Dana-Farber Cancer Institute, Boston, MA, USA.
Center for Cancer Therapeutic Innovation, Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue -DA2010, Boston, MA, 02215, USA.
Cancer Chemother Pharmacol. 2020 Dec;86(6):815-827. doi: 10.1007/s00280-020-04176-z. Epub 2020 Oct 23.
We conducted a phase 1 trial of the HSP90 inhibitor onalespib in combination with the CDK inhibitor AT7519, in patients with advanced solid tumors to determine the safety profile and maximally tolerated dose, pharmacokinetics, preliminary antitumor activity, and to assess the pharmacodynamic (PD) effects on HSP70 expression in patient-derived PBMCs and plasma.
This study followed a 3 + 3 trial design with 1 week of intravenous (IV) onalespib alone, followed by onalespib/AT7519 (IV) on days 1, 4, 8, and 11 of a 21-days cycle. PK and PD samples were collected at baseline, after onalespib alone, and following combination therapy.
Twenty-eight patients were treated with the demonstration of downstream target engagement of HSP70 expression in plasma and PBMCs. The maximally tolerated dose was onalespib 80 mg/m IV + AT7519 21 mg/m IV. Most common drug-related adverse events included Grade 1/2 diarrhea (79%), fatigue (54%), mucositis (57%), nausea (46%), and vomiting (50%). Partial responses were seen in a palate adenocarcinoma and Sertoli-Leydig tumor; a colorectal and an endometrial cancer patient both remained on study for ten cycles with stable disease as the best response. There were no clinically relevant PK interactions for either drug.
Combined onalespib and AT7519 is tolerable, though below monotherapy RP2D. Promising preliminary clinical activity was seen. Further benefit may be seen with the incorporation of molecular signature pre-selection. Further biomarker development will require the assessment of the on-target impact on relevant client proteins in tumor tissue.
我们进行了一项 HSP90 抑制剂 onalespib 与 CDK 抑制剂 AT7519 联合治疗晚期实体瘤患者的 1 期试验，以确定安全性概况和最大耐受剂量、药代动力学、初步抗肿瘤活性，并评估对患者来源的 PBMCs 和血浆中 HSP70 表达的药效学（PD）影响。
该研究采用 3+3 试验设计，首先单独静脉注射（IV） 1 周 onalespib，然后在 21 天周期的第 1、4、8 和 11 天静脉注射 onalespib/AT7519。在基线、单独使用 onalespib 后和联合治疗后采集 PK 和 PD 样本。
28 例患者接受了治疗，显示 HSP70 表达的下游靶标参与在血浆和 PBMCs 中。最大耐受剂量为 onalespib 80mg/m IV+AT7519 21mg/m IV。最常见的药物相关不良反应包括 1/2 级腹泻（79%）、疲劳（54%）、粘膜炎（57%）、恶心（46%）和呕吐（50%）。在一个腭腺癌和 Sertoli-Leydig 细胞瘤中观察到部分缓解；一名结直肠癌和一名子宫内膜癌患者均在研究中进行了十个周期，最佳反应为稳定疾病。两种药物均无临床相关的 PK 相互作用。
联合使用 onalespib 和 AT7519 是可耐受的，尽管低于单药治疗的 RP2D。初步临床活性有一定前景。通过纳入分子特征预筛选，可能会有进一步获益。需要评估肿瘤组织中相关靶蛋白的靶向作用，以进一步开发生物标志物。
