Clinical and Translational Studies of a Phase II Trial of the Novel Oral Akt Inhibitor Perifosine in Relapsed or Relapsed/Refractory Waldenstrom's Macroglobulinemia

被引：90

作者：

Ghobrial, Irene M. ^{[1
]}

Roccaro, Aldo ^{[1
]}

Hong, Fangxin ^{[1
]}

Weller, Edie ^{[1
]}

Rubin, Nancy ^{[3
]}

Leduc, Renee ^{[1
]}

Rourke, Meghan ^{[1
]}

Chuma, Stacey ^{[1
]}

Sacco, Antonio ^{[1
]}

Jia, Xiaoying ^{[1
]}

Azab, Feda ^{[1
]}

Azab, Abdel Kareem ^{[1
]}

Rodig, Scott ^{[2
]}

Warren, Diane ^{[1
]}

Harris, Brianna ^{[1
]}

Varticovski, Lyuba ^{[4
]}

Sportelli, Peter ^{[5
]}

Leleu, Xavier ^{[1
]}

Anderson, Kenneth C. ^{[1
]}

Richardson, Paul G. ^{[1
]}

机构：

[1] Dana Farber Canc Inst, Boston, MA 02115 USA

[2] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

[3] Community Hosp Monterey Peninsula, Monterey, CA USA

[4] NCI, Ctr Canc Res, Bethesda, MD 20892 USA

[5] Keryx Biopharmaceut Inc, New York, NY USA

来源：

CLINICAL CANCER RESEARCH | 2010年 / 16卷 / 03期

关键词：

CONSENSUS PANEL RECOMMENDATIONS; 2ND INTERNATIONAL WORKSHOP; THERAPY; PATHWAY; BORTEZOMIB; APOPTOSIS; SURVIVAL; CRITERIA;

D O I：

10.1158/1078-0432.CCR-09-1837

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Background: Waldenstrom's macroglobulinemia (WM) is a rare, low-grade lymphoproliferative disorder. Based on preclinical studies, we conducted a phase II clinical trial testing the efficacy and safety of the Akt inhibitor perifosine in patients with relapsed/refractory WM. Patients and Methods: Thirty-seven patients were treated with oral perifosine (150 mg daily) for six cycles. Stable or responding patients were allowed to continue therapy until progression. Results: The median age was 65 years (range, 44-82). The median number of prior therapy lines was two (range, one to five). Of the 37 patients, 4 achieved partial response (11%), 9 minimal response (24%), and 20 showed stable disease (54%). The median progression-free survival was 12.6 months. Additionally, beta 2 microglobulin of >3.5 mg/dL was associated with poor event-free survival (P = 0.002). Perifosine was generally well tolerated; adverse events related to therapy were cytopenias (grade 3-4, 13%), gastrointestinal symptoms (grade 1-2, 81%), and arthritis flare (all grades, 11%). Translational studies using gene expression profiling and immunohistochemistry showed that perifosine inhibited pGSK activity downstream of Akt, and inhibited nuclear factor kappa B activity. Conclusion: Perifosine resulted in at least a minimal response in 35% of patients and a median progression-free survival of 12.6 months in patients with relapsed or relapsed/refractory WM, as well as in vivo inhibition of pGSK activity. The results of this study warrant further evaluation of perifosine in combination with rituximab or other active agents in patients with WM. Clin Cancer Res; 16(3); 1033-41. (C) 2010 AACR.

引用

页码：1033 / 1041

页数：9

共 33 条

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