帕比司他和硼替佐米治疗复发或复发难治性多发性骨髓瘤的 Ib 期研究。
Phase Ib study of panobinostat and bortezomib in relapsed or relapsed and refractory multiple myeloma.
机构信息
Jesús F. San-Miguel and María Victoria Mateos, Servicio e Hematologia, Hospital Universitario de Salamanca, Instituto de Investigación Biomédica de Salamanca, Institut de Bilogia Molecular de Barcelona (Universidad de Salamanca-Spanish National Research Council), Salamanca; Joan Bladé, Hospital Clinic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Paul G. Richardson and Kenneth C. Anderson, Dana-Farber Cancer Institute, Boston, MA; David Siegel, Hackensack University Medical Center, Hackensack; Kaushal K. Mishra and Song Mu, Novartis Pharmaceuticals Corporation, East Hanover, NJ; Andreas Günther, University of Kiel, Kiel; Orhan Sezer, Charité Universitätsmedizin Berlin, Berlin, Germany; Richard LeBlanc, Maisonneuve-Rosemont Hospital, Montreal, Quebec; Heather Sutherland, Vancouver General Hospital, Vancouver, British Columbia, Canada; and Monika Sopala and Priscille M. Bourquelot, Novartis Pharma AG, Basel, Switzerland.
出版信息
J Clin Oncol. 2013 Oct 10;31(29):3696-703. doi: 10.1200/JCO.2012.46.7068. Epub 2013 Sep 9.
PURPOSE
Despite advancements, prognosis for patients with relapsed/refractory multiple myeloma (MM) is poor, and novel therapies are needed. Panobinostat is a potent deacetylase inhibitor that elicits synergistic effects on MM cells in combination with bortezomib. This phase Ib study sought to determine the maximum-tolerated dose (MTD) of panobinostat plus bortezomib in patients with relapsed or relapsed and refractory MM.
PATIENTS AND METHODS
In the dose-escalation phase (n = 47), panobinostat was administered orally thrice weekly every week in combination with bortezomib (21-day cycles). After MTD determination, patients were evaluated in an expansion phase (n = 15) that incorporated a 1-week treatment holiday of panobinostat, with dexamethasone added in cycle 2. Additional assessments included safety, pharmacokinetics, and efficacy per International Myeloma Working Group criteria.
RESULTS
The MTD was established at panobinostat 20 mg plus bortezomib 1.3 mg/m(2). Grade 3 or 4 adverse events (AEs) included thrombocytopenia (85.1%), neutropenia (63.8%), and asthenia (29.8%) in the escalation phase, and thrombocytopenia (66.7%), neutropenia (46.7%), and fatigue (20.0%) in the expansion phase. At MTD in the escalation phase, eight patients (47.1%) discontinued therapy as a result of AEs, whereas five patients (33.3%) discontinued treatment in the expansion phase. Expansion phase patients demonstrated greater median treatment duration. Overall response rate (ORR) was 73.3% in the expansion phase and 52.9% at the escalation phase MTD. Among bortezomib-refractory patients, the ORR was 26.3%, and 42.1% of patients had ≥ minimal response.
CONCLUSION
The MTD of panobinostat plus bortezomib was determined and demonstrated activity in patients with relapsed or relapsed/refractory MM, including bortezomib-refractory patients. A phase II/III clinical trial program (Panobinostat or Placebo With Bortezomib and Dexamethasone in Patients With Relapsed Multiple Myeloma [PANORAMA]) has been initiated.
目的
尽管取得了进展，但复发/难治性多发性骨髓瘤（MM）患者的预后仍然较差，需要新的治疗方法。帕比司他是一种有效的去乙酰化酶抑制剂，与硼替佐米联合使用时可对 MM 细胞产生协同作用。这项 Ib 期研究旨在确定复发或复发/难治性 MM 患者中帕比司他联合硼替佐米的最大耐受剂量（MTD）。
方法
在剂量递增阶段（n = 47），帕比司他每周口服 3 次，与硼替佐米联合使用（21 天周期）。确定 MTD 后，在扩展阶段（n = 15）中评估患者，其中包括帕比司他 1 周的治疗假期，并在第 2 周期中加入地塞米松。其他评估包括安全性、药代动力学和国际骨髓瘤工作组标准的疗效。
结果
帕比司他 20 mg 加硼替佐米 1.3 mg/m2 确定为 MTD。递增阶段中 3 级或 4 级不良事件（AE）包括血小板减少症（85.1%）、中性粒细胞减少症（63.8%）和乏力（29.8%），扩展阶段中血小板减少症（66.7%）、中性粒细胞减少症（46.7%）和疲劳（20.0%）。在递增阶段的 MTD 时，8 名患者（47.1%）因 AE 而停止治疗，而在扩展阶段中有 5 名患者（33.3%）停止治疗。扩展阶段患者的中位治疗持续时间更长。扩展阶段的总缓解率（ORR）为 73.3%，递增阶段 MTD 时为 52.9%。在硼替佐米耐药患者中，ORR 为 26.3%，≥最小反应的患者为 42.1%。
结论
确定了帕比司他联合硼替佐米的 MTD，并在复发或复发/难治性 MM 患者中显示出活性，包括硼替佐米耐药患者。已经启动了一项 II/III 期临床试验计划（复发多发性骨髓瘤患者中帕比司他或安慰剂联合硼替佐米和地塞米松[PANORAMA]）。
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