Phase I trial to evaluate the addition of alisertib to fulvestrant in women with endocrine-resistant, ER+ metastatic breast cancer

Tufia C Haddad, Antonio D'Assoro, Vera Jean Suman, Mateusz Opyrchal, Prema Peethambaram, Minetta C Liu, Matthew Philip Goetz, James N. Ingle

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Purpose: In estrogen receptor-positive (ER+) breast cancer models, activation of Aurora A kinase (AURKA) is associated with downregulation of ERα expression and resistance to endocrine therapy. Alisertib is an oral selective inhibitor of AURKA. The primary objectives of this phase I trial were to determine the recommended phase II dose (RP2D) and evaluate the toxicities and clinical activity of alisertib combined with fulvestrant in patients with ER+ metastatic breast cancer (MBC). Methods: In this standard 3 + 3 dose-escalation phase I study, postmenopausal patients with endocrine-resistant, ER+ MBC previously treated with endocrine therapy were assigned to one of two dose levels of alisertib (40 or 50 mg) in combination with fixed-dose fulvestrant. Results: Ten patients enrolled, of which nine were evaluable for the primary endpoint. The median patient age was 59. All patients had secondary (acquired) endocrine resistance, and all had received prior aromatase inhibitor. Six had experienced disease progression on fulvestrant. There were no severe (grade 3+) toxicities reported during cycle 1 at either dose level. The median progression-free survival time was 12.4 months (95% CI 5.3–not met), and the 6-month clinical benefit rate was 77.8% (95% CI 40.0–87.2%). Conclusions: In patients with endocrine-resistant, ER+ MBC, alisertib in combination with fulvestrant was well tolerated. A favorable safety profile was observed. The RP2D is 50 mg twice daily on days 1–3, 8–10, and 15–17 of a 28-day cycle with standard dose fulvestrant. Promising antitumor activity was observed, including activity among patients with prior progression on fulvestrant.

Original languageEnglish (US)
Pages (from-to)1-9
Number of pages9
JournalBreast Cancer Research and Treatment
DOIs
StateAccepted/In press - Dec 30 2017

Fingerprint

Breast Neoplasms
Aurora Kinase A
Aromatase Inhibitors
fulvestrant
MLN 8237
Estrogen Receptors
Disease-Free Survival
Disease Progression
Down-Regulation
Safety
Therapeutics

Keywords

  • Alisertib
  • Aurora A kinase
  • Breast cancer
  • Estrogen receptor
  • Fulvestrant

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

@article{440a06ef3976432ab2f48ba925832f5e,
title = "Phase I trial to evaluate the addition of alisertib to fulvestrant in women with endocrine-resistant, ER+ metastatic breast cancer",
abstract = "Purpose: In estrogen receptor-positive (ER+) breast cancer models, activation of Aurora A kinase (AURKA) is associated with downregulation of ERα expression and resistance to endocrine therapy. Alisertib is an oral selective inhibitor of AURKA. The primary objectives of this phase I trial were to determine the recommended phase II dose (RP2D) and evaluate the toxicities and clinical activity of alisertib combined with fulvestrant in patients with ER+ metastatic breast cancer (MBC). Methods: In this standard 3 + 3 dose-escalation phase I study, postmenopausal patients with endocrine-resistant, ER+ MBC previously treated with endocrine therapy were assigned to one of two dose levels of alisertib (40 or 50 mg) in combination with fixed-dose fulvestrant. Results: Ten patients enrolled, of which nine were evaluable for the primary endpoint. The median patient age was 59. All patients had secondary (acquired) endocrine resistance, and all had received prior aromatase inhibitor. Six had experienced disease progression on fulvestrant. There were no severe (grade 3+) toxicities reported during cycle 1 at either dose level. The median progression-free survival time was 12.4 months (95{\%} CI 5.3–not met), and the 6-month clinical benefit rate was 77.8{\%} (95{\%} CI 40.0–87.2{\%}). Conclusions: In patients with endocrine-resistant, ER+ MBC, alisertib in combination with fulvestrant was well tolerated. A favorable safety profile was observed. The RP2D is 50 mg twice daily on days 1–3, 8–10, and 15–17 of a 28-day cycle with standard dose fulvestrant. Promising antitumor activity was observed, including activity among patients with prior progression on fulvestrant.",
keywords = "Alisertib, Aurora A kinase, Breast cancer, Estrogen receptor, Fulvestrant",
author = "Haddad, {Tufia C} and Antonio D'Assoro and Suman, {Vera Jean} and Mateusz Opyrchal and Prema Peethambaram and Liu, {Minetta C} and Goetz, {Matthew Philip} and Ingle, {James N.}",
year = "2017",
month = "12",
day = "30",
doi = "10.1007/s10549-017-4616-7",
language = "English (US)",
pages = "1--9",
journal = "Breast Cancer Research and Treatment",
issn = "0167-6806",
publisher = "Springer New York",

}

TY - JOUR

T1 - Phase I trial to evaluate the addition of alisertib to fulvestrant in women with endocrine-resistant, ER+ metastatic breast cancer

AU - Haddad, Tufia C

AU - D'Assoro, Antonio

AU - Suman, Vera Jean

AU - Opyrchal, Mateusz

AU - Peethambaram, Prema

AU - Liu, Minetta C

AU - Goetz, Matthew Philip

AU - Ingle, James N.

PY - 2017/12/30

Y1 - 2017/12/30

N2 - Purpose: In estrogen receptor-positive (ER+) breast cancer models, activation of Aurora A kinase (AURKA) is associated with downregulation of ERα expression and resistance to endocrine therapy. Alisertib is an oral selective inhibitor of AURKA. The primary objectives of this phase I trial were to determine the recommended phase II dose (RP2D) and evaluate the toxicities and clinical activity of alisertib combined with fulvestrant in patients with ER+ metastatic breast cancer (MBC). Methods: In this standard 3 + 3 dose-escalation phase I study, postmenopausal patients with endocrine-resistant, ER+ MBC previously treated with endocrine therapy were assigned to one of two dose levels of alisertib (40 or 50 mg) in combination with fixed-dose fulvestrant. Results: Ten patients enrolled, of which nine were evaluable for the primary endpoint. The median patient age was 59. All patients had secondary (acquired) endocrine resistance, and all had received prior aromatase inhibitor. Six had experienced disease progression on fulvestrant. There were no severe (grade 3+) toxicities reported during cycle 1 at either dose level. The median progression-free survival time was 12.4 months (95% CI 5.3–not met), and the 6-month clinical benefit rate was 77.8% (95% CI 40.0–87.2%). Conclusions: In patients with endocrine-resistant, ER+ MBC, alisertib in combination with fulvestrant was well tolerated. A favorable safety profile was observed. The RP2D is 50 mg twice daily on days 1–3, 8–10, and 15–17 of a 28-day cycle with standard dose fulvestrant. Promising antitumor activity was observed, including activity among patients with prior progression on fulvestrant.

AB - Purpose: In estrogen receptor-positive (ER+) breast cancer models, activation of Aurora A kinase (AURKA) is associated with downregulation of ERα expression and resistance to endocrine therapy. Alisertib is an oral selective inhibitor of AURKA. The primary objectives of this phase I trial were to determine the recommended phase II dose (RP2D) and evaluate the toxicities and clinical activity of alisertib combined with fulvestrant in patients with ER+ metastatic breast cancer (MBC). Methods: In this standard 3 + 3 dose-escalation phase I study, postmenopausal patients with endocrine-resistant, ER+ MBC previously treated with endocrine therapy were assigned to one of two dose levels of alisertib (40 or 50 mg) in combination with fixed-dose fulvestrant. Results: Ten patients enrolled, of which nine were evaluable for the primary endpoint. The median patient age was 59. All patients had secondary (acquired) endocrine resistance, and all had received prior aromatase inhibitor. Six had experienced disease progression on fulvestrant. There were no severe (grade 3+) toxicities reported during cycle 1 at either dose level. The median progression-free survival time was 12.4 months (95% CI 5.3–not met), and the 6-month clinical benefit rate was 77.8% (95% CI 40.0–87.2%). Conclusions: In patients with endocrine-resistant, ER+ MBC, alisertib in combination with fulvestrant was well tolerated. A favorable safety profile was observed. The RP2D is 50 mg twice daily on days 1–3, 8–10, and 15–17 of a 28-day cycle with standard dose fulvestrant. Promising antitumor activity was observed, including activity among patients with prior progression on fulvestrant.

KW - Alisertib

KW - Aurora A kinase

KW - Breast cancer

KW - Estrogen receptor

KW - Fulvestrant

UR - http://www.scopus.com/inward/record.url?scp=85039742948&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85039742948&partnerID=8YFLogxK

U2 - 10.1007/s10549-017-4616-7

DO - 10.1007/s10549-017-4616-7

M3 - Article

C2 - 29289986

AN - SCOPUS:85039742948

SP - 1

EP - 9

JO - Breast Cancer Research and Treatment

JF - Breast Cancer Research and Treatment

SN - 0167-6806

ER -