Clinical Trials /

Fulvestrant and EVerolimus Plus EXemestane in Metastatic Breast Cancer

NCT02404051

Description:

This is a multi-center, randomized, open-label, parallel group study designed to evaluate efficacy and safety of fulvestrant followed, at progression, by examestane and everolimus versus examestane and everolimus followed, at progression, by fulvestrant in postmenopausal women with HR+ and HER2- LABC or MBC whose disease has progressed to NSAI in the adjuvant or metastatic setting.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Unknown status

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Fulvestrant and EVerolimus Plus EXemestane in Metastatic Breast Cancer
  • Official Title: Fulvestrant Followed by Everolimus Plus Exemestane vs Examestane and Everolimus Followed by Fulvestrant in Postmenopausal Women With HR+ and HER2- Locally Advanced (LABC) or Metastatic Breast Cancer (MBC) Previously Treated With NSAI

Clinical Trial IDs

  • ORG STUDY ID: GIM16-FEVEX
  • SECONDARY ID: 2014-004035-38
  • NCT ID: NCT02404051

Conditions

  • Metastatic Breast Cancer
  • Breast Cancer
  • Hormone Receptor Positive Tumor
  • Human Epidermal Growth Factor 2 Negative Carcinoma of Breast
  • Locally Advanced Malignant Neoplasm

Interventions

DrugSynonymsArms
EverolimusAfinitorARM 1
ExemestaneAromasinARM 1
FulvestrantFaslodexARM 1

Purpose

This is a multi-center, randomized, open-label, parallel group study designed to evaluate efficacy and safety of fulvestrant followed, at progression, by examestane and everolimus versus examestane and everolimus followed, at progression, by fulvestrant in postmenopausal women with HR+ and HER2- LABC or MBC whose disease has progressed to NSAI in the adjuvant or metastatic setting.

Detailed Description

      In this study everolimus will be administered in combination with exemestane, which is an
      irreversible steroidal aromatase inactivator that has demonstrated efficacy in the treatment
      of postmenopausal patients with ABC. Exemestane is indicated for adjuvant treatment of
      postmenopausal women with HR+ EBC who have received two to three years of tamoxifen and are
      switched to exemestane for completion of a total of five consecutive years of adjuvant
      hormonal therapy. It is also indicated for the treatment of ABC in postmenopausal women whose
      disease has progressed following tamoxifen therapy (in the USA) or following antiestrogen
      therapy (in Europe). In 2011, the BOLERO-2 trial reported (5; 33) a significant benefit for
      HR+ HER2- postmenopausal pretreated women in the ABC setting by combining everolimus with
      exemestane. In this randomized, double-blind, placebo-controlled trial a statistically
      significant improvement in PFS by adding everolimus to exemestane versus exemestane alone was
      reported. Adding everolimus determined a 2.4-fold prolongation in PFS from 3.2 up to 7.4
      months and so lowered the risk of cancer progression by 56% for these women. These findings
      were confirmed by an independent assessment (4.1 vs. 11.0 months, risk reduction: 64%). The
      QoL data shows positive trend in the everolimus plus exemestane treatment arm.
    

Trial Arms

NameTypeDescriptionInterventions
ARM 1ExperimentalEverolimus plus Exemestane -> progression disease (PD) -> fulvestrant (ARM 1)
  • Everolimus
  • Exemestane
  • Fulvestrant
ARM 2ExperimentalFulvestrant -> progression disease (PD) -> everolimus plus exemestane (ARM 2)
  • Everolimus
  • Exemestane
  • Fulvestrant

Eligibility Criteria

        Inclusion Criteria:

          1. Adult women (≥ 18 years of age) with LABC or MBC not amenable to curative treatment by
             surgery or radiotherapy, refractory to NSAI

          2. Histological or cytological confirmation of ER+ BC and/or PgR+.

          3. Postmenopausal women.

          4. Radiological or objective evidence of recurrence or progression on or after the last
             systemic therapy prior to randomization

          5. Patients must have:

               -  At least one lesion that can be accurately measured in at least one dimension ≥
                  20 mm with conventional imaging techniques or ≥ 10 mm with spiral CT or MRI

               -  Bone lesions: lytic or mixed (lytic + sclerotic) in the absence of measurable
                  disease as defined above.

          6. Adequate bone marrow and coagulation according RCP

          7. Adequate liver function, according RCP

          8. Adequate renal function, according RCP

          9. ECOG Performance Status ≤ 2

         10. Written informed consent

        Exclusion Criteria:

          1. HER2-overexpressing patients by local laboratory testing (IHC3+ staining or in situ
             hybridization positive).

          2. Patients who received chemotherapy for MBC

          3. Patients who received more than one NSAI treatment for LABC or MBC

          4. Pre-menopausal, pregnant, lactating women.

          5. Known hypersensitivity to mTOR inhibitors

          6. Patients with rare hereditary problems of galactose intolerance, Lapp lactase
             deficiency or glucose galactose malabsorption.

          7. Radiotherapy within four weeks prior to enrollment

          8. Currently receiving hormone replacement therapy, unless discontinued prior to
             enrollment.

          9. Patients receiving concomitant immunosuppressive agents or chronic corticosteroids
             use, at the time of study entry except in some cases

         10. Patients with symptomatic visceral disease in need of urgent disease control

         11. Symptomatic brain or other CNS metastases.

         12. Patients with a known history of HIV seropositivity.

         13. Active, bleeding diathesis, or on oral anti-vitamin K medication (except cases).

         14. Any severe and / or uncontrolled medical conditions such as:

               -  Unstable angina pectoris, symptomatic congestive heart failure, myocardial
                  infarction ≤6 months prior to enrollment, serious uncontrolled cardiac arrhythmia

               -  Uncontrolled diabetes as defined by fasting serum glucose > 1.5 × ULN

               -  Acute and chronic, active infectious disorders

               -  Impairment of gastrointestinal function or gastrointestinal disease that may
                  significantly alter the absorption of the study treatments (e.g., ulcerative
                  disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome)

               -  Inability to swallow oral medications

               -  Significant symptomatic deterioration of lung function.

         15. Hepatic-related exclusion criteria:

               -  History of liver disease, such as cirrhosis or chronic active hepatitis B and C.

               -  Presence of Hepatitis B surface antigen (HbsAg) and/or of Hepatitis B Virus -
                  Deoxyribonucleic acid (HBV-DNA)

               -  Presence of anti-HCV and/or HCV-RNA-PCR

               -  History of, or current alcohol misuse/abuse within the past 12 months

               -  Patients being treated with drugs recognized as being strong inhibitors or
                  inducers of the isoenzyme CYP3A within the last 5 days prior to enrollment.

               -  History of non-compliance to medical regimens.

               -  Patients unwilling to or unable to comply with the protocol

         16. Patients being treated with drugs recognized as being strong inhibitors or inducers of
             the isoenzyme CYP3A

         17. History of non-compliance to medical regimens.

         18. Patients unwilling to or unable to comply with the protocol.

        Screening for hepatitis B

        Prior to enrollment, peculiar patients should be tested for hepatitis B viral load and
        serologic markers, that is, HBV-DNA, HBsAg, HBsAb, and HBcAb:

        Screening for hepatitis C Patients with any of the following risk factors for hepatitis C
        should be tested
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-free survival (PFS1)
Time Frame:Time elapsed from randomization to progression or death for any cause whichever occurred first assessed up to 30 months
Safety Issue:
Description:The number of events required for the other primary endpoint (PFS1), and the expected time needed to achieve it are derived from previous calculations. Assuming an average accrual rate of 31 pts/month (677pts/22 months), a median PFS1 of 6 months in the Fulvestrant arm (control), a Hazard ratio of 0.70 (implying that a median PFS1 of 8,6 months is expected in the experimental arm, a 2-sided significance level of 0.025 and power of 0.90, 391 events are required for PFS1, that will be achieved in about 22 months (East 6 software).

Secondary Outcome Measures

Measure:Response Rate
Time Frame:Time elapsed from randomization to progression or death for any cause whichever occurred first assessed up to 30 months
Safety Issue:
Description:Objective Response Rate (ORR), the Clinical Benefit, the overall survival, and the safety profile and the QOLof of the sequence of fulvestrant followed, at progression by exemestane and everolimus versus the sequence of examestane and everolimus followed, at progression, by fulvestrant in postmenopausal women with HR + and HER2- LABC or MBC previously treated with NSAI in the adjuvant or metastatic setting.
Measure:Clinical Benefit Rate
Time Frame:Time elapsed from randomization to progression or death for any cause whichever occurred first assessed up to 30 months
Safety Issue:
Description:Objective Response Rate (ORR), the Clinical Benefit, the overall survival, and the safety profile and the QOLof of the sequence of fulvestrant followed, at progression by exemestane and everolimus versus the sequence of examestane and everolimus followed, at progression, by fulvestrant in postmenopausal women with HR + and HER2- LABC or MBC previously treated with NSAI in the adjuvant or metastatic setting.
Measure:Overall Survival
Time Frame:Time elapsed from randomization to progression or death for any cause whichever occurred first assessed up to 30 months
Safety Issue:
Description:Objective Response Rate (ORR), the Clinical Benefit, the overall survival, and the safety profile and the QOLof of the sequence of fulvestrant followed, at progression by exemestane and everolimus versus the sequence of examestane and everolimus followed, at progression, by fulvestrant in postmenopausal women with HR + and HER2- LABC or MBC previously treated with NSAI in the adjuvant or metastatic setting.
Measure:Safety - 5D5L questionnaire
Time Frame:up to 31 days since last treatment
Safety Issue:
Description:The overall observation period will be divided into three mutually exclusive segments per treatment phase: pre-treatment period: from day of patient's informed consent to the day before first dose of study medication (phase 1) on-treatment period: from day of first dose of study medication to 30 days (minimum washout) after last dose of study medication (phase 2) or first dose of second phase treatment after cross-over post-treatment period: starting at day 31 after last dose of study medication (phase 2)

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Consorzio Oncotech

Trial Keywords

  • Breast cancer
  • HER2Negative
  • hormone receptor positive (HR+)
  • Metastatic
  • Locally Advanced
  • fulvestrant
  • everolimus
  • exemestane

Last Updated

June 14, 2016