Breast Cancer Research and Treatment

, Volume 125, Issue 2, pp 447–455 | Cite as

Phase I trial of oral mTOR inhibitor everolimus in combination with trastuzumab and vinorelbine in pre-treated patients with HER2-overexpressing metastatic breast cancer

  • Guy Jerusalem
  • Angelica Fasolo
  • Veronique Dieras
  • Fatima Cardoso
  • Jonas Bergh
  • Luc Vittori
  • Yufen Zhang
  • Cristian Massacesi
  • Tarek Sahmoud
  • Luca Gianni
Clinical trial


To determine the feasible dose and schedule for everolimus, an oral mTOR inhibitor, combined with vinorelbine and trastuzumab for patients with HER2-overexpressing metastatic breast cancer pretreated with trastuzumab. In this phase Ib multicenter, Bayesian dose-escalation study, 50 patients received everolimus 5 mg/day, 20 mg/week, or 30 mg/week plus vinorelbine (25 mg/m2 on day 1 and 8 every 3 weeks) and trastuzumab (2 mg/kg weekly). Endpoints included end-of-cycle-1 dose-limiting toxicity (DLT) rate (primary endpoint), safety, relative dose intensity, overall response rate (ORR), and pharmacokinetics. Grade 3/4 neutropenia was the most common end-of-cycle-1 DLT and occurred in 10 of 30 and 4 of 14 patients in the 5 mg/day and 30 mg/week cohorts, respectively. Other end-of-cycle-1 DLTs included single cases of febrile neutropenia, grade 3 stomatitis with concomitant fatigue, grade 2 stomatitis, grade 3 anorexia, and grade 2 acneiform dermatitis, all in the 5-mg/day cohort. Based on the recorded DLTs and global safety, everolimus 5 mg/day and 30 mg/week were chosen as the optimal dose levels for the daily and weekly arms. Forty-seven patients were evaluable for efficacy. ORR was 19.1%, with a disease control rate of 83.0% and median progression-free survival of 30.7 weeks. No drug interaction was observed between everolimus and vinorelbine. Everolimus combined with weekly vinorelbine and trastuzumab generally was well tolerated and had encouraging antitumor activity in heavily pretreated patients with HER2-overexpressing metastatic breast cancer that progressed on trastuzumab (NCT00426530).


mTOR Everolimus Trastuzumab Vinorelbine Phase I HER2-overexpressing metastatic breast cancer 



Research support was provided by Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. Editorial support was provided by Scientific Connexions and funded by Novartis Pharmaceuticals. We thank the patients, their families, and the study personnel: Claire Senay, Corinne Manlius, Karen Osborne, Philippe Thevenaz (clinical); Ilona Pylvaenaeinen, Pabak Mukhopadhyay (statistics); Penny Phillips (biomarkers); and Shweta Urva, Wing Cheung (pharmacokinetics).

Conflicts of interest

G. Jerusalem: Consultant/advisory role, honoraria, and research funding from Novartis, A. Fasolo: No conflicts to disclose, V. Dieras: Consultant/advisory role for Novartis, F. Cardoso: Consultant/advisory role, honoraria, and research funding from Novartis, J. Bergh: Consultant/advisory role for Affybodies, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, GlaxoSmithKline, i3 Innovus, Onyx/Bayer, Pfizer, Roche, Sanofi-Aventis, and Tapestry Network on behalf of Asklepios Medicin Hb; honoraria from Amgen, AstraZeneca, Novartis, Pfizer, Roche, and Sanofi-Aventis on behalf of Asklepios Medicin Hb; research funding from Pfizer (grant to Karolinska University Hospital enabling substudy of SUN 1064 with biopsies, PET, and gene expression profiling); Karolinska has received grants or funding from Merck (array and SNP studies) for which Prof. Bergh served as principal investigator, L. Vittori: Employee of Novartis (Clinical Trial Head); stock ownership in Novartis, Y. Zhang: Employee of Novartis (Senior Biostatistician), C. Massacesi: Employee of Novartis (Global Clinical Leader); stock ownership in Novartis, T. Sahmoud: Employee of Novartis (Executive Medical Director); stock ownership in Novartis, L. Gianni: Consultant/advisory role for Roche, Genentech, Wyeth, Novartis, Eisai, Pfizer, Millennium, Takeda, Sanofi-Aventis, Boehringer-Ingelheim, and Wellcare.

Supplementary material

10549_2010_1260_MOESM1_ESM.doc (40 kb)
Supplementary material 1 (DOC 39 kb)
10549_2010_1260_MOESM2_ESM.doc (29 kb)
Supplementary material 2 (DOC 29 kb)
10549_2010_1260_MOESM3_ESM.doc (32 kb)
Supplementary material 3 (DOC 31 kb)


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Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Guy Jerusalem
    • 1
  • Angelica Fasolo
    • 2
  • Veronique Dieras
    • 3
  • Fatima Cardoso
    • 4
  • Jonas Bergh
    • 5
    • 6
  • Luc Vittori
    • 7
    • 8
  • Yufen Zhang
    • 7
    • 8
  • Cristian Massacesi
    • 7
    • 8
  • Tarek Sahmoud
    • 7
    • 8
  • Luca Gianni
    • 2
  1. 1.CHU Sart-TilmanLiègeBelgium
  2. 2.Fondazione IRCCS Istituto Nazionale TumoriMilanItaly
  3. 3.Institute CurieParisFrance
  4. 4.Jules Bordet InstituteBrusselsBelgium
  5. 5.Karolinska Institutet and University HospitalStockholmSweden
  6. 6.University of Manchester/Christie HospitalManchesterUK
  7. 7.Novartis PharmaceuticalsBaselSwitzerland
  8. 8.Novartis PharmaceuticalsFlorham ParkUSA

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