Breast Cancer Research and Treatment

, Volume 149, Issue 1, pp 151–161 | Cite as

Phase I/II study of pilaralisib (SAR245408) in combination with trastuzumab or trastuzumab plus paclitaxel in trastuzumab-refractory HER2-positive metastatic breast cancer

  • Sara TolaneyEmail author
  • Howard Burris
  • Elaina Gartner
  • Ingrid A. Mayer
  • Cristina Saura
  • Matthew Maurer
  • Eva Ciruelos
  • Agustin A. Garcia
  • Frank Campana
  • Bin Wu
  • Yi Xu
  • Jason Jiang
  • Eric Winer
  • Ian Krop
Clinical Trial


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 ≥3 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.


HER2-positive PI3K Pilaralisib Trastuzumab Metastatic breast cancer 



This study was funded by Sanofi. The authors received editorial support from Simone Blagg of MediTech Media, funded by Sanofi. The authors would like to thank the patients included in the trial and Patricia M. LoRusso, DO at the Yale Cancer Center for her contributions to the study.

Conflict of interest

Frank Campana, Bin Wu, Yi Xu, and Jason Jiang are employees of Sanofi. Ingrid A. Mayer has had a consultant/advisory role for Novartis and Genentech. Cristina Saura has had a consultant/advisory role for Puma Biotechnology. Eric Winer has received remuneration for travel from Novartis and has received funding from Genentech. Ian Krop has received funding from Genentech. Sara Tolaney, Howard Burris, Elaina Gartner, Matthew Maurer, Eva Ciruelos, and Agustin A. Garcia have no conflicts to disclose.

Ethical declaration

These experiments comply with the current laws of the countries in which they were performed.


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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Sara Tolaney
    • 1
    Email author
  • 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. 1.Dana-Farber Cancer InstituteBostonUSA
  2. 2.Sarah Cannon Research InstituteNashvilleUSA
  3. 3.Karmanos Cancer InstituteWayne State UniversityDetroitUSA
  4. 4.Vanderbilt Ingram Cancer CenterNashvilleUSA
  5. 5.Vall d’Hebron University HospitalVall d’Hebron Institute of Oncology (VHIO)BarcelonaSpain
  6. 6.Columbia University Medical CenterNew YorkUSA
  7. 7.Hospital 12 de OctubreMadridSpain
  8. 8.University of Southern CaliforniaLos AngelesUSA
  9. 9.SanofiCambridgeUSA
  10. 10.SanofiBridgewaterUSA

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