Clinical Trials /

Study of Fulvestrant +/- Everolimus in Post-Menopausal, Hormone-Receptor + Metastatic Breast Ca Resistant to AI

NCT01797120

Description:

Post-menopausal women with hormone-receptor positive (HR+) metastatic breast cancer resistant to aromatase inhibitor (AI) therapy will be randomized to receive Fulvestrant (Faslodex) with Everolimus or Fulvestrant (Faslodex) with a placebo (no active ingredients). Fulvestrant has demonstrated activity when used as first, second, or third line endocrine therapy, making it an attractive therapy for combination with other agents. In addition, it is commonly reserved for use following disease progression on AI therapy. Everolimus is an orally administered drug that blocks a signaling pathway called "mTOR". "mTOR" acts as a regulator for many processes in the body, including cell growth. Blocking this pathway may have an effect on cell growth. The combination of a novel class of agents (mTOR inhibitors) and an established standard treatment for metastatic HR+ breast cancer may potentially increase the clinical benefit by targeting multiple different biological pathways.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Completed

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of Fulvestrant +/- Everolimus in Post-Menopausal, Hormone-Receptor + Metastatic Breast Ca Resistant to AI
  • Official Title: Randomized, Double-Blind, Placebo-Controlled Phase II Trial of Fulvestrant (Faslodex) Plus Everolimus in Post-Menopausal Patients With Hormone-Receptor Positive Metastatic Breast Cancer Resistant to Aromatase Inhibitor Therapy

Clinical Trial IDs

  • ORG STUDY ID: PrE0102
  • NCT ID: NCT01797120

Conditions

  • Metastatic Breast Cancer

Interventions

DrugSynonymsArms
FulvestrantFaslodexFulvestrant & Everolimus
EverolimusmTOR Inhibitor, RAD001, AfinitorFulvestrant & Everolimus
Placebo (for Everolimus)Sugar PillFulvestrant & Placebo

Purpose

Post-menopausal women with hormone-receptor positive (HR+) metastatic breast cancer resistant to aromatase inhibitor (AI) therapy will be randomized to receive Fulvestrant (Faslodex) with Everolimus or Fulvestrant (Faslodex) with a placebo (no active ingredients). Fulvestrant has demonstrated activity when used as first, second, or third line endocrine therapy, making it an attractive therapy for combination with other agents. In addition, it is commonly reserved for use following disease progression on AI therapy. Everolimus is an orally administered drug that blocks a signaling pathway called "mTOR". "mTOR" acts as a regulator for many processes in the body, including cell growth. Blocking this pathway may have an effect on cell growth. The combination of a novel class of agents (mTOR inhibitors) and an established standard treatment for metastatic HR+ breast cancer may potentially increase the clinical benefit by targeting multiple different biological pathways.

Detailed Description

      Breast cancer is the most commonly diagnosed malignancy in women worldwide. In the United
      States, an estimated 230,480 new cases of invasive breast cancer were diagnosed in 2011, with
      39,520 breast cancer deaths. In 40-80% of women with node-positive disease at diagnosis,
      their breast cancer will recur. When distant metastases occur, median survival is 18 to 36
      months from time of recurrence. Among the 60-70% of women with HR+ breast cancer, 40-60% of
      them will benefit from endocrine therapy. Endocrine therapy has shown to yield similar
      survival rates in hormone-sensitive disease as compared to chemotherapy; although response
      rates are lower and responses develop more slowly. Endocrine therapy is considerably less
      toxic than chemotherapy, and is therefore the preferred treatment option for patients with
      HR+ disease.

      Endocrine therapy represents the foundation of treatment for HR+ metastatic and locally
      advanced breast cancer. Multiple compounds in varying classes exist, and those most widely
      used include the selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs),
      and the selective estrogen receptor down-regulators (SERDs). Although the utility of these
      drugs is well established, as many as 50% of women with HR+ breast cancer will fail to
      respond to endocrine treatment. Moreover, those who do respond will inevitably develop
      acquired resistance.

      Fulvestrant is the first drug which acts as a pure estrogen receptor (ER) antagonist without
      known agonist effects. It competitively binds to the ERs with an approximately 100 times
      greater affinity than that of tamoxifen. Fulvestrant promotes the degradation of ERs and
      subsequently prevents ER-mediated gene transcription.

      Everolimus (RAD001) is an oral derivative of rapamycin that is an m-TOR inhibitor. At
      cellular and molecular levels, everolimus acts as a signal transduction inhibitor. Everolimus
      selectively inhibits mTOR (mammalian target of rapamycin); a key and highly conserved
      serine-threonine kinase which is present in all cells and is a central regulator of protein
      synthesis and ultimately cell growth, cell proliferation, angiogenesis and cell survival.
      mTOR is the only currently known target of everolimus.

      In oncology, everolimus has been in clinical development since 2002 for patients with various
      hematologic and non-hematologic malignancies as a single agent or in combination with
      antitumor agents, including cytotoxic chemotherapeutic agents, targeted therapies, antibodies
      and hormonal agents.

      Patients will be randomized (1:1) to receive everolimus or placebo with fulvestrant after
      consideration of stratification factors of performance status (0 vs. 1), measurable disease
      (with or without non-measurable) vs. non-measurable disease, and prior chemotherapy for
      metastatic disease vs. no prior chemotherapy.

      Patients will be evaluated for disease response every 12 weeks and treated until disease
      progression or unacceptable toxicity for a total of 12 cycles.

      Patients with no evidence of progressive disease who remain on study after completing 12
      cycles are unblinded and continue to receive fulvestrant alone (if originally randomized to
      placebo) or in combination with everolimus (if originally randomized to everolimus) at the
      same dose and schedule. Patients will continue to be evaluated for disease response every 12
      weeks and continue until disease progression or unacceptable toxicity.
    

Trial Arms

NameTypeDescriptionInterventions
Fulvestrant & EverolimusActive ComparatorFulvestrant Day 1 & 15 of Cycle 1, then Day 1 of all subsequent cycles (every 28 days for 12 cycles) plus everolimus daily x 12 cycles.
  • Fulvestrant
  • Everolimus
Fulvestrant & PlaceboPlacebo ComparatorFulvestrant Day 1 & 15 of Cycle 1, then Day 1 of all subsequent cycles (every 28 days for 12 cycles) plus placebo daily x 12 cycles.
  • Fulvestrant
  • Placebo (for Everolimus)

Eligibility Criteria

        Inclusion Criteria:

          1. Signed informed consent.

          2. ≥18 years.

          3. ECOG Performance Status 0 or 1.

          4. Histologically or cytologically confirmed adenocarcinoma of the breast.

          5. Stage IV disease or inoperable locally advanced disease.

          6. ER and/or PR-positive disease. Tumors must be HER-2/neu negative or equivocal.

          7. Aromatase Inhibitor (AI) resistant, defined as:

               -  relapsed while receiving adjuvant therapy with an AI or,

               -  progressive disease while receiving an AI for metastatic disease

          8. Received one prior cycle of fulvestrant within 28 days of randomization are eligible.

               -  ≥2 prior doses of fulvestrant are not eligible

          9. Must be female and postmenopausal.

         10. May have received ≤1 prior systemic chemotherapy regimen for metastatic disease.

         11. Adequate organ function:

               -  WBC ≥3.0 x 10⁹/L, ANC ≥1.5 x 10⁹/L and platelet count ≥100 x 10⁹/L

               -  hemoglobin ≥9 g/dL

               -  serum bilirubin ≤1.5 X ULN (Upper Limit of Normal)

               -  AST or ALT ≤2.5 X ULN (≤5 x ULN in patients with liver metastases)

               -  serum creatinine ≤1.5 X ULN

               -  serum albumin ≥3 g/dL

               -  fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglycerides
                  ≤2.5 x ULN.

               -  PT with INR ≤1.5

         12. May have measurable disease, non-measurable disease, or both.

         13. Basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix
             within the past five years treated with curative intent. History of prior malignancy
             are eligible if disease-free for >3 years.

        Exclusion Criteria:

          1. Major surgery or significant traumatic injury within 4 weeks of randomization or
             patients that may require major surgery during the course of the study.

          2. Investigational agents within 4 weeks of randomization.

          3. Anticancer treatment within 4 weeks of randomization, with the following exceptions:

               -  Bisphosphonates or Zometa for bone metastases

               -  a GnRH analog is permitted if the patient had progressive disease on a GnRH
                  (Gonadotropin-Releasing Hormone) analog plus a SERM (Selective Estrogen Receptor
                  Modulators) or an AI; the GnRH analog may continue but the SERM or AI must be
                  discontinued.

          4. Prior treatment with an mTOR inhibitor.

          5. Receiving chronic, systemic treatment with corticosteroids or another
             immunosuppressive agent ≥ 5 mg prednisone or equivalent daily.

          6. Receive immunization with attenuated live vaccines within one week of randomization or
             during the study period.

          7. Current or a prior history of brain metastases or leptomeningeal disease. Must not
             have rapidly progressive, life-threatening metastases.

          8. Known hypersensitivity/history of allergic reactions attributed to compounds of
             similar chemical or biologic composition to everolimus or fulvestrant.

          9. Congenital or acquired immune deficiency at increased risk of infection.

         10. Impairment of gastrointestinal function/disease that may significantly alter the
             absorption of everolimus.

         11. Active, bleeding diathesis.

         12. History of any condition or uncontrolled intercurrent illness that in the opinion of
             the local investigator might interfere with or limit the patient's ability to comply
             with the protocol or pose additional or unacceptable risk to the patient.

         13. Severe and/or uncontrolled medical conditions or other conditions that could affect
             their participation in the study such as:

               -  Symptomatic congestive heart failure of New York Heart Association Class III or
                  IV

               -  Unstable angina pectoris, myocardial infarction within 6 months of randomization,
                  serious uncontrolled cardiac arrhythmia or any other clinically significant
                  cardiac disease

               -  History of symptomatic pulmonary disease or non-malignant pulmonary disease
                  requiring treatment.

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

               -  Active (acute or chronic) or uncontrolled severe infections

               -  Liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh Class
                  C).

        Note: Detailed assessment of Hepatitis B/C medical history and risk factors must be done at
        screening.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-free survival
Time Frame:Every 3 months until progression or up to 3 years
Safety Issue:
Description:Progression-free survival documented by Physical Exam, CT Scan or MRI in post-menopausal patients with hormone-receptor positive metastatic breast cancer that is resistant to aromatase inhibitor therapy treated with fulvestrant and everolimus compared to fulvestrant alone from randomization to documented disease progression or death.

Secondary Outcome Measures

Measure:Participant Adverse Events as a Measure of Safety and Tolerability
Time Frame:Monthly up to 3 years
Safety Issue:
Description:Comparison of overall toxicity and of grade 3-4 toxicity in the combination arm and the fulvestrant arm.
Measure:Objective Response Rate
Time Frame:Every 3 months until progression or up to 3 years
Safety Issue:
Description:Objective response rates (by Physical Exam, CT or MRI) will be provided for each arm.
Measure:Time to Progression
Time Frame:Every 3 months until progression or up to 3 years
Safety Issue:
Description:Median time to progression (by Physical Exam, CT or MRI) will be estimated for each arm.
Measure:Overall Survival
Time Frame:Every 3 months until progression or up to 3 years
Safety Issue:
Description:Overall survival will be characterized using Kaplan-Meier plots and other descriptive metrics.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Completed
Lead Sponsor:PrECOG, LLC.

Trial Keywords

  • Post-Menopausal Patients
  • Hormone-Receptor Positive
  • Resistant to Aromatase Inhibitor Therapy
  • Fulvestrant
  • Faslodex
  • mTOR Inhibitor
  • Everolimus
  • RAD001
  • Afinitor

Last Updated

December 28, 2017