A Phase I Clinical, Pharmacokinetic, and Pharmacodynamic Study of Weekly or Every Three Week Ixabepilone and Daily Sunitinib in Patients with Advanced Solid Tumors.
A Phase I Clinical, Pharmacokinetic, and Pharmacodynamic Study of Weekly or Every Three Week Ixabepilone and Daily Sunitinib in Patients with Advanced Solid Tumors.
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DOI：
10.1158/1078-0432.ccr-15-2184
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发表时间：
2016-07-01
期刊：
影响因子：
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通讯作者：
Merchan JR
中科院分区：
文献类型：
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作者：
Montero AJ;Kwon D;Flores A;Kovacs K;Trent JC;Benedetto P;Rocha-Lima C;Merchan JR
目的：评价在晚期实体瘤患者中每周或每三周联合应用伊克沙比平和每日舒尼替尼的安全性、最大耐受量(MTD)、药代动力学/药效学和早期临床活性。符合条件的患者从第一周期的第8天开始每周(方案A)或每3周(方案B)递增剂量(方案A：7.5、15或20 mg/m2；方案B：20、30或40 mg/m2)和口服舒尼替尼(每天37.5 mg)。在第一周期中评估剂量限制毒性(DLTS)。在3名受试者中观察到DLT(附表3A中1例，附表3B中2例)。最常见的3-4级血液学和非血液学不良事件(AEs)分别是白细胞减少和乏力。4例患者(附表A中3例)部分缓解(PR)，13例病情稳定(SD)。在17名经过深度预处理的结直肠癌患者中，有9名患者获得了临床益处。每周(但不是每3周)联合服用舒尼替尼和伊克沙比隆与显著增加半衰期和显著降低伊克沙比隆的清除量有关。相关研究表明，A组患者较高的基线血浆血管生成活性(PAA)与临床获益显著相关。每周一次，而不是每三周一次，伊克沙比隆导致基线后PAA显著下降。在经过大量预治疗的患者，尤其是转移性结直肠癌患者中，联合应用伊克沙比隆和舒尼替尼具有可接受的毒性和令人鼓舞的临床活性。
To evaluate the safety, maximum tolerated dose (MTD), pharmacokinetics/pharmacodynamics, and early clinical activity of ixabepilone given either weekly or every three weeks in combination with daily sunitinib in patients with advanced solid tumors. Eligible patients received either weekly (Schedule A) or every 3 weeks (schedule B) Ixabepilone at escalating doses (schedule A: 7.5, 15, or 20 mg/m2;; schedule B: 20, 30, or 40 mg/m2), and oral sunitinib (37.5 mg daily), starting on day 8 of cycle 1. Dose-limiting toxicities (DLTs) were assessed during cycle 1. The ixabepilone and sunitinib combination was fairly well tolerated. DLTs were observed in 3 subjects (1 in schedule 3A and 2 in schedule 3B). The most common grade 3–4 hematological and non-hematological adverse events (AEs) were leukopenia and fatigue, respectively. Four patients (3 in schedule A) achieved a partial response (PR), while 13 patients had stable disease (SD). Nine of 17 heavily pretreated colorectal cancer patients had clinical benefit. Co-administration of sunitinib with ixabepilone on a weekly (but not every 3 week) schedule was associated with a significant increase in the half-life and a significant decrease in clearance of ixabepilone. Correlative studies demonstrated a significant association between higher baseline plasma angiogenic activity (PAA) and clinical benefit in schedule A patients. Weekly, but not every 3 weeks Ixabepilone led to a significant decrease in PAA post-baseline. Co-administration of ixabepilone with sunitinib has acceptable toxicity and encouraging clinical activity in heavily pretreated patients, particularly in patients with metastatic colorectal cancer.