A phase 1/2 study of oral panobinostat combined with melphalan for patients with relapsed or refractory multiple myeloma

被引:37
作者
Berenson, James R. [1 ,2 ,3 ]
Hilger, James D. [1 ]
Yellin, Ori [1 ]
Boccia, Ralph V. [4 ]
Matous, Jeffrey [5 ]
Dressler, Kenneth [6 ]
Ghazal, Hassan H. [7 ]
Jamshed, Saad [8 ]
Kingsley, Edwin C. [9 ]
Harb, Wael A. [10 ]
Noga, Stephen J. [11 ]
Nassir, Youram [2 ]
Swift, Regina A. [2 ]
Vescio, Robert [12 ]
机构
[1] Oncotherapeutics, Los Angeles, CA USA
[2] James R Berenson MD Inc, Los Angeles, CA USA
[3] Inst Myeloma & Bone Canc Res, West Hollywood, CA 90069 USA
[4] Ctr Canc & Blood Disorders, Bethesda, MD USA
[5] Colorado Blood Canc Inst, Denver, CO USA
[6] St Vincents Med Ctr, Bridgeport, CT USA
[7] Kentucky Canc Clin, Hazard, KY USA
[8] Linden Oaks Lipson Canc Ctr, Rochester, NY USA
[9] Comprehens Canc Centers Nevada, Las Vegas, NV USA
[10] Horizon Oncol Res Inc, Lafayette, IN USA
[11] Harry & Jeanette Weinberg Canc Inst, Baltimore, MD USA
[12] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA
关键词
Panobinostat; Melphalan; Multiple myeloma; Relapsed/refractory; HISTONE DEACETYLASE INHIBITOR; SINGLE-AGENT; LBH589; BORTEZOMIB; COMBINATION; VORINOSTAT; POTENT; DEXAMETHASONE; DISEASE; CANCER;
D O I
10.1007/s00277-013-1910-2
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Panobinostat is a histone deacetylase inhibitor that has shown synergistic preclinical anti-myeloma activity when combined with other agents, recently exhibiting synergy with the alkylating agent melphalan (Sanchez et al., Leuk Res 35(3):373-379, 2011). This phase 1/2 trial investigated the safety and efficacy of panobinostat in combination with melphalan for relapsed/refractory multiple myeloma patients. There were four different trial treatment schedules due to tolerability issues, with the final treatment schedule (treatment schedule D) consisting of panobinostat (15 or 20 mg) and melphalan (0.05 or 0.10 mg/kg), both administered on days 1, 3, and 5 of a 28-day cycle. A total of 40 patients were enrolled; 3 in treatment schedule A, 9 in schedule B, 7 in schedule C, and finally 21 schedule D. Patients had been treated with a median of four regimens (range, 1-16) and two prior bortezomib-containing regimens (range, 0-9). Maximum-tolerated dose was established at 20 mg panobinostat and 0.05 mg/kg melphalan in treatment schedule D. Overall, 3 patients (7.5 %) achieved a parts per thousand yenpartial response (two very good PRs and one PR) while 23 exhibited stable disease and 14 showed progressive disease. All three responders were enrolled in cohort 2 of treatment schedule B (panobinostat 20 mg thrice weekly continuously with melphalan 0.05 mg/kg on days 1, 3, and 5). Neutropenia and thrombocytopenia were common, with 30.8 and 23.1 % of patients exhibiting a parts per thousand yengrade 3, respectively. Panobinostat + melphalan appears to have tolerability issues in a dosing regimen capable of producing a response. Care must be taken to balance tolerability and efficacy with this combination.
引用
收藏
页码:89 / 98
页数:10
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