClinicalTrials.gov, NCT00707707）。
This Phase I study evaluated the safety, tolerability and efficacy of olaparib, a potent oral poly(ADP-ribose) polymerase (PARP) inhibitor, in combination with paclitaxel in patients with metastatic triple-negative breast cancer (mTNBC). Eligible patients who had received ≤1 prior cytotoxic regimen for mTNBC were treated with olaparib 200 mg bid continuously plus weekly paclitaxel 90 mg/m2 for three weeks per four-week cycle. Dose modifications in a large proportion of patients due to neutropenia resulted in enrollment of a second cohort of patients who, if they experienced grade ≥2 neutropenia in cycle 1, received granulocyte-colony stimulating factor, which was continued prophylactically in subsequent cycles. All patients had measurable disease; tumor responses were evaluated according to RECIST (version 1.0). Nineteen patients (cohort 1, n = 9; cohort 2, n = 10) received treatment; 15 had received prior taxane chemotherapy. The most frequent adverse events were diarrhea (n = 12, 63%), nausea (n = 11, 58%) and neutropenia (n = 11, 58%). Seven neutropenia events were reported in cohort 1 (four grade ≥3) and four in cohort 2 (two grade ≥3, including one event of febrile neutropenia). The median (range) dose intensity of paclitaxel was 57% (26 to 100%) in cohort 1 and 73% (29 to 100%) in cohort 2. Seven patients (37%) had a confirmed partial response; one patient remains on olaparib monotherapy without progression. The combination of olaparib and weekly paclitaxel was complicated by a significant clinical interaction, with higher-than-expected rates of neutropenia despite secondary prophylaxis. Given the encouraging response rate, alternative scheduling and dosing strategies should be considered (funded by AstraZeneca; ClinicalTrials.gov, NCT00707707).
登录
查看更多内容
影响因子：
45.3
作者：
Perez, EA;Vogel, CL;Patel, R
通讯作者：
Patel, R
影响因子：
45.3
作者：
Fong, Peter C.;Yap, Timothy A.;Kaye, Stan B.
通讯作者：
Kaye, Stan B.
影响因子：
50.5
作者：
Andre, F.;Zielinski, C. C.
通讯作者：
Zielinski, C. C.
影响因子：
11.2
作者：
Kummar S;Chen A;Ji J;Zhang Y;Reid JM;Ames M;Jia L;Weil M;Speranza G;Murgo AJ;Kinders R;Wang L;Parchment RE;Carter J;Stotler H;Rubinstein L;Hollingshead M;Melillo G;Pommier Y;Bonner W;Tomaszewski JE;Doroshow JH
通讯作者：
Doroshow JH
DOI：
10.1158/1078-0432.ccr-11-2425
发表时间：
2012-04-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Rajan A;Carter CA;Kelly RJ;Gutierrez M;Kummar S;Szabo E;Yancey MA;Ji J;Mannargudi B;Woo S;Spencer S;Figg WD;Giaccone G
通讯作者：
Giaccone G