一项 Taselisib（GDC-0032）联合多西他赛或紫杉醇治疗 HER2 阴性、局部晚期或转移性乳腺癌患者的 Ib 期、开放性、剂量递增研究，评估 Taselisib 的安全性和药理学。

A phase Ib, open-label, dose-escalation study of the safety and pharmacology of taselisib (GDC-0032) in combination with either docetaxel or paclitaxel in patients with HER2-negative, locally advanced, or metastatic breast cancer.

机构信息

Vanderbilt University Medical Center, Nashville, TN, USA.

Department of Medical Oncology, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.

出版信息

Breast Cancer Res Treat. 2019 Nov;178(1):121-133. doi: 10.1007/s10549-019-05360-3. Epub 2019 Jul 31.

DOI:10.1007/s10549-019-05360-3

PMID:31368034

Abstract

PURPOSE

This open-label, phase Ib, dose-escalation, and dose-expansion study (NCT01862081) evaluated taselisib with a taxane in locally advanced or metastatic breast cancer (BC) and/or non-small cell lung cancer (NSCLC).

METHODS

Patients received taselisib (2-6 mg tablet or 3-6 mg capsule) plus docetaxel or paclitaxel. Primary endpoints were safety, dose-limiting toxicities, maximum tolerated dose, and identification of a recommended phase II dose. Secondary endpoints included pharmacokinetics and antitumor activity assessment.

RESULTS

Eighty patients (BC: 72; NSCLC: 7; BC/NSCLC: 1) were enrolled (docetaxel-receiving arms: 21; paclitaxel-receiving arms: 59). Grade ≥ 3 adverse events (AEs), serious AEs, and AEs leading to death were reported in 90.5%, 42.9%, and 14.3% of patients, respectively (docetaxel-receiving arms), and 78.9%, 40.4%, and 3.5% of patients, respectively (paclitaxel-receiving arms). Eight patients experienced dose-limiting toxicities. The maximum tolerated dose was exceeded with 3 mg taselisib (capsule) for 21 consecutive days plus 75 mg/m docetaxel and not exceeded with 6 mg taselisib (tablet) for 5 days on/2 days off plus 80 mg/m paclitaxel. Objective response rates and clinical benefit rates were 35.0% and 45.0%, respectively (docetaxel-receiving arms), and 20.4% and 27.8%, respectively (paclitaxel-receiving arms). Exposure for paclitaxel or docetaxel plus taselisib was consistent with the single agents.

CONCLUSIONS

Taselisib in combination with a taxane has a challenging safety profile. Despite evidence of antitumor activity, the benefit-risk profile was deemed not advantageous. Further development is not planned.

摘要

目的

这项开放标签、Ib 期、剂量递增和剂量扩展研究（NCT01862081）评估了 taselisib 联合紫杉烷类药物在局部晚期或转移性乳腺癌（BC）和/或非小细胞肺癌（NSCLC）中的应用。

方法

患者接受 taselisib（2-6mg 片剂或 3-6mg 胶囊）加多西他赛或紫杉醇。主要终点为安全性、剂量限制性毒性、最大耐受剂量和确定 II 期推荐剂量。次要终点包括药代动力学和抗肿瘤活性评估。

结果

共纳入 80 例患者（BC：72 例；NSCLC：7 例；BC/NSCLC：1 例）（多西他赛组：21 例；紫杉醇组：59 例）。90.5%、42.9%和 14.3%的患者分别发生了≥3 级不良事件（AE）、严重 AE 和导致死亡的 AE（多西他赛组），78.9%、40.4%和 3.5%的患者分别发生了这些 AE（紫杉醇组）。8 例患者发生剂量限制性毒性。3mg 剂量的 taselisib（胶囊）连续 21 天加 75mg/m2 多西他赛和 6mg 剂量的 taselisib（片剂）连续 5 天/2 天加 80mg/m2 紫杉醇的最大耐受剂量均被超过。多西他赛组客观缓解率和临床获益率分别为 35.0%和 45.0%，紫杉醇组分别为 20.4%和 27.8%。紫杉醇或多西他赛加 taselisib 的暴露量与单药治疗一致。