A phase I/II study of preoperative letrozole, everolimus, and carotuximab in stage 2 and 3 hormone receptor-positive and Her2-negative breast cancer

Christos Vaklavas, Erica M. Stringer-Reasor, Ahmed M. Elkhanany, Kevin J. Ryan, Yufeng Li, Charles P. Theuer, Edward P. Acosta, Shi Wei, Eddy S. Yang, William E. Grizzle, Andres Forero-Torres

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Purpose: In nonmetastatic hormone receptor-positive and Her2-negative breast cancer, preoperative endocrine therapies can yield outcomes similar with chemotherapy. We evaluated the tolerability and preliminary antitumor activity of preoperative letrozole, everolimus, and carotuximab, a monoclonal antibody targeting endoglin, in nonmetastatic breast cancer. Methods: Eligible patients had newly diagnosed, stage 2 or 3, hormone receptor-positive and Her2/neu-negative breast cancer. Patients received escalating doses of everolimus; the dose of letrozole and carotuximab were fixed at 2.5 mg PO daily and 15 mg/kg intravenously every 2 weeks, respectively. The primary objective was to determine the safety and tolerability of the combination. Secondary objectives included pharmacokinetic and pharmacodynamic studies and assessments of antitumor activity. Results: Fifteen patients enrolled. The recommended phase 2 dose of everolimus in combination with letrozole and carotuximab was 10 mg PO daily. The most frequent adverse events were headache (67%), fatigue (47%), facial flushing and swelling (47%), gingival hemorrhage (40%), epistaxis (33%), nausea and vomiting (27%). Headache constituted a dose-limiting toxicity. At least two signs of mucocutaneous telangiectasia developed in 92% of patients. Carotuximab accumulated in the extravascular space and accelerated the biodistribution and clearance of everolimus. All patients had residual disease. Gene expression analyses were consistent with downregulation of genes involved in proliferation and DNA repair. Among 6 patients with luminal B breast cancer, 5 converted to luminal A after one cycle of therapy. Conclusion: Letrozole, everolimus, and carotuximab were tolerated in combination at their single-agent doses. Pharmacokinetic studies revealed an interaction between everolimus and carotuximab. Trial registration: This trial is registered with ClinicalTrials.gov (Identifier: NCT02520063), first posted on August 11, 2015, and is active, not recruiting.

Original languageEnglish
Pages (from-to)217-229
Number of pages13
JournalBreast Cancer Research and Treatment
Issue number2
StatePublished - Apr 2023

Bibliographical note

Funding Information:
This study was supported by O’Neal Comprehensive Cancer Center at the University of Alabama at Birmingham. Correlative studies were supported by Young Supporters Board Faculty Development Grant (to C.V.). Support in the form of provision of the investigational agents was provided by Novartis and TRACON Pharmaceuticals. The funding agencies were not involved in the design of the study and collection, analysis, or in the interpretation of data and writing of the manuscript.

Publisher Copyright:
© 2023, The Author(s).


  • Angiogenesis inhibitors
  • Breast cancer
  • Carotuximab
  • Everolimus
  • Letrozole
  • Neoadjuvant therapy

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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