Olaparib in combination with irinotecan, cisplatin, and mitomycin C in patients with advanced pancreatic cancer.
Olaparib in combination with irinotecan, cisplatin, and mitomycin C in patients with advanced pancreatic cancer.
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DOI：
10.18632/oncotarget.17237
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发表时间：
2017-07-04
期刊：
影响因子：
--
通讯作者：
Goggins M
中科院分区：
文献类型：
--
作者：
Yarchoan M;Myzak MC;Johnson BA 3rd;De Jesus-Acosta A;Le DT;Jaffee EM;Azad NS;Donehower RC;Zheng L;Oberstein PE;Fine RL;Laheru DA;Goggins M
奥拉帕尼是一种口服聚腺苷 5'-二磷酸核糖聚合 (PARP) 抑制剂，此前已在 BRCA 突变和胰腺导管腺癌 (PDAC) 患者中显示出活性迹象。在这项针对不可切除的 PDAC 患者的 1 期剂量递增试验中，我们确定了奥拉帕尼（片剂）在 28 天周期（奥拉帕尼加 IC）的第 1 天和第 8 天联合伊立替康 70 mg/m2，以及第 1 天和第 8 天联合顺铂 25 mg/m2 的最大耐受剂量 (MTD)。然后，我们研究了在该方案（奥拉帕尼加 ICM）的第一天添加丝裂霉素 C 5 mg/m2 的安全性和耐受性。 18 名无法切除的 PDAC 患者入组。奥拉帕尼加 IC 的 MTD 为奥拉帕尼 100 mg，每日两次，第 1 天和第 8 天。在此剂量水平添加丝裂霉素 C 是不耐受的。 16 名患者 (89%) 发生了≥3 级药物相关不良事件 (AE)。最常见的 ≥3 级药物相关毒性包括中性粒细胞减少症 (89%)、淋巴细胞减少症 (72%) 和贫血 (22%)。两名患者 (11%) 均接受了超过 12 个周期的研究，并出现了药物相关的骨髓增生异常综合征 (MDS)。所有可评估患者的客观缓解率 (ORR) 为 23%。一名携带有害种系 BRCA2 突变的患者具有持续四年多的持久临床反应，但死于治疗相关的 MDS 并发症。奥拉帕尼与 IC 或 ICM 联合治疗 PDAC 患者时具有显着的毒性，并且这种治疗组合不具有可接受的风险/获益情况以供进一步研究。然而，在部分患者中观察到持久的临床反应，因此有必要对 PDAC 中的 PARP 抑制剂进行进一步的临床研究。该临床试验在 ClinicalTrials.gov 上注册为 NCT01296763。
Olaparib is an oral inhibitor of polyadenosine 5’-diphosphoribose polymerization (PARP) that has previously shown signs of activity in patients with BRCA mutations and pancreatic ductal adenocarcinoma (PDAC). In this phase 1 dose-escalation trial in patients with unresectable PDAC, we determined the maximum tolerated dose (MTD) of olaparib (tablet formulation) in combination with irinotecan 70 mg/m2 on days 1 and 8 and cisplatin 25 mg/m2 on days 1 and 8 of a 28-day cycle (olaparib plus IC). We then studied the safety and tolerability of adding mitomycin C 5 mg/m2 on day 1 to this regimen (olaparib plus ICM). 18 patients with unresectable PDAC were enrolled. The MTD of olaparib plus IC was olaparib 100 mg twice-daily on days 1 and 8. The addition of mitomycin C to this dose level was not tolerated. Grade ≥3 drug-related adverse events (AEs) were encountered in 16 patients (89%). The most common grade ≥3 drug-related toxicities included neutropenia (89%), lymphopenia (72%), and anemia (22%). Two patients (11%), both of whom had remained on study for more than 12 cycles, developed drug-related myelodysplastic syndrome (MDS). The objective response rate (ORR) for all evaluable patients was 23%. One patient who carried a deleterious germline BRCA2 mutation had a durable clinical response lasting more than four years, but died from complications of treatment-related MDS. Olaparib had substantial toxicity when combined with IC or ICM in patients with PDAC, and this treatment combination did not have an acceptable risk/benefit profile for further study. However, durable clinical responses were observed in a subset of patients and further clinical investigation of PARP inhibitors in PDAC is warranted. This clinical trial was registered on ClinicalTrials.gov as NCT01296763.
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影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
通讯作者：
Verweij, J.
影响因子：
8.8
作者：
Slater, S;Shamash, J;Slevin, ML
通讯作者：
Slevin, ML
DOI：
10.1073/pnas.0806092105
发表时间：
2008-11-04
影响因子：
11.1
作者：
Rottenberg, Sven;Jaspers, Janneke E.;Jonkers, Jos
通讯作者：
Jonkers, Jos
影响因子：
11.5
作者：
Kim, Geoffrey;Ison, Gwynn;Pazdur, Richard
通讯作者：
Pazdur, Richard
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