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

Sponsor

Asan Medical Center (Other)

Overall Status

Completed

CT.gov ID

NCT02344550

Collaborator

(none)

137

Enrollment

Location

Arms

Actual Duration (Months)

2.4

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Breast Cancer	Drug: Everolimus(afinitor) Drug: Letrozole Drug: Leuprolide(Lorelin Depot)	Phase 2

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

137 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Jan 1, 2014

Actual Primary Completion Date :

Oct 1, 2018

Actual Study Completion Date :

Oct 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Everolimus arm Everolimus 10mg p.o. daily Letrozole 2.5 mg p.o. daily Leuprorelin (Leuprolide) 3.75mg SC every 4 weeks	Drug: Everolimus(afinitor) Everolimus 10mg p.o. daily Other Names: Afinitor Drug: Letrozole Letrozole 2.5 mg p.o. daily Other Names: Femara Drug: Leuprolide(Lorelin Depot) Leuprorelin (Lorelin Depot)3.75 mg SC in every 4 weeks Other Names: Leuprorelin (Dongkook Pharm Co Ltd)
Active Comparator: Control arm Letrozole 2.5 mg p.o. daily Leuprorelin (Leuprolide) 3.75mg SC every 4 weeks	Drug: Letrozole Letrozole 2.5 mg p.o. daily Other Names: Femara Drug: Leuprolide(Lorelin Depot) Leuprorelin (Lorelin Depot)3.75 mg SC in every 4 weeks Other Names: Leuprorelin (Dongkook Pharm Co Ltd)

Arm

Intervention/Treatment

Experimental: Everolimus arm

Everolimus 10mg p.o. daily Letrozole 2.5 mg p.o. daily Leuprorelin (Leuprolide) 3.75mg SC every 4 weeks

Drug: Everolimus(afinitor)

Everolimus 10mg p.o. daily

Other Names:

Afinitor

Drug: Letrozole

Letrozole 2.5 mg p.o. daily

Other Names:

Femara

Drug: Leuprolide(Lorelin Depot)

Leuprorelin (Lorelin Depot)3.75 mg SC in every 4 weeks

Other Names:

Leuprorelin (Dongkook Pharm Co Ltd)

Active Comparator: Control arm

Letrozole 2.5 mg p.o. daily Leuprorelin (Leuprolide) 3.75mg SC every 4 weeks

Drug: Letrozole

Letrozole 2.5 mg p.o. daily

Other Names:

Femara

Drug: Leuprolide(Lorelin Depot)

Leuprorelin (Lorelin Depot)3.75 mg SC in every 4 weeks

Other Names:

Leuprorelin (Dongkook Pharm Co Ltd)

Outcome Measures

Primary Outcome Measures

Progression free survival (PFS) [Participants will be followed every 8 weeks , up to 12 Months]
At time disease progression

Secondary Outcome Measures

Overall Response rate [Participants will be followed every 8 weeks, up to 12 Months]
At time disease evaluation

Other Outcome Measures

Clinical benefit rate (CBR) [Participants will be followed every 8 weeks, up to 12 Months]
At time disease progression
Overall survival [Participants will be followed every 8 weeks, up to 12 Months]
At time of death occur or follow-up loss
Number of patients with adverse events [Participants will be followed every 8 weeks, up to 12 Months]
During treatment period

Eligibility Criteria

Criteria

Ages Eligible for Study:

20 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

Age ≥ 20 years
Histologically or cytologically confirmed, HER-2 negative breast cancer with recurrent or metastatic disease
No HER2 overexpressing breast cancer
Premenopausal status, defined as either
ER and/or PR positive
Progressive disease on tamoxifen treatment or sequential or combined treatment of tamoxifen and GnRH agonist as a palliative or an adjuvant endocrine treatment
Duration of tamoxifen treatment should be at least 3 months or more
No prior treatment with an aromatase inhibitor or inactivator or fulvestrant, or mTOR inhibitors
One line of chemotherapy in metastatic setting is permitted
ECOG performance status 0,1 or 2
At least one measurable lesion or mainly lytic bone lesions in the absence of measurable disease
Adequate hematologic, liver and kidney function

Exclusion Criteria:

Pregnant women or patients in lactation
More than one line of prior chemotherapy for metastatic breast cancer
GnRH agonist with tamoxifen treatment within 2 weeks.
Active malignancy other than breast cancer, in situ carcinoma of the cervix, controlled resected thyroid well differentiated carcinoma or non-melanomatous skin cancer in the past 5 years
Active cardiovascular disease such as angina, ventricular tachycardia, uncontrolled hypertension
Active uncontrolled infection
Symptomatic brain metastases
Lymphangitic carcinomatosis involving >50% of the lungs
Evidence of metastases involving more than one third of the liver on sonogram or CT
Patients not able or unwilling to give informed consent