Everolimus trIal for Advanced prememopausaL Breast Cancer Patients — MIRACLE  

Metastatic Breast Cancer Clinical Trial

Official title: A Multicenter, Randomized Phase ll Study of Letrozole Versus Letrozole Plus Everolimus for Hormone Receptor-PositivePremenopausal Women With Recurrent or Metastatic Breast Cancer on Goserelin Treatment After Progression on Tamoxifen

Status Not yet recruiting

Clinical Trial Summary

Everolimus has been approved to be effective when used with exemestane after progression on non-steroidal aromatase inhibitors in postmenopausal women based on the BOLERO-2 clinical trial. However, the superiority of addition of everolimus to endocrine therapy hasn't been established in the premenopausal women. This is a phase 2, multicentre clinical trial to evaluate the role of everolimus in the first-line endocrine treatment of premenopausal MBC patients after progression on tamoxifen.

Clinical Trial 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 history.

In premenopausal women with HR-positive advanced breast cancer, ovarian function suppression combined with aromatase inhibitors is a standard first-line choice of hormone treatment, especially patients progressed after tamoxifen. Unfortunately, not all patients have a response to first-line endocrine therapy, and even patients who have a response will eventually become resistant.

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. Everolimus is a sirolimus derivative that inhibits mTORactivation11. 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 alone. 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 11 and 4 months, corresponding to a 62% reduction in the hazard ratio14 which is impressive and practice changing.

However, different from western countries, the majority (50-55%) of patients are premenopausal women in Asia including China.The benefit of everolimus plus endocrine therapy in premenopausal women have not yet been well delineated. Although there was a report that efficacy was comparable between premenopausal metastatic breast cancer patients treated with letrozole plus goserelin and postmenopausal patients treated with letrozole alone as first line hormone therapy, it is generally accepted that endocrine treatment outcome in premenopausal women, especially in younger age is known to be poor. So the addition of everolimusin this population would be a potential viable treatment option to overcome resistance to endocrine therapies that needs to be evaluated.

In addition, the feasibility of patients progressed on the endocrine continue to receive the same endocrine agent plus everolimus is unclear. At the same time, the difference between concurrent and sequential medication of endocrine agent and everolimus is not yet addressed.

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 and also explore the best schedule of endocrine therapy together with everolimus. ;

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Breast Neoplasms
• Metastatic Breast Cancer

• NCT number: NCT02313051
• Study type: Interventional
• Source: Chinese Academy of Medical Sciences
• Contact: Ying Fan, MD
• Phone: 861087788114
• Email: fanyingfy@medmail.com.cn
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: December 2014
• Completion date: December 2017