Phase I/Ib Study of Olaparib and Carboplatin in BRCA1 or BRCA2 Mutation-Associated Breast or Ovarian Cancer With Biomarker Analyses
Phase I/Ib Study of Olaparib and Carboplatin in BRCA1 or BRCA2 Mutation-Associated Breast or Ovarian Cancer With Biomarker Analyses
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DOI：
10.1093/jnci/dju089
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发表时间：
2014-06-01
影响因子：
10.3
通讯作者：
Kohn, Elise C.
中科院分区：
文献类型：
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作者：
Lee, Jung-Min;Hays, John L.;Kohn, Elise C.
奥拉帕尼对生殖系BRCA 1或BRCA 2突变携带者（gBRCAm）中的乳腺癌/卵巢癌（BrCa/OvCa）具有单药活性。我们假设添加奥拉帕尼卡铂可以安全地管理，并产生初步的clinical activity.Methods符合条件的患者有可测量或可评估的疾病，gBRCAm，和良好的终末器官功能。3 + 3剂量递增测试每日口服胶囊奥拉帕尼（每12小时100或200 mg;剂量水平1或2），第8天（AUC 3第8天）卡铂曲线下面积（AUC），然后每21天。对于剂量水平3至6，患者在第1至7天接受奥拉帕尼200和400 mg，每12小时一次，第1或2天卡铂AUC为3至5，每21天一次;最多允许8个联合周期，之后每天维持奥拉帕尼400 mg，每12小时一次，直至进展。在前两个周期中定义剂量限制性毒性。收集外周血单个核细胞进行多态性分析和聚ADP-核糖掺入。配对肿瘤活检（前/后周期1）获得生物标志物蛋白质组学和细胞凋亡endpoints.Results四十五名妇女（37 OvCa/8 BrCa）进行了治疗。在间歇给药方案中未达到剂量限制性毒性。在第1 - 7天，使用奥拉帕尼400 mg每12小时一次/卡铂AUC 5进行扩增。3/4级不良事件包括中性粒细胞减少（42.2%）、血小板减少（20.0%）和贫血（15.6%）。缓解包括1例完全缓解（1例BrCa; 23个月）和21例部分缓解（50.0%; 15例OvCa; 6例BrCa; OvCa中位值= 16 [4至>45]个月，BrCa中位值= 10 [6至>40]个月）。蛋白质组学分析表明高的预处理pS209-eIF 4 E和FOXO 3a与反应持续时间相关（双侧P < .001; Pearson's R-2 = 0.94）。结论奥拉帕尼胶囊400 mg每12小时一次，第1至7天/卡铂AUC 5在gBRCAm BrCa/OvCa患者中是安全的，并且具有活性。探索性转化研究表明，治疗前组织FOXO 3a表达可能预测对治疗的反应，需要前瞻性验证。
Background Olaparib has single-agent activity against breast/ovarian cancer (BrCa/OvCa) in germline BRCA1 or BRCA2 mutation carriers (gBRCAm). We hypothesized addition of olaparib to carboplatin can be administered safely and yield preliminary clinical activity.Methods Eligible patients had measurable or evaluable disease, gBRCAm, and good end-organ function. A 3 + 3 dose escalation tested daily oral capsule olaparib (100 or 200 mg every 12 hours; dose level1 or 2) with carboplatin area under the curve (AUC) on day 8 (AUC3 day 8), then every 21 days. For dose levels 3 to 6, patients were given olaparib days 1 to 7 at 200 and 400 mg every 12 hours, with carboplatin AUC3 to 5 on day 1 or 2 every 21 days; a maximum of eight combination cycles were permitted, after which daily maintenance of olaparib 400 mg every12 hours continued until progression. Dose-limiting toxicity was defined in the first two cycles. Peripheral blood mononuclear cells were collected for polymorphism analysis and polyADP-ribose incorporation. Paired tumor biopsies (before/after cycle 1) were obtained for biomarker proteomics and apoptosis endpoints.Results Forty-five women (37 OvCa/8 BrCa) were treated. Dose-limiting toxicity was not reached on the intermittent schedule. Expansion proceeded with olaparib 400 mg every 12 hours on days 1 to 7/carboplatin AUC5. Grade 3/4 adverse events included neutropenia (42.2%), thrombocytopenia (20.0%), and anemia (15.6%). Responses included 1 complete response (1 BrCa; 23 months) and 21 partial responses (50.0%; 15 OvCa; 6 BrCa; median = 16 [4 to >45] in OvCa and 10 [6 to >40] months in BrCa). Proteomic analysis suggests high pretreatment pS209-eIF4E and FOXO3a correlated with duration of response (two-sided P < .001; Pearson's R-2 = 0.94).Conclusions Olaparib capsules 400 mg every 12 hours on days 1 to 7/carboplatin AUC5 is safe and has activity in gBRCAm BrCa/OvCa patients. Exploratory translational studies indicate pretreatment tissue FOXO3a expression may be predictive for response to therapy, requiring prospective validation.