A phase I clinical-pharmacodynamic study of the farnesyltransferase inhibitor tipifarnib in combination with the proteasome inhibitor bortezomib in advanced acute leukemias.
A phase I clinical-pharmacodynamic study of the farnesyltransferase inhibitor tipifarnib in combination with the proteasome inhibitor bortezomib in advanced acute leukemias.
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DOI：
10.1158/1078-0432.ccr-10-1878
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发表时间：
2011-03-01
期刊：
影响因子：
--
通讯作者：
Sullivan DM
中科院分区：
文献类型：
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作者：
Lancet JE;Duong VH;Winton EF;Stuart RK;Burton M;Zhang S;Cubitt C;Blaskovich MA;Wright JJ;Sebti S;Sullivan DM
确定替吡法尼联合硼替佐米治疗晚期急性白血病患者的安全性、靶点抑制和临床活性信号。在3 + 3设计中，患者每3周接受递增剂量的替吡法尼（第1 - 14天）和硼替佐米（第1、4、8、11天），直到达到最大耐受剂量。在第1、8和22天收集外周血单核细胞（PBMC）用于测量胰凝乳蛋白酶样和法尼基转移酶活性。在基线和第8天收集纯化的骨髓白血病原始细胞用于测量NF-κ B活性。联合用药耐受性良好，未达到最大耐受剂量。剂量限制性毒性包括腹泻、疲劳和感觉运动神经病。在第8天，大多数患者PBMC内的胰凝乳蛋白酶样和法尼基转移酶活性降低。在第8天，大多数患者白血病原始细胞内的NF-κ B活性降低。在2例患者中观察到完全缓解伴计数不完全恢复，另外5例患者病情稳定。替吡法尼和硼替佐米联合治疗晚期白血病患者耐受性良好，表现出相关的靶点抑制作用，并与晚期和难治性急性白血病患者的临床活性信号相关。这种组合的未来研究可能需要在更多选定的患者群体中进行，这些分子靶点在这些患者中特别重要。
To determine the safety, target inhibition, and signals of clinical activity of tipifarnib in combination with bortezomib in patients with advanced acute leukemias. In a 3+3 design, patients received escalating doses of tipifarnib (days 1–14) and bortezomib (days 1, 4, 8, 11) every 3 weeks until maximum tolerated dose was reached. Peripheral blood mononuclear cells (PBMCs) were collected at days 1, 8, and 22 for measurement of chymotrypsin-like and farnesyltransferase activity. Purified bone marrow leukemic blasts were collected at baseline and at day 8 for measurement of NF-kB activity. The combination was well-tolerated, and maximum tolerated dose was not reached. Dose-limiting toxicities included diarrhea, fatigue, and sensorimotor neuropathy. Chymotrypsin-like and farnesyltransferase activity within PBMCs were decreased in a majority of patients at day 8. NF-kB activity within leukemic blasts was decreased in a majority of patients at day 8. Complete response with incomplete count recovery was observed in 2 patients, and an additional 5 patients had stable disease. Tipifarnib and bortezomib combination in patients with advanced leukemias was well-tolerated, demonstrated relevant target inhibition, and was associated with signals of clinical activity in patients with advanced and refractory acute leukemias. Future studies of this combination may be warranted in more selected groups of patients in whom these molecular targets are of particular importance.