Phase I study of olaparib in combination with liposomal doxorubicin in patients with advanced solid tumours.
Phase I study of olaparib in combination with liposomal doxorubicin in patients with advanced solid tumours.
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DOI：
10.1038/bjc.2014.345
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发表时间：
2014-08-12
影响因子：
8.8
通讯作者：
Gianni, L.
中科院分区：
文献类型：
--
作者：
Del Conte, G.;Sessa, C.;von Moos, R.;Vigano, L.;Digena, T.;Locatelli, A.;Gallerani, E.;Fasolo, A.;Tessari, A.;Cathomas, R.;Gianni, L.
奥拉帕尼是一种口服PARP抑制剂，在生殖系BRCA 1/2（gBRCA）突变的乳腺癌和卵巢癌患者中显示出单药治疗的抗肿瘤活性。本研究评价了奥拉帕尼胶囊联合多柔比星脂质体（PLD）治疗晚期实体瘤患者的疗效（NCT 00819221）。患者接受28天周期的奥拉帕尼，连续（第1-28天）或间歇（第1-7天），加上PLD（40 mg m-2，第1天）;探索7个奥拉帕尼剂量队列（50-400 mg bid）以确定推荐剂量。评估包括安全性、药代动力学、药效学和初步疗效（客观缓解率（ORR））。在接受治疗的44例患者中（卵巢，n=28;乳腺，n=13;其他/未知，n=3），2例发生剂量限制性毒性（3级口腔炎和致死性肺炎/肺炎（200 mg/28天周期）; 4级血小板减少症（400 mg/7天周期））。使用连续奥拉帕尼400 mg bid加PLD未达到最大耐受剂量。分别有27例（61%）和12例（27%）患者报告了≥ 3级和严重AE。奥拉帕尼和PLD之间未观察到重大药代动力学干扰。ORR为33%（n=14/42;完全缓解，n=3）。共有13名应答者患有卵巢癌：10名为铂类药物敏感，11名为gBRCA突变。持续/间歇奥拉帕尼（高达400 mg bid）联合PLD（40 mg m−2）通常耐受，并显示出卵巢癌抗肿瘤活性的证据。
Olaparib, an oral PARP inhibitor, has shown antitumour activity as monotherapy in patients with germline BRCA1/2 (gBRCA)-mutated breast and ovarian cancer. This study evaluated olaparib capsules in combination with liposomal doxorubicin (PLD) in patients with advanced solid tumours (NCT00819221). Patients received 28-day cycles of olaparib, continuously (days 1–28) or intermittently (days 1–7), plus PLD (40 mg m−2, day 1); seven olaparib dose cohorts (50–400 mg bid) were explored to determine the recommended dose. Assessments included safety, pharmacokinetics, pharmacodynamics and preliminary efficacy (objective response rate (ORR)). Of 44 patients treated (ovarian, n=28; breast, n=13; other/unknown, n=3), two experienced dose-limiting toxicities (grade 3 stomatitis and fatal pneumonia/pneumonitis (200 mg per 28-day cycle); grade 4 thrombocytopenia (400 mg per 7-day cycle)). The maximum tolerated dose was not reached using continuous olaparib 400 mg bid plus PLD. Grade ⩾3 and serious AEs were reported for 27 (61%) and 12 (27%) patients, respectively. No major pharmacokinetic interference was observed between olaparib and PLD. The ORR was 33% (n=14 out of 42; complete response, n=3). A total of 13 responders had ovarian cancer: 10 were platinum-sensitive, 11 had a gBRCA mutation. Continuous/intermittent olaparib (up to 400 mg bid) combined with PLD (40 mg m−2) was generally tolerated and showed evidence of antitumour activity in ovarian cancer.
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DOI：
10.1158/1078-0432.ccr-11-2821
发表时间：
2012-03-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Kummar S;Ji J;Morgan R;Lenz HJ;Puhalla SL;Belani CP;Gandara DR;Allen D;Kiesel B;Beumer JH;Newman EM;Rubinstein L;Chen A;Zhang Y;Wang L;Kinders RJ;Parchment RE;Tomaszewski JE;Doroshow JH
通讯作者：
Doroshow JH
DOI：
10.1186/bcr3484
发表时间：
2013
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Dent RA;Lindeman GJ;Clemons M;Wildiers H;Chan A;McCarthy NJ;Singer CF;Lowe ES;Watkins CL;Carmichael J
通讯作者：
Carmichael J
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：
9.7
作者：
Munoz-Gamez, J. A.;Quiles-Perez, R.;Salmeron, J.
通讯作者：
Salmeron, J.
影响因子：
8.8
作者：
Khan, O. A.;Gore, M.;Lorigan, P.;Stone, J.;Greystoke, A.;Burke, W.;Carmichael, J.;Watson, A. J.;McGown, G.;Thorncroft, M.;Margison, G. P.;Califano, R.;Larkin, J.;Wellman, S.;Middleton, M. R.
通讯作者：
Middleton, M. R.