Olaparib和alpha-specific PI3K抑制剂alpelisib上皮卵巢癌患者:剂量递增和dose-expansion阶段1 b的审判。
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Konstantinopoulos PA,巴里WT, bir M,威斯汀SN, Cadoo KA,夏皮罗GI,梅耶尔EL, O 'Cearbhaill再保险,科尔曼RL, Kochupurakkal B, C惠伦,柯蒂斯J, Farooq年代,罗W, Eismann J,巴斯可,Aghajanian C,米尔斯GB, Palakurthi年代,Kirschmeier P,刘J,坎特LC,考夫曼SH,史伟莎EM, D 'Andrea广告,维纳E,沃尔夫通用,Matulonis UA
Olaparib和alpha-specific PI3K抑制剂alpelisib上皮卵巢癌患者:剂量递增和dose-expansion阶段1 b的审判。
4月柳叶刀杂志。2019;20 (4):570 - 580。doi: 10.1016 / s1470 - 2045 (18) 30905 - 7。Epub 2019年3月14日。
- PubMed ID
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30880072 (在PubMed]
- 文摘
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背景:临床前期工作基础上,我们发现,结合聚(ADP-ribose)聚合酶(PARP)抑制剂药物抑制同源重组修复(嗯)途径(如PI3K抑制剂)可能会使敏感HRR-proficient上皮卵巢癌PARP抑制剂。我们旨在评估安全并确定推荐的第二阶段剂量的PARP抑制剂olaparib结合PI3K抑制剂患者alpelisib上皮卵巢癌和乳腺癌患者。方法:多中心、非盲、3 + 3剂量递增后1 b阶段试验设计,我们招募患者18岁或以上以下关键合格标准:证实诊断复发性卵巢,输卵管,高档浆液性或原发性腹膜癌组织学;确认诊断复发性卵巢,输卵管,或原发性腹膜癌组织学与已知的生殖系BRCA突变;三阴性乳腺癌复发组织学证实诊断;复发性乳腺癌的诊断或确诊的组织学与已知的生殖系BRCA突变。额外的卵巢上皮癌患者参加dose-expansion队列。四个剂量水平计划:起始剂量水平的alpelisib每天250毫克一次+ olaparib 100毫克,一天两次(剂量级别0);alpelisib每天250毫克一次+ olaparib 200毫克,一天两次(剂量1级);alpelisib每天300毫克一次+ olaparib 200毫克,一天两次(剂量级别2); and alpelisib 200 mg once a day plus olaparib 200 mg twice a day (dose level 3). Both drugs were administered orally, in tablet formulation. The primary objective was to identify the maximum tolerated dose and the recommended phase 2 dose of the combination of alpelisib and olaparib for patients with epithelial ovarian cancer and patients with breast cancer. Analyses included all patients who received at least one dose of the study drugs. The trial is active, but closed to enrolment; follow-up for patients who completed treatment is ongoing. This trial is registered with ClinicalTrials.gov, number NCT01623349. FINDINGS: Between Oct 3, 2014, and Dec 21, 2016, we enrolled 34 patients (28 in the dose-escalation cohort and six in the dose-expansion cohort); two in the dose-escalation cohort were ineligible at the day of scheduled study initiation. Maximum tolerated dose and recommended phase 2 dose were identified as alpelisib 200 mg once a day plus olaparib 200 mg twice a day (dose level 3). Considering all dose levels, the most common treatment-related grade 3-4 adverse events were hyperglycaemia (five [16%] of 32 patients), nausea (three [9%]), and increased alanine aminotransferase concentrations (three [9%]). No treatment-related deaths occurred. Dose-limiting toxic effects included hyperglycaemia and fever with decreased neutrophil count. Of the 28 patients with epithelial ovarian cancer, ten (36%) achieved a partial response and 14 (50%) had stable disease according to Response Evaluation Criteria in Solid Tumors 1.1. INTERPRETATION: Combining alpelisib and olaparib is feasible with no unexpected toxic effects. The observed activity provides preliminary clinical evidence of synergism between olaparib and alpelisib, particularly in epithelial ovarian cancer, and warrants further investigation. FUNDING: Ovarian Cancer Dream Team (Stand Up To Cancer, Ovarian Cancer Research Alliance, National Ovarian Cancer Coalition), Breast Cancer Research Foundation, Novartis.
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