NCT02344550

Study of GnRH-A [Leuprorelin(Lorelin Depot] Plus Leterozole +/- Everolimus for Premenopausal Women With Metastatic Breast Cancer

Ovarian Suppression Plus Letrozole Plus Everolimus for Hormone Receptor-Positive, Tamoxifen and Ovarian Suppression Pretreated, Premenopausal Women With Recurrent or Metastatic Breast Cancer[LEO]

• Status: Completed
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 137 (actual)
• Sponsor: Asan Medical Center · Academic / Other
• Sex: Female
• Age: 20 Years
• Healthy volunteers: Not accepted

Summary

The purpose of this study is to evaluate the efficacy of addition of everolimus to letrozole with LHRH agonist in premenopausal metastatic breast cancer patients who failed to tamoxifen treatment.

Detailed description

Endocrine therapy is the cornerstone of treatment for patients with hormone receptor (HR)-positive advanced breast cancer. The selection of endocrine agents takes account of the menopausal status, the type of previous adjuvant endocrine treatment, the disease free interval and past medical history1. The goal of endocrine treatment is to block or interfere with the function of estrogen or progesterone. The major source of estrogen in premenopausal women is the ovaries. In premenopausal women with HR-positive advanced breast cancer, tamoxifen, ovarian function suppression or a combination of those have been used. Unfortunately, not all patients have a response to first-line endocrine therapy, and even patients who have a response will eventually become resistant. Patients experiencing disease progression with a first-line endocrine therapy may benefit from other endocrine agents, such as aromatase inhibitors (steroidal or nonsteroidal) and the estrogen receptor (ER) antagonist2-5. Aromatase inhibitors combined with luteinizing hormone-releasing hormone (LHRH) analogs or ovarian ablation are also a feasible treatment modality for premenopausal patients with HR-positive advanced breast cancer6. An emerging mechanism of endocrine resistance in aberrant signaling through the phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) signaling pathway7-9. Growing evidence supports a close interaction between the mTOR pathway and ER signaling. A substrate of mTOR complex 1 (mTORC1), called S6 kinase 1, phosphorylates the activation function domain 1 of ER, which is responsible for ligand-independent receptor activation10. Everolimus is a sirolimus derivative that inhibits mTOR through allosteric binding to mTORC111. In preclinical models, the use of everolimus in combination with aromatase inhibitors results in synergistic inhibition of the proliferation and induction of apoptosis12. In a randomized, phase 2 study comparing neoadjuvant everolimus plus letrozole with letrozole alone in patients with newly diagnosed ER-positive breast cancer, the response rate for the combination was higher than that for letrozole alone13. Recently, the Breast Cancer Trials of Oral Everolimus-2 (BOLERO-2) study showed that the addition of everolimus to exemestane significantly improved progression-free survival, with observed medians of 6.9 and 2.8 months, corresponding to a 57% reduction in the hazard ratio14. Based on this rationale, the investigators introduced randomized trial to evaluate the efficacy of addition of everolimus to letrozole with LHRH agonist in premenopausal metastatic breast cancer patients who failed to tamoxifen treatment.

Conditions

• Metastatic Breast Cancer

Interventions

Type	Name	Description
DRUG	Everolimus(afinitor)	Everolimus 10mg p.o. daily
DRUG	Letrozole	Letrozole 2.5 mg p.o. daily
DRUG	Leuprolide(Lorelin Depot)	Leuprorelin (Lorelin Depot)3.75 mg SC in every 4 weeks

Timeline

• Start date: 2014-01-01
• Primary completion: 2018-10-01
• Completion: 2018-10-01
• First posted: 2015-01-26
• Last updated: 2020-07-30

Locations

1 site across 1 country: South Korea