Clinical Trials /

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

NCT02344550

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: AMC 2013-0720
  • SECONDARY ID: AMC
  • NCT ID: NCT02344550

Conditions

  • Metastatic Breast Cancer

Interventions

DrugSynonymsArms
Everolimus(afinitor)AfinitorEverolimus arm
LetrozoleFemaraEverolimus arm
Leuprolide(Lorelin Depot)Leuprorelin (Dongkook Pharm Co Ltd)Everolimus arm

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Everolimus armExperimentalEverolimus 10mg p.o. daily Letrozole 2.5 mg p.o. daily Leuprorelin (Leuprolide) 3.75mg SC every 4 weeks
  • Everolimus(afinitor)
  • Letrozole
  • Leuprolide(Lorelin Depot)
Control armActive ComparatorLetrozole 2.5 mg p.o. daily Leuprorelin (Leuprolide) 3.75mg SC every 4 weeks
  • Letrozole
  • Leuprolide(Lorelin Depot)

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:20 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression free survival (PFS)
Time Frame:Participants will be followed every 8 weeks , up to 12 Months
Safety Issue:
Description:At time disease progression

Secondary Outcome Measures

Measure:Overall Response rate
Time Frame:Participants will be followed every 8 weeks, up to 12 Months
Safety Issue:
Description:At time disease evaluation

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Asan Medical Center

Trial Keywords

  • metastatic breast cancer
  • HER2 negative
  • hormone-receptor positive

Last Updated

August 26, 2017