HSP90抑制剂奥纳莱斯匹布（AT13387）与紫杉醇联合用于晚期三阴性乳腺癌患者的Ib期研究。
Phase Ib study of HSP90 inhibitor, onalespib (AT13387), in combination with paclitaxel in patients with advanced triple-negative breast cancer.
作者信息
Williams Nicole O, Quiroga Dionisia, Johnson Courtney, Brufsky Adam, Chambers Mara, Bhattacharya Saveri, Patterson Maria, Sardesai Sagar D, Stover Daniel, Lustberg Maryam, Noonan Anne M, Cherian Mathew, Bystry Darlene M, Hill Kasey L, Chen Min, Phelps Mitch A, Grever Michael, Stephens Julie A, Ramaswamy Bhuvaneswari, Carson William E, Wesolowski Robert
机构信息
The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA.
出版信息
Ther Adv Med Oncol. 2023 Dec 25;15:17588359231217976. doi: 10.1177/17588359231217976. eCollection 2023.
BACKGROUND
Heat shock protein 90 (HSP90) is a molecular chaperone required for stabilization of client proteins over-activated in triple-negative breast cancer (TNBC). Over-expression of HSP90 client proteins has been implicated in paclitaxel resistance. Onalespib (AT13387) is a potent inhibitor of HSP90 that could improve paclitaxel efficacy when administered in combination.
DESIGN
This phase Ib trial administered onalespib with paclitaxel in patients with advanced TNBC to assess safety and establish a recommended phase II dose (RP2D).
OBJECTIVES
The primary objectives were determining the dose-limiting toxicities and maximum tolerated dose of combination therapy. Secondary objectives included pharmacokinetic (PK) analysis and determination of overall response rate (ORR), duration of response (DOR), and progression-free survival (PFS).
METHODS
Patients with advanced TNBC were treated with standard dose intravenous paclitaxel in combination with intravenous onalespib at doses ranging from 120 to 260 mg/m administered on days 1, 8, and 15 of a 28-day cycle using a standard 3 + 3 design. A total of 15 patients were enrolled to dose expansion cohort at RP2D to confirm safety profile.
RESULTS
Thirty-one patients were enrolled in the study, of which over 90% had received prior taxane therapy. Paclitaxel was given for metastatic disease in 23% of patients. Adverse events (AEs) included anemia (grade 3: 20%), lymphopenia (grade 3: 17%), and neutropenia (grade 3: 33%, grade 4: 4%). The most frequent grade ⩾3 non-hematologic AE was diarrhea (7%). The established RP2D was 260 mg/m onalespib when given with paclitaxel at 80 mg/m. PK analysis revealed a modest drug interaction profile for onalespib in the combination regimen. ORR was 20%. Three patients achieved complete responses, all of whom had received prior taxane therapy. Median DOR was 5.6 months; median PFS was 2.9 months.
CONCLUSION
Combination treatment with onalespib and paclitaxel had an acceptable toxicity profile and RP2D was determined to be 260 mg/m of onalespib. Combination therapy showed antitumor activity in patients with advanced TNBC.
TRIAL REGISTRATION
Onalespib and paclitaxel in treating patients with advanced TNBC https://clinicaltrials.gov/ct2/show/NCT02474173.
背景
热休克蛋白90（HSP90）是一种分子伴侣，对于三阴性乳腺癌（TNBC）中过度激活的客户蛋白的稳定至关重要。HSP90客户蛋白的过表达与紫杉醇耐药有关。奥纳莱斯匹（AT13387）是一种有效的HSP90抑制剂，联合使用时可提高紫杉醇疗效。
设计
这项Ib期试验在晚期TNBC患者中给予奥纳莱斯匹联合紫杉醇，以评估安全性并确定推荐的II期剂量（RP2D）。
目的
主要目的是确定联合治疗的剂量限制性毒性和最大耐受剂量。次要目的包括药代动力学（PK）分析以及确定总缓解率（ORR）、缓解持续时间（DOR）和无进展生存期（PFS）。
方法
晚期TNBC患者在28天周期的第1、8和15天接受标准剂量静脉注射紫杉醇，联合静脉注射剂量为120至260mg/m²的奥纳莱斯匹，采用标准的3+3设计。共有15名患者入组RP2D剂量扩展队列以确认安全性。
结果
31名患者入组本研究，其中超过90%曾接受过紫杉烷类治疗。23%的患者因转移性疾病接受紫杉醇治疗。不良事件（AE）包括贫血（3级：20%）、淋巴细胞减少（3级：17%）和中性粒细胞减少（3级：33%，4级：4%）。最常见的≥3级非血液学AE是腹泻（7%）。确定的RP2D是奥纳莱斯匹260mg/m²与80mg/m²紫杉醇联合使用时的剂量。PK分析显示联合方案中奥纳莱斯匹的药物相互作用较小。ORR为20%。3名患者达到完全缓解，所有这些患者均曾接受过紫杉烷类治疗。中位DOR为5.6个月；中位PFS为2.9个月。
结论
奥纳莱斯匹与紫杉醇联合治疗具有可接受的毒性特征，确定的RP2D为奥纳莱斯匹260mg/m²。联合治疗在晚期TNBC患者中显示出抗肿瘤活性。
试验注册
奥纳莱斯匹和紫杉醇治疗晚期TNBC患者https://clinicaltrials.gov/ct2/show/NCT02474173 。
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