Phase Ib Study of Panobinostat and Bortezomib in Relapsed or Relapsed and Refractory Multiple Myeloma
Phase Ib Study of Panobinostat and Bortezomib in Relapsed or Relapsed and Refractory Multiple Myeloma
复制标题
DOI：
10.1200/jco.2012.46.7068
复制
发表时间：
2013-10-10
影响因子：
45.3
通讯作者：
Anderson, Kenneth C.
中科院分区：
文献类型：
--
作者：
San-Miguel, Jesus F.;Richardson, Paul G.;Anderson, Kenneth C.
目的尽管取得了进展，但复发/难治性多发性骨髓瘤 (MM) 患者的预后很差，需要新的治疗方法。 Panobinostat 是一种有效的脱乙酰酶抑制剂，与硼替佐米联合使用可对 MM 细胞产生协同作用。这项 Ib 期研究旨在确定帕比司他加硼替佐米治疗复发或复发难治性 MM 患者的最大耐受剂量 (MTD)。 患者和方法在剂量递增阶段 (n = 47)，每周三次口服帕比司他与硼替佐米联合用药（21 天周期）。 MTD确定后，在扩展阶段（n = 15）对患者进行评估，其中包括帕比司他1周的治疗假期，并在第2周期中添加地塞米松。其他评估包括按照国际骨髓瘤工作组标准的安全性、药代动力学和疗效。结果MTD是在帕比司他20 mg加硼替佐米1.3 mg/m2建立的。 3级或4级不良事件（AE）包括升级阶段的血小板减少症（85.1%）、中性粒细胞减少症（63.8%）和乏力（29.8%），以及扩展阶段的血小板减少症（66.7%）、中性粒细胞减少症（46.7%）和疲劳（20.0%）。在升级阶段的 MTD，8 名患者 (47.1%) 由于 AE 停止治疗，而 5 名患者 (33.3%) 在扩展阶段停止治疗。扩展期患者表现出更长的中位治疗持续时间。扩展阶段的总体缓解率 (ORR) 为 73.3%，升级阶段的 MTD 为 52.9%。在硼替佐米难治性患者中，ORR 为 26.3%，42.1% 的患者反应最小。 结论 确定了帕比司他加硼替佐米的 MTD，并在复发或复发/难治性 MM 患者（包括硼替佐米难治性患者）中证明了活性。 II/III 期临床试验计划（Panobinostat 或安慰剂联合硼替佐米和地塞米松治疗复发性多发性骨髓瘤患者[PANORAMA]）已经启动。
PurposeDespite 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 MethodsIn 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.ResultsThe 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.ConclusionThe 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.