Phase I study of vorinostat in combination with bortezomib for relapsed and refractory multiple myeloma.
Phase I study of vorinostat in combination with bortezomib for relapsed and refractory multiple myeloma.
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Vorinostat与Bortezomib结合的I阶段研究，用于复发和难治性多发性骨髓瘤。
DOI：
10.1158/1078-0432.ccr-08-2850
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发表时间：
2009-08-15
影响因子：
11.5
通讯作者：
Grant, Steven
中科院分区：
文献类型：
--
作者：
Badros, Ashraf;Burger, Angelika M.;Philip, Sunita;Niesvizky, Ruben;Kolla, Sarah S.;Goloubeva, Olga;Harris, Carolynn;Zwiebel, James;Wright, John J.;Espinoza-Delgado, Igor;Baer, Maria R.;Holleran, Julianne L.;Egorin, Merrill J.;Grant, Steven
伏立诺他是一种组蛋白去乙酰化酶抑制剂，在体外通过蛋白酶体抑制剂硼替佐米增强细胞死亡。我们试图在临床上测试这种组合。一项I期试验评估了在复发性/难治性多发性骨髓瘤患者中，在每个21天周期的第1、4、8和11天静脉注射1- 1.3 mg/ m2硼替佐米和口服伏立诺他100-500 mg每日8天的序贯剂量递增。评价伏立诺他药物动力学和动力学。23名患者接受了治疗。患者接受了中位7种既往治疗方案（范围：3-13），包括20例自体移植，所有23例沙利度胺，17例来那度胺和19例硼替佐米，其中9例为硼替佐米难治性。2例接受500 mg伏立诺他治疗的患者出现QT间期延长和疲劳，这是剂量限制性毒性。最常见的≥3级毒性为骨髓抑制（n=13）、疲乏（n=11）和腹泻（n=5）。无药物相关死亡。总缓解率为42%，包括9例硼替佐米难治性患者中的3例部分缓解。伏立诺他药代动力学为非线性。血清Cmax在400 mg以上达到平台。CD-138+骨髓细胞在给药前和第11天的药效学变化显示，NF-κB、IκB、乙酰化微管蛋白和p21 CIP 1蛋白水平与临床应答之间无相关性。在我们的研究中，伏立诺他的最大耐受剂量为每天400 mg，每21天给药8天，硼替佐米在第1、4、8和11天以1.3 mg/m2的剂量给药。该方案在难治性患者中有希望的抗骨髓瘤活性值得进一步评价。
Vorinostat, a histone deacetylase inhibitor, enhances cell death by the proteasome inhibitor bortezomib in vitro. We sought to test the combination clinically. A phase I trial evaluated sequential dose escalation of bortezomib at 1– 1.3 mg/ m2 intravenously on days 1, 4, 8 and 11 and vorinostat at 100–500 mg orally daily for 8 days of each 21-day cycle in relapsed/refractory multiple myeloma patients. Vorinostat pharmaco-kinetics and dynamics were assessed. Twenty-three patients were treated. Patients had received a median of 7 prior regimens (range: 3–13), including autologous transplantation in 20, thalidomide in all 23, lenalidomide in 17, and bortezomib in 19, 9 of whom were bortezomib-refractory. Two patients receiving 500 mg vorinostat had prolonged QT interval and fatigue as dose-limiting toxicities. The most common grade ≥3 toxicities were myelo-suppression (n=13), fatigue (n=11) and diarrhea (n=5). There were no drug-related deaths. Overall response rate was 42%, including 3 partial responses among 9 bortezomib refractory patients. Vorinostat pharmacokinetics were non-linear. Serum Cmax reached a plateau above 400 mg. Pharmacodynamic changes in CD-138+ bone marrow cells pre- and on day 11 showed no correlation between protein levels of NF-κB, IκB, acetylated tubulin and p21CIP1 and clinical response. The maximum tolerated dose of vorinostat in our study was 400 mg daily for 8 days every 21 days, with bortezomib administered at a dose of 1.3 mg/m2 on days 1, 4, 8, and 11. The promising anti-myeloma activity of the regimen in refractory patients merits further evaluation.