An Open Label Study of Postmenopausal Women With Oestrogen Receptor Positive Locally Advanced or Metastatic Breast Cancer Treated With Everolimus (RAD001) With Exemestane, With Exploratory Epigenetic Marker Analysis (4EVER UK)

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01743560
First received: October 24, 2012
Last updated: January 17, 2014
Last verified: January 2014
  Purpose

Determine the overall response rate (ORR) at 48 weeks to everolimus (RAD001, 10mg daily p.o.) and exemestane (25mg daily p.o.) treatment in postmenopausal women with oestrogen receptor positive breast cancer who have previous experienced recurrence or progression on non-steriodal aromatase inhibitor (NSAI) therapy.


Condition Intervention Phase
Oestrogen Receptor Positive Advanced Breast Cancer
Drug: RAD001
Drug: Exemestane
Phase 4

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase IV Multicentre, Open Label Study of Postmenopausal Women With Oestrogen Receptor Positive Locally Advanced or Metastatic Breast Cancer Treated With Everolimus (RAD001) in Combination With Exemestane, With Exploratory Epigenetic Marker Analysis

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Response rate of everolimus and exemestane treatment in postmenopausal women with hormone receptor positive locally advanced or metastatic breast cancer [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
    Treatment success is defined as: The best overall response for each patient is determined from the sequence of investigator overall lesion responses according to RECIST 1.1. To be assigned a best overall response of CR at least two determinations of CR at least 4 weeks apart before progression are required. To be assigned a best overall response of PR at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR) are required.


Secondary Outcome Measures:
  • Progression Free Survival [ Time Frame: Start of treatment to the date of event defined as first documented progression due to any cause up to 24 months ] [ Designated as safety issue: No ]
    Progression-free survival (PFS) is the time from date of start of treatment to the date of event defined as the first documented progression or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment.

  • Overall Survival (OS) [ Time Frame: Start of treatment to date of death due to any cause up to 36 months ] [ Designated as safety issue: No ]
    Overall survival (OS) is defined as the time from date of start of treatment to date of death due to any cause. If a patient is not known to have died, survival will be censored at the date of last contact.

  • Quality of life (EuroQol Standardised Health Outcome Questionnaire EQ-5D) [ Time Frame: 48 weeks and 30 day follow up ] [ Designated as safety issue: No ]
    Descriptive statistics for the changes from baseline to months 3, 6, 9, 12 and follow-up in composite health index and health utility score.

  • Quality of life (EORTC Quality of Life Questionnaire of cancer patients QLQ-C30) [ Time Frame: 48 weeks and 30 day follow up ] [ Designated as safety issue: No ]
    Descriptive statistics will be used to summarize the individual item and scored sub-scale scores at each scheduled assessment time point. Patients will be included if they completed at least one questionnaire item. Additionally, change from baseline in the domain scores at the time of each assessment will be summarized. Patients with an evaluable baseline score and at least one evaluable post-baseline score during the treatment period will be included in the change from baseline analyses

  • Number of Participants with Adverse Events as a Measure of Safety and Tolerability [ Time Frame: Baseline to 48 Weeks and will be followed-up for 30 days after end of treatment for safety. ] [ Designated as safety issue: No ]

Enrollment: 52
Study Start Date: January 2013
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: RAD001 and Exemestane
Postmenopausal women diagnosed with oestrogen receptor positive locally advanced or metastatic breast cancer will receive RAD001 at a dose of 10mg daily p.o. and exemestane 25mg daily p.o. for 48 weeks.
Drug: RAD001
All postmenopausal women with oestrogen receptor positive locally advanced or metastatic breast cancer will be treated with oral RAD001 at a dose of 10mg daily and oral exemestane 25mg daily. The study treatment for an individual patient will begin on Study Day 1 and will continue until the last patient enrolled has completed the study at day 336 or until disease progression; unacceptable toxicity, death or early discontinuation from the study for any other reason, whichever occurs first.
Other Name: Everolimus
Drug: Exemestane
All postmenopausal women with oestrogen receptor positive locally advanced or metastatic breast cancer will be treated with oral RAD001 at a dose of 10mg daily and oral exemestane 25mg daily. The study treatment for an individual patient will begin on Study Day 1 and will continue until the last patient enrolled has completed the study at day 336 or until disease progression; unacceptable toxicity, death or early discontinuation from the study for any other reason, whichever occurs first.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histological or cytological confirmation of oestrogen receptor positive (ER+) and/or progesterone receptor positive (PgR+), human epidermal growth factor receptor 2 (HER2) negative breast cancer.
  • Availability of archival tumour tissue (the tissue block or slides will be sent to the central laboratory for analysis).
  • Postmenopausal women. The investigator must confirm postmenopausal status. Postmenopausal status is defined either by:

    • Age ≥ 55 years and one year or more of amenorrhea
    • Age < 55 years and one year or more of amenorrhea and postmenopausal levels of FSH and LH per local institutional standards
    • Prior hysterectomy and has postmenopausal levels of FSH and LH per local institutional standards Surgical menopause with bilateral oophorectomy
  • Disease progression following prior therapy with NSAI, defined as:

    • Recurrence while on or after completion of an adjuvant treatment including letrozole or anastrozole, or
    • Progression while on or following the completion of letrozole or anastrozole treatment for locally advanced or metastatic breast cancer

Note: Non-steroidal aromatase inhibitors (i.e. letrozole or anastrozole) do not have to be the last treatment prior to enrollment. Other prior anticancer therapy, e.g. tamoxifen, fulvestrant, exemestane are also allowed. Patients must have recovered to grade 1 or better from any adverse events (except alopecia) related to previous therapy prior to enrollment.

- Radiological evidence of recurrence or progression on last systemic therapy prior to enrollment.

Patients must have:

  • At least one lesion that can be accurately measured or
  • Bone lesions: lytic or mixed (lytic + sclerotic) in the absence of measurable disease

    - Adequate bone marrow and coagulation function as shown by:

  • Absolute neutrophil count (ANC) ≥ 1.5 109/L
  • Platelets ≥ 100 ×109/L
  • Hemoglobin (Hb) ≥ 9.0 g/dL
  • INR ≤ 2 .

    - Adequate liver function as shown by:

  • Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 ULN (or ≤ 5 if hepatic metastases are present)
  • Total serum bilirubin ≤ 1.5 × ULN (≤ 3 × ULN for patients known to have Gilbert Syndrome)

    - Adequate renal function as shown by:

  • Serum creatinine ≤ 1.5 × ULN - Fasting serum cholesterol ≤ 300 mg/dl or 7.75 mmol/L and fasting triglycerides ≤ 2.5 × ULN. In case one or both of these thresholds are exceeded, the patient can only be included after initiation of statin therapy and when the above mentioned values have been achieved

Exclusion Criteria:

  • HER2-overexpressing patients by local laboratory testing (IHC 3+ staining or in situ hybridization positive).
  • Pre-menopausal, pregnant, lactating women.
  • Known hypersensitivity to mTOR inhibitors, e.g. sirolimus (rapamycin) or to their excipients.
  • Known hypersensitivity to exemestane, to the active substance or to any of the excipients.
  • Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose galactose malabsorption.
  • Radiotherapy within four weeks prior to enrollment except in case of localized radiotherapy for analgesic purpose or for lytic lesions at risk of fracture which can then be completed within two weeks prior to enrollment. Patients must have recovered from radiotherapy toxicities prior to enrollment.
  • Currently receiving hormone replacement therapy, unless discontinued prior to enrollment.
  • Patients receiving concomitant immunosuppressive agents or chronic corticosteroids use, at the time of study entry except in cases outlined below:

Prolonged systemic corticosteroid treatment during study, except for topical applications (e.g. rash),inhaled sprays (e.g. obstructive airways diseases), eye drops or local injections (e.g. intra-articular) should not be given. However:

  • short duration (<2 weeks) of systemic corticosteroids is allowed (e.g. chronic obstructive pulmonary disease, anti-emetic)
  • low doses of corticosteroids for brain metastasis treatment is allowed
  • Patients with symptomatic visceral metastasis (e.g. significant dyspnoea related to pulmonary lymphangitic carcinomatosis and lung metastases or clinically meaningful symptomatic liver metastasis)
  • Symptomatic brain or other CNS metastases.
  • Active, bleeding diathesis, or on oral anti-vitamin K medication (except low dose warfarin, LMWH and acetylsalicylic acid or equivalent, as long as the INR is 2.0)
  • 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 (except for Hep B and Hep C positive patients) and nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the complications of this study therapy
    • Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of study drugs (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhoea, malabsorption syndrome)
    • Significant symptomatic deterioration of lung function. If clinically indicated, pulmonary function tests including measures of predicted lung volumes, DLco, O2 saturation at rest on room air should be considered to exclude restrictive pulmonary disease, pneumonitis or pulmonary infiltrates.
  • Patients being treated with drugs recognized as being strong inhibitors or inducers of the isoenzyme CYP3A (rifabutin, rifampicin, clarithromycin, ketoconazole, itroconazole, voriconazole, ritinavir, telithromycin) within the last 5 days prior to enrollment
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01743560

Locations
United Kingdom
Novartis Investigative Site
Epping, Essex, United Kingdom, CM16 6TN
Novartis Investigative Site
Ipswich, Suffolk, United Kingdom, IP4 5PD
Novartis Investigative Site
Sutton, Surrey, United Kingdom, SM2 5PT
Novartis Investigative Site
Cardiff, United Kingdom, CF14 2TL
Novartis Investigative Site
Denbighshire, United Kingdom, LL18 5UJ
Novartis Investigative Site
East Kilbride, United Kingdom, G75 8RG
Novartis Investigative Site
East Yorkshire, United Kingdom, HU16 5JQ
Novartis Investigative Site
Edinburgh, United Kingdom, EH4 2XU
Novartis Investigative Site
Inverness, United Kingdom, IV2 3UJ
Novartis Investigative Site
London, United Kingdom, SW3 6JJ
Novartis Investigative Site
Portsmouth, United Kingdom, PO6 3LY
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

No publications provided

Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT01743560     History of Changes
Other Study ID Numbers: CRAD001YGB11, 2012-003689-41
Study First Received: October 24, 2012
Last Updated: January 17, 2014
Health Authority: United Kingdom: National Institute for Health Research

Keywords provided by Novartis:
Breast Neoplasms
Neoplasms
Breast diseases
Skin diseases
Exemastane
Antibiotics, Antineoplastic
Everolimus
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Immunosuppressive Agents
Physiological Effects of Drugs
Aromatase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Antibiotics, Antineoplastic
Sirolimus
Exemestane
Antineoplastic Agents
Estrogens
Immunosuppressive Agents
Everolimus
Aromatase Inhibitors
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Therapeutic Uses
Pharmacologic Actions
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Immunologic Factors
Enzyme Inhibitors
Anti-Bacterial Agents
Anti-Infective Agents
Antifungal Agents

ClinicalTrials.gov processed this record on August 01, 2014