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

NCT ID: NCT01743560

Last Updated: 2019-07-18

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 52 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-01-31
• Study Completion Date: 2016-08-15

Brief Summary

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-steroidal aromatase inhibitor (NSAI) therapy.

Conditions

Oestrogen Receptor Positive Advanced Breast Cancer

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Everolimus 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.

Group Type: EXPERIMENTAL

RAD001

Intervention Type: DRUG

All postmenopausal women with oestrogen receptor positive locally advanced or metastatic breast cancer were treated with oral tablet RAD001 at a dose of 10mg daily and oral tablet exemestane 25mg daily. The study treatment for an individual patient was to begin on Study Day 1 and continue until the last patient enrolled 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.

Exemestane

Intervention Type: DRUG

All postmenopausal women with oestrogen receptor positive locally advanced or metastatic breast cancer were to be treated with oral tablet RAD001 at a dose of 10mg daily and oral tablet exemestane 25mg daily. The study treatment for an individual patient was to begin on Study Day 1 and continue until the last patient enrolled 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.

Interventions

RAD001

All postmenopausal women with oestrogen receptor positive locally advanced or metastatic breast cancer were treated with oral tablet RAD001 at a dose of 10mg daily and oral tablet exemestane 25mg daily. The study treatment for an individual patient was to begin on Study Day 1 and continue until the last patient enrolled 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.

Intervention Type: DRUG

Exemestane

All postmenopausal women with oestrogen receptor positive locally advanced or metastatic breast cancer were to be treated with oral tablet RAD001 at a dose of 10mg daily and oral tablet exemestane 25mg daily. The study treatment for an individual patient was to begin on Study Day 1 and continue until the last patient enrolled 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.

Intervention Type: DRUG

Other Intervention Names

Everolimus

Eligibility 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 Follicle stimulating hormone (FSH) and Luteinizing Hormone (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
• International Normalized Ratio (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
• Eastern Cooperative Oncology Group (ECOG) performance status of PS </ 2
• Written informed consent obtained before any screening procedure and according to local guidelines.

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 mammilian target of Rapamycin (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 Central Nervous system (CNS) metastases.
• Active, bleeding diathesis, or on oral anti-vitamin K medication (except low dose warfarin, low molecular weight heparin (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, itraconazole, voriconazole, ritonavir, telithromycin) 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
• Another malignancy within 5 years prior to randomization, with the exception of adequately treated in-situ carcinoma of the cervix, uteri, basal or squamous cell carcinoma or non-melanomatous skin cancer

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Novartis Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Novartis Pharmaceuticals

Role: STUDY_DIRECTOR

Novartis Pharmaceuticals

Locations

Novartis Investigative Site

Epping, Essex, United Kingdom

Novartis Investigative Site

Inverness, Invernesshire, United Kingdom

Novartis Investigative Site

Ipswich, Suffolk, United Kingdom

Novartis Investigative Site

Sutton, Surrey, United Kingdom

Novartis Investigative Site

Cardiff, , United Kingdom

Novartis Investigative Site

Denbighshire, , United Kingdom

Novartis Investigative Site

East Kilbride, , United Kingdom

Novartis Investigative Site

East Yorkshire, , United Kingdom

Novartis Investigative Site

Edinburgh, , United Kingdom

Novartis Investigative Site

London, , United Kingdom

Novartis Investigative Site

Portsmouth, , United Kingdom

Countries

United Kingdom

Other Identifiers

2012-003689-41

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CRAD001YGB11

Identifier Type: -

Identifier Source: org_study_id