A phase I combination study of olaparib with cisplatin and gemcitabine in adults with solid tumors.
A phase I combination study of olaparib with cisplatin and gemcitabine in adults with solid tumors.
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DOI：
10.1158/1078-0432.ccr-11-2425
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发表时间：
2012-04-15
期刊：
影响因子：
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通讯作者：
Giaccone G
中科院分区：
文献类型：
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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
确定奥拉帕尼联合顺铂和吉西他滨的安全性和耐受性，确定最大耐受剂量（MTD），并评价联合用药的药效学和药代动力学特征。我们在晚期实体瘤患者中进行了奥拉帕尼与顺铂和吉西他滨的I期研究。剂量水平1（DL 1）的治疗包括第1 - 4天每12小时口服100 mg奥拉帕尼，第3和10天口服500 mg/m2吉西他滨，第3天口服60 mg/m2顺铂。在外周血单核细胞（PBMC）中测量PAR水平。DL 1时，2/3例患者的剂量限制性毒性（DLT）包括血小板减少和发热性中性粒细胞减少。对方案进行了修订，以入组既往接受过≤2种重度骨髓抑制化疗方案治疗并在第1 - 4天接受奥拉帕尼100 mg每日一次治疗的患者（DL- 1）。DL-1时，6例患者未观察到DLT。由于恢复至DL 1后持续性血小板减少症和中性粒细胞减少症，患者仅在第1天每12小时接受100 mg奥拉帕尼治疗。未观察到血液学DLT;非血液学DLT包括胃肠道出血、晕厥和缺氧。在21例可评价缓解的患者中，2例部分缓解。奥拉帕尼抑制PBMC和肿瘤组织中的PARP，尽管当奥拉帕尼短时间使用时，PAR水平的抑制效果较差。奥拉帕尼联合顺铂和吉西他滨与骨髓抑制相关，即使在相对低的剂量下。在化疗初治患者中，必须采用标准剂量的化疗探索奥拉帕尼的改良方案。
To determine the safety and tolerability of olaparib with cisplatin and gemcitabine, establish the maximum tolerated dose (MTD), and evaluate the pharmacodynamic and pharmacokinetic profile of the combination. We conducted a phase I study of olaparib with cisplatin and gemcitabine in patients with advanced solid tumors. Treatment at dose level 1 (DL1) consisted of olaparib 100 mg orally every 12 hours on days 1 to 4, gemcitabine 500 mg/m2 on days 3 and 10, and cisplatin 60 mg/m2 on day 3. PAR levels were measured in peripheral blood mononuclear cells (PBMC). Dose-limiting toxicities (DLT) in two of three patients at DL1 included thrombocytopenia and febrile neutropenia. The protocol was amended to enroll patients treated with ≤2 prior severely myelosuppressive chemotherapy regimens and treated with olaparib 100 mg once daily on days 1 to 4 (DL– 1). No DLTs were seen in six patients at DL–1. Because of persistent thrombocytopenia and neutropenia following a return to DL1, patients received 100 mg olaparib every 12 hours on day 1 only. No hematologic DLTs were observed; nonhematologic DLTs included gastrointestinal bleed, syncope, and hypoxia. Of 21 patients evaluable for response, two had partial response. Olaparib inhibited PARP in PBMCs and tumor tissue, although PAR levels were less effectively inhibited when olaparib was used for a short duration. Olaparib in combination with cisplatin and gemcitabine is associated with myelosuppression even at relatively low doses. Modified schedules of olaparib in chemotherapy naive patients will have to be explored with standard doses of chemotherapy.