Phase Ib study of HSP90 inhibitor, onalespib (AT13387), in combination with paclitaxel in patients with advanced triple-negative breast cancer.
Phase Ib study of HSP90 inhibitor, onalespib (AT13387), in combination with paclitaxel in patients with advanced triple-negative breast cancer.
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DOI：
10.1177/17588359231217976
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发表时间：
2023
影响因子：
4.9
通讯作者：
Wesolowski, Robert
中科院分区：
文献类型：
--
作者：
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 III, William E.;Wesolowski, Robert
关键词：
热休克蛋白90(HSP90)是稳定三阴性乳腺癌(TNBC)中过度激活的客户蛋白所必需的分子伴侣。HSP90客户蛋白的过度表达与紫杉醇耐药有关。Onalespib(AT13387)是一种有效的HSP90抑制剂，联合应用可提高紫杉醇的疗效。这项Ib期试验在晚期TNBC患者中使用onalespib和紫杉醇，以评估安全性并建立推荐的II期剂量(RP2D)。主要目标是确定联合治疗的剂量限制毒性和最大耐受量。次要目标包括药代动力学(PK)分析和总有效率(ORR)、有效持续时间(DOR)和无进展生存期(PFS)的测定。晚期TNBC患者采用标准的3+3设计，在28天周期的第1天、第8天和第15天静脉注射标准剂量的紫杉醇和奥那司匹布，剂量从120到260 mg/m2不等。共有15名患者参加了RP2D的剂量扩展队列，以确认安全性。31名患者参加了这项研究，其中超过90%的患者以前接受过紫杉烷治疗。有23%的患者使用紫杉醇治疗转移性疾病。不良反应包括贫血(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级非血液性AE为腹泻(7%)。紫杉醇80 mg/m2给药时，奥那司匹布的RP2D为260 mg/m2。PK分析显示，在联合方案中，onalespib有适度的药物相互作用。ORR为20%。3名患者完全缓解，他们都曾接受过紫杉烷治疗。中位DOR为5.6个月，中位PFS为2.9个月。奥那司匹布和紫杉醇联合治疗具有可接受的毒性特征，RP2D被确定为260 mg/m2。联合治疗在晚期TNBC患者中显示出抗肿瘤活性。奥那司匹布联合紫杉醇治疗晚期https://clinicaltrials.gov/ct2/show/NCT02474173.名为onalespib的HSP90抑制剂联合紫杉醇治疗晚期三阴性乳腺癌的1b期研究这项1b期研究表明，大多数患者对onalespib和紫杉醇的联合治疗耐受性良好。奥那司匹布260 mg/m2在28天周期的第1、8和15天静脉给药，并结合紫杉醇的标准剂量和时间表被确定为推荐的第二阶段剂量，用于进一步的临床开发。尽管这两种药物之间的药物相互作用很小，但onalespib没有改变紫杉醇的暴露，紫杉醇也没有影响onalespib的暴露。虽然onalespib和紫杉醇联合治疗没有产生持久的客观反应或延长无进展生存期，但有几名患者从这种联合治疗中获得了长期的好处，其中包括以前经历过紫杉烷治疗进展的患者。
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. This phase Ib trial administered onalespib with paclitaxel in patients with advanced TNBC to assess safety and establish a recommended phase II dose (RP2D). 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). Patients with advanced TNBC were treated with standard dose intravenous paclitaxel in combination with intravenous onalespib at doses ranging from 120 to 260 mg/m2 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. 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/m2 onalespib when given with paclitaxel at 80 mg/m2. 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. Combination treatment with onalespib and paclitaxel had an acceptable toxicity profile and RP2D was determined to be 260 mg/m2 of onalespib. Combination therapy showed antitumor activity in patients with advanced TNBC. Onalespib and paclitaxel in treating patients with advanced TNBC https://clinicaltrials.gov/ct2/show/NCT02474173. Phase 1b study of HSP90 inhibitor called onalespib in combination with paclitaxel in patients with advanced triple-negative breast cancer This Phase 1b study demonstrated that treatment with a combination of onalespib and paclitaxel was reasonably well tolerated by most patients. Onalespib at 260 mg/m2 given intravenously on days 1, 8 and 15 on 28-day cycles in combination with standard dose and schedule of paclitaxel was established as the recommended phase 2 dose for further clinical development. Despite minor drug-drug interactions between these 2 agents, onalespib did not alter paclitaxel exposure and paclitaxel did not affect exposure to onalespib. While onalespib with paclitaxel combination therapy did not yield durable objective responses or prolonged progression-free survival, there were several patients with long-lasting benefit from this combination including patients who previously experienced progression on taxane therapy.
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影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
通讯作者：
Verweij, J.
影响因子：
20.4
作者：
Felip, Enriqueta;Barlesi, Fabrice;Garon, Edward B.
通讯作者：
Garon, Edward B.
影响因子：
3.8
作者：
Gartner, Elaina M.;Silverman, Paula;Simon, Michael;Flaherty, Lawrence;Abrams, Judith;Ivy, Percy;LoRusso, Patricia M.
通讯作者：
LoRusso, Patricia M.
DOI：
10.1186/s13058-017-0879-5
发表时间：
2017-08-02
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Jhaveri K;Wang R;Teplinsky E;Chandarlapaty S;Solit D;Cadoo K;Speyer J;D'Andrea G;Adams S;Patil S;Haque S;O'Neill T;Friedman K;Esteva FJ;Hudis C;Modi S
通讯作者：
Modi S
DOI：
10.1098/rstb.1993.0023
发表时间：
1993-03-29
期刊：
PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY OF LONDON SERIES B-BIOLOGICAL SCIENCES
影响因子：
--
作者：
ELLIS, RJ
通讯作者：
ELLIS, RJ