Phase I/II study of pilaralisib (SAR245408) in combination with trastuzumab or trastuzumab plus paclitaxel in trastuzumab-refractory HER2-positive metastatic breast cancer
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- 作者：Sara Tolaney ; Howard Burris ; Elaina Gartner…
- 关键词：HER2 ; positive ; PI3K ; Pilaralisib ; Trastuzumab ; Metastatic breast cancer
- 刊名：Breast Cancer Research and Treatment
- 出版年：2015
- 出版时间：January 2015
- 年：2015
- 卷：149
- 期：1
- 页码：151-161
- 全文大小：282 KB
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14. Berns K, Horlings HM, Hennessy BT, Madiredjo M, Hijmans EM, Beelen K, Linn SC, Gonzalez-Angulo AM, Stemke-Hale K, Hauptmann M, Beijersbergen RL, Mills GB, van de Vijver MJ, - 作者单位：Sara Tolaney (1)
Howard Burris (2)
Elaina Gartner (3)
Ingrid A. Mayer (4)
Cristina Saura (5)
Matthew Maurer (6)
Eva Ciruelos (7)
Agustin A. Garcia (8)
Frank Campana (9)
Bin Wu (9)
Yi Xu (9)
Jason Jiang (10)
Eric Winer (1)
Ian Krop (1)
1. Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA, 02215, USA
2. Sarah Cannon Research Institute, Nashville, TN, USA
3. Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA
4. Vanderbilt Ingram Cancer Center, Nashville, TN, USA
5. Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain
6. Columbia University Medical Center, New York, NY, USA
7. Hospital 12 de Octubre, Madrid, Spain
8. University of Southern California, Los Angeles, CA, USA
9. Sanofi, Cambridge, MA, USA
10. Sanofi, Bridgewater, NJ, USA - 刊物类别：Medicine
- 刊物主题：Medicine & Public Health
Oncology - 出版者：Springer Netherlands
- ISSN：1573-7217
文摘
This phase I/II dose-escalation study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, and efficacy of the pan-class I phosphoinositide 3-kinase inhibitor pilaralisib in combination with trastuzumab (Arm 1) or trastuzumab plus paclitaxel (Arm 2) in patients with HER2-positive metastatic breast cancer. Patients had progressed on prior trastuzumab (Arms 1 and 2) and received prior taxane (Arm 2). The MTD of pilaralisib was determined using a 3?+?3 dose-escalation design (starting dose 200?mg once daily). Forty-two patients were enrolled (21 in each arm). Five patients had a dose-limiting toxicity (DLT; three in Arm 1 and two in Arm 2). Dose-limiting toxicities were rash (three patients) and neutropenia (two patients). The MTD of pilaralisib was determined at 400?mg once daily in both arms. The most frequently reported treatment-related adverse events (AEs) were diarrhea (23.8?% in Arm 1 vs. 66.7?% in Arm 2), fatigue (14.3 vs. 42.9?%), and rash (33.3 vs. 38.1?%). The most frequently reported treatment-related grade ? AEs were erythematous rash (9.5?%) in Arm 1 and diarrhea, peripheral neuropathy, and neutropenia (14.3?% each) in Arm 2. Steady-state pilaralisib exposure was similar to previous studies with pilaralisib monotherapy. No responses occurred in Arm 1; four of 20 evaluable patients (20?%) in Arm 2 had a partial response. Observed PIK3CA mutations in cell-free circulating DNA did not correlate with response. Pilaralisib in combination with trastuzumab with or without paclitaxel had an acceptable safety profile in metastatic HER2-positive breast cancer, with clinical activity in the paclitaxel arm.