Rodón Jordi, Carducci Michael, Sepulveda-Sánchez Juan M, Azaro Analía, Calvo Emiliano, Seoane Joan, Braña Irene, Sicart Elisabet, Gueorguieva Ivelina, Cleverly Ann, Pillay N Sokalingum, Desaiah Durisala, Estrem Shawn T, Paz-Ares Luis, Holdhoff Matthias, Blakeley Jaishri, Lahn Michael M, Baselga Jose
Medical Oncology, Vall d'Hebron University Hospital and Universitat Autonoma de Barcelona, Barcelona, Spain,
Invest New Drugs. 2015 Apr;33(2):357-70. doi: 10.1007/s10637-014-0192-4. Epub 2014 Dec 23.
Purpose Transforming growth factor-beta (TGF-β) signaling plays a key role in epithelial-mesenchymal transition (EMT) of tumors, including malignant glioma. Small molecule inhibitors (SMI) blocking TGF-β signaling reverse EMT and arrest tumor progression. Several SMIs were developed, but currently only LY2157299 monohydrate (galunisertib) was advanced to clinical investigation. Design The first-in-human dose study had three parts (Part A, dose escalation, n = 39; Part B, safety combination with lomustine, n = 26; Part C, relative bioavailability study, n = 14). Results A preclinical pharmacokinetic/pharmacodynamic (PK/PD) model predicted a therapeutic window up to 300 mg/day and was confirmed in Part A after continuous PK/PD. PK was not affected by co-medications such as enzyme-inducing anti-epileptic drugs or proton pump inhibitors. Changes in pSMAD2 levels in peripheral blood mononuclear cells were associated with exposure indicating target-related pharmacological activity of galunisertib. Twelve (12/79; 15%) patients with refractory/relapsed malignant glioma had durable stable disease (SD) for 6 or more cycles, partial responses (PR), or complete responses (CR). These patients with clinical benefit had high plasma baseline levels of MDC/CCL22 and low protein expression of pSMAD2 in their tumors. Of the 5 patients with IDH1/2 mutation, 4 patients had a clinical benefit as defined by CR/PR and SD ≥6 cycles. Galunisertib had a favorable toxicity profile and no cardiac adverse events. Conclusion Based on the PK, PD, and biomarker evaluations, the intermittent administration of galunisertib at 300 mg/day is safe for future clinical investigation.
目的 转化生长因子-β（TGF-β）信号传导在包括恶性胶质瘤在内的肿瘤上皮-间质转化（EMT）中起关键作用。阻断TGF-β信号传导的小分子抑制剂（SMI）可逆转EMT并阻止肿瘤进展。已开发出几种SMI，但目前只有一水合LY2157299（加鲁尼西替）进入临床研究阶段。设计 首次人体剂量研究分为三个部分（A部分，剂量递增，n = 39；B部分，与洛莫司汀的安全性联合研究，n = 26；C部分，相对生物利用度研究，n = 14）。结果 临床前药代动力学/药效学（PK/PD）模型预测治疗窗可达300 mg/天，并在A部分连续PK/PD后得到证实。PK不受酶诱导抗癫痫药物或质子泵抑制剂等联合用药的影响。外周血单核细胞中pSMAD2水平的变化与暴露相关，表明加鲁尼西替具有与靶点相关的药理活性。12例（12/79；15%）难治性/复发性恶性胶质瘤患者病情持续稳定（SD）达6个或更多周期、部分缓解（PR）或完全缓解（CR）。这些具有临床获益的患者血浆中MDC/CCL22基线水平较高，肿瘤中pSMAD2蛋白表达较低。在5例异柠檬酸脱氢酶1/2（IDH1/2）突变的患者中，4例患者有CR/PR和SD≥6周期所定义的临床获益。加鲁尼西替具有良好的毒性特征，无心脏不良事件。结论 基于PK、PD和生物标志物评估，每日300 mg间歇给药加鲁尼西替对未来临床研究是安全的。
