Phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory diffuse large B-cell lymphoma
Phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory diffuse large B-cell lymphoma
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DOI：
10.1200/jco.2006.09.3146
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发表时间：
2007-05-01
影响因子：
45.3
通讯作者：
Shipp, Margaret A.
中科院分区：
文献类型：
--
作者：
Robertson, Michael J.;Kahl, Brad S.;Shipp, Margaret A.
目的通过基因表达谱分析、临床前评估和免疫组化分析，确定蛋白激酶C β（PKC β）是弥漫性大B细胞淋巴瘤（DLBCL）的合理治疗靶点。我们进行了一个多中心的第二阶段研究的PKC β，enzavin，在复发性或难治性DLBL.Patients和MethodsEnzavin患者口服每日一次，直到疾病进展或不可接受的毒性发生的有效抑制剂。研究终点包括自由从进展（FFP）>=两个周期（一个周期= 28天），客观反应，和toxicity. ResultsFifteen患者（中位年龄，68岁）参加。患者接受了两种既往治疗的中位数（范围，1至5）; 6例患者在高剂量治疗和自体干细胞移植后复发。仅发生1例4级毒性（低镁血症）。3级毒性包括疲乏（n = 2）、水肿（n = 1）、头痛（n = 1）、运动神经病变（n = 1）和血小板减少症（n = 1）。未发生3级或4级中性粒细胞减少症。未报告因毒性导致死亡或停药的情况。15例患者完成了不到一个周期的治疗。55例患者中有12例（22%; 95% CI，13%-46%）经历了≥ 2个周期的FFP，8例患者在≥ 4个周期内保持无进展（15%; 95% CI，6%-27%）。4例患者（7%; 95%CI，2%至18%），包括三个完全响应者和一个稳定的疾病患者，继续经历FFP 20 +至50 + months后study entry.ConclusionTreatment与恩扎鲁肽是耐受性良好，并与长期FFP复发或难治性DLBCL患者的一小部分。需要进一步研究恩扎鲁肽在DLBCL中的作用。
PurposeProtein kinase C beta (PKC beta) was identified by gene-expression profiling, preclinical evaluation, and independent immunohistochemical analysis as a rational therapeutic target in diffuse large B-cell lymphoma (DLBCL). We conducted a multicenter phase II study of a potent inhibitor of PKC beta, enzastaurin, in patients with relapsed or refractory DLBCL.Patients and MethodsEnzastaurin was taken orally once daily until disease progression or unacceptable toxicity occurred. Study end points included freedom from progression (FFP) for >= two cycles ( one cycle = 28 days), objective response, and toxicity.ResultsFifty-five patients ( median age, 68 years) were enrolled. Patients had received a median number of two prior therapies ( range, one to five); six patients relapsed after high-dose therapy and autologous stem-cell transplantation. Only one grade 4 toxicity (hypomagnesemia) occurred. Grade 3 toxicities included fatigue ( n = 2), edema ( n = 1), headache ( n = 1), motor neuropathy ( n = 1), and thrombocytopenia ( n = 1). No grade 3 or 4 neutropenia occurred. No deaths or discontinuations due to toxicity were reported. Fifteen patients completed less than one cycle of therapy. Twelve of 55 patients (22%; 95% CI, 13% to 46%) experienced FFP for >= two cycles, and eight patients remained free from progression for >= four cycles (15%; 95% CI, 6% to 27%). Four patients (7%; 95% CI, 2% to 18%), including three complete responders and one patient with stable disease, continue to experience FFP 20 + to 50 + months after study entry.ConclusionTreatment with enzastaurin was well-tolerated and associated with prolonged FFP in a small subset of patients with relapsed or refractory DLBCL. Further studies of enzastaurin in DLBCL are warranted.