Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA.
Division of Hematology, Mayo Clinic, Rochester, MN, USA.
Target Oncol. 2017 Oct;12(5):643-654. doi: 10.1007/s11523-017-0524-3.
The oral proteasome inhibitor ixazomib has been approved by regulatory authorities around the world, including in the United States and the European Union, for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy, based on the pivotal phase III TOURMALINE-MM1 study.
The objective of this study was to quantitatively characterize the benefit-risk profile of ixazomib in relapsed/refractory MM in support of the approved dose and schedule.
We report early-phase study data and exposure-response analyses of TOURMALINE-MM1 data that support the selection of the recommended ixazomib dose and schedule.
Single-agent ixazomib studies showed a favorable efficacy/safety profile with weekly versus twice-weekly dosing; a phase I/II study of ixazomib in combination with lenalidomide and dexamethasone (IRd) identified a weekly ixazomib dose that offered an acceptable efficacy/safety profile. In IRd exposure-response analyses from TOURMALINE-MM1, ixazomib systemic exposure was not a significant predictor of progression-free survival or probability of response. Significant associations were observed between ixazomib exposure and the probability of grade ≥3 anemia and thrombocytopenia, and grade ≥2 diarrhea, fatigue, nausea, peripheral neuropathy, and rash. Additionally, higher ixazomib exposure was associated with lower lenalidomide relative dose intensity.
These analyses support a favorable benefit-risk profile for weekly ixazomib 4.0 mg on days 1, 8, and 15 of 28-day cycles, which was selected for the phase III TOURMALINE registration program.
ClinicalTrials.gov NCT00932698, NCT00963820, NCT01217957, NCT01564537.
口服蛋白酶体抑制剂伊沙佐米已在包括美国和欧盟在内的全球监管机构获得批准，用于治疗至少接受过一种前期治疗的多发性骨髓瘤（MM）患者，其依据是关键性 III 期 TOURMALINE-MM1 研究。
本研究旨在定量描述伊沙佐米在复发性/难治性 MM 中的获益-风险概况，以支持批准的剂量和方案。
我们报告了支持选择推荐剂量和方案的 TOURMALINE-MM1 数据的早期研究数据和暴露-反应分析。
单药伊沙佐米研究显示每周一次与每两周一次给药具有良好的疗效/安全性特征；一项伊沙佐米联合来那度胺和地塞米松（IRd）的 I/II 期研究确定了每周一次伊沙佐米剂量，具有可接受的疗效/安全性特征。在来自 TOURMALINE-MM1 的 IRd 暴露-反应分析中，伊沙佐米系统暴露不是无进展生存期或反应概率的显著预测因素。伊沙佐米暴露与 3 级及以上贫血和血小板减少症以及 2 级及以上腹泻、疲劳、恶心、周围神经病和皮疹的发生概率之间存在显著关联。此外，较高的伊沙佐米暴露与较低的来那度胺相对剂量强度相关。
这些分析支持每周一次 4.0mg 伊沙佐米在 28 天周期的第 1、8 和 15 天给药的良好获益-风险概况，这一方案被选为 III 期 TOURMALINE 注册研究。
ClinicalTrials.gov NCT00932698、NCT00963820、NCT01217957、NCT01564537。
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