Phase I Study of Zotiraciclib in Combination with Temozolomide for Patients with Recurrent High-grade Astrocytomas.
Phase I Study of Zotiraciclib in Combination with Temozolomide for Patients with Recurrent High-grade Astrocytomas.
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复发性高级星形胶质细胞瘤患者的唑吡迪布与替莫唑胺结合的I期研究。
DOI：
10.1158/1078-0432.ccr-20-4730
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发表时间：
2021-06-15
期刊：
影响因子：
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通讯作者：
Gilbert MR
中科院分区：
文献类型：
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作者：
Wu J;Yuan Y;Long Priel DA;Fink D;Peer CJ;Sissung TM;Su YT;Pang Y;Yu G;Butler MK;Mendoza TR;Vera E;Ahmad S;Bryla C;Lindsley M;Grajkowska E;Mentges K;Boris L;Antony R;Garren N;Siegel C;Lollo N;Cordova C;Aboud O;Theeler BJ;Burton EM;Penas-Prado M;Leeper H;Gonzales J;Armstrong TS;Calvo KR;Figg WD;Kuhns DB;Gallin JI;Gilbert MR
探讨替莫唑胺（TMZ）联合唑替拉西尼治疗复发性高级别星形细胞瘤的毒副作用，并建立最佳给药方案。这项两阶段的1期试验使用贝叶斯最优区间设计确定了唑替拉西lib与剂量密集（Arm1）或节拍性（Arm2） TMZ联合的最大耐受剂量（MTD）；然后进行随机队列扩展，比较两组患者的4个月无进展生存率（PFS4），以有效确定TMZ联合左替拉西尼治疗MTD的方案。包括药代动力学（PK）和药物基因组学（PG）分析。通过纵向症状负担评估患者报告的结果。53名患者入组。剂量限制性毒性为中性粒细胞减少、腹泻、肝酶升高和疲劳。唑替拉西布在两组的MTD均为250mg，因此入选队列扩展。剂量密集型TMZ +左替拉西lib （PSF4 40%）优于节拍型TMZ （PFS4 25%）。症状负担在第2周期加重，但在第4周期稳定。口服左替拉西布后12-24小时中性粒细胞绝对计数和中性粒细胞活性氧产生显著下降，但72小时后两者均恢复。PK/PG分析显示CYP1A2_5347T>C （rs2470890）多态性与较高的AUCinf值相关。唑替拉西尼联合TMZ治疗复发性高级别星形细胞瘤是安全的。仲他拉西利诱发的中性粒细胞减少症可能是严重的，但大多是短暂的，需要密切监测，而不是停止治疗。一旦验证，预测药物代谢的多态性可能允许个体化给药。
To investigate the toxicity profile and establish an optimal dosing schedule of zotiraciclib with temozolomide (TMZ) in patients with recurrent high-grade astrocytoma. This two-stage phase 1 trial determined the maximum tolerated dose (MTD) of zotiraciclib combined with either dose-dense (Arm1) or metronomic (Arm2) TMZ using a Bayesian Optimal Interval design; then a randomized cohort-expansion compared the progression-free survival rate at 4 month (PFS4) of the two arms for an efficient determination of a TMZ schedule to combine with zotiraciclib at MTD. Pharmacokinetics (PK) and pharmacogenomic (PG) profiling were included. Patient-reported outcome was evaluated by longitudinal symptom burden. Fifty-three patients were enrolled. Dose-limiting toxicities were neutropenia, diarrhea, elevated liver enzymes, and fatigue. MTD of zotiraciclib was 250mg in both arms and thus selected for the cohort expansion. Dose-dense TMZ plus zotiraciclib (PSF4 40%) compared favorably with metronomic TMZ (PFS4 25%). Symptom burden worsened at Cycle 2 but stabilized by Cycle 4 in both arms. A significant decrease in absolute neutrophil count and neutrophil reactive oxygen species production occurred 12–24 hours after an oral dose of zotiraciclib but both recovered by 72 hours. PK/PG analyses revealed that the CYP1A2_5347T>C (rs2470890) polymorphism was associated with higher AUCinf value. Zotiraciclib combined with TMZ is safe in patients with recurrent high-grade astrocytomas. Zotiraciclib-induced neutropenia can be profound but mostly transient, warranting close monitoring rather than treatment discontinuation. Once validated, polymorphisms predicting drug metabolism may allow personalized dosing of zotiraciclib.