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

Phase 4

Completed

Conditions: Oestrogen Receptor Positive Advanced Breast Cancer

Interventions: Drug: RAD001
Drug: Exemestane

Registration Number: NCT01743560

Lead Sponsor: Novartis Pharmaceuticals

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 52

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Everolimus and Exemestane	RAD001	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.
Everolimus and Exemestane	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.

Primary Outcome Measures

Name	Time	Method
Best Overall Response of Everolimus and Exemestane Treatment in Postmenopausal Women With Hormone Receptor Positive Locally Advanced or Metastatic Breast Cancer	At 48 weeks	The best Overall Response (OR) for each patient is determined from the sequence of investigator overall lesion responses according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1.). To be assigned a best OR of Complete Responese (CR) at least two determinations of CR at least 4 weeks apart before progression are required. To be assigned a best OR of Partial Response (PR) at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR) are required.The Overall Response Rate (ORR) was defined as the proportion of patients with a best OR of confirmed CR or PR by week 48.
Overall Response Rate of Everolimus and Exemestane Treatment in Postmenopausal Women With Hormone Receptor Positive Locally Advanced or Metastatic Breast Cancer	At 48 weeks	The Overall Response Rate (ORR) was defined as the proportion of patients with a best OR of confirmed CR or PR by week 48. Treatment success is defined as: The best Overall Response (OR) for each patient is determined from the sequence of investigator overall lesion responses according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1.). To be assigned a best OR of Complete Responese (CR) at least two determinations of CR at least 4 weeks apart before progression are required. To be assigned a best OR of Partial Response (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

Name	Time	Method
Progression-free Survival (PFS) by Median Time in Weeks as Per Investigators - FAS	Start of treatment to the date of event defined as first documented progression due to any cause up to approximately 48 weeks	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. Tumor assessment and response was evaluated according to RECIST v1.1Response was assessed by local radiology review.
Change From Baseline EORTC Quality of Life Questionnaire of Cancer Patients QLQ-C30 at Each Time Point	Baseline 12,24,36,48 weeks	The QLQ-C30 is composed of multi-item scales and single-item measures including 5 functional scales, 3 symptom scales, a global health status-QoL scale, and 6 single items. Each of the multi-item scales includes a different set of items - no item occurs in more than 1 scale. High scale score=higher response level; a high score for a functional scale=a healthy level of function, high score for the global health status/QoL=high quality of life but a high score for a symptom scale / item=high level of symptomatology/problems. The principle for scoring these scales: 1.) Estimate the average of the items that contribute to the scale = raw score. 2.) Linear transformation to standardize the raw score, so that scores range from 0 to 100. Results should be interpreted with caution as the numbers of patients with available data over time were limited, and because of high variances as evidenced by large standard deviations
Percentage of Patient Responses in EuroQoL 5-dimension Questionnaire - FAS	Baseline 12,24,36,48 weeks	EuroQoL Quality of Life Scale (EQ-5D) is a standardized instrument to assess health state values is a standardized instrument to assess health state values. The EQ-5D essentially consists of 2 pages: the EQ-5D descriptive system and the EQ visual analogue scale (VAS). The EQ-5D descriptive system is comprised of the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. Percentage of participants' responses were presented by visits. Results should be interpreted with caution as the numbers of patients with available data over time were limited.
Change From Baseline in EuroQoL 5-dimension Visual Analogue Scores - FAS	Baseline 12,24,36,48 weeks	EuroQoL Quality of Life Scale (EQ-5D) is a standardized instrument to assess health state values. The EQ-5D essentially consists of 2 pages: the EQ-5D descriptive system and the EQ visual analogue scale (VAS). For the visual analogue scale, participants draw a line from a box to the point on the thermometer-like scale corresponding to their health state, 0-100 (100 = Best health state). Weights are used to score the responses to the 5 domains, with scores ranging from 0 to 1 (where a score of 1 represents a perfect state). Scores for the visual analogue scale reflect the position where participant's line crosses the thermometer-like scale. Results should be interpreted with caution as the numbers of patients with available data over time were limited, and because of high variances as evidenced by large standard deviations
Progression-free Survival (PFS) - % Event-free Probability Estimate - FAS	Start of treatment to the date of event defined as first documented progression due to any cause up to approximately 48 weeks	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. Tumor assessment and response was evaluated according to RECIST v1.1Response was assessed by local radiology review. The PFS was analyzed using the Kaplan Meier method.
Progression-free Survival (PFS) Events as Per Investigators - FAS	Start of treatment to the date of event defined as first documented progression due to any cause up to approximately 48 weeks	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. Tumor assessment and response was evaluated according to RECIST v1.1Response was assessed by local radiology review.
Overall Survival (OS) Events (Number of Deaths) - FAS	Start of treatment to the date of death up to approximately 48 weeks	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. Time to median OS was not estimable.
Overall Survival (OS) - % Event-free Probability Estimate - FAS	Start of treatment to the date of death up to approximately 48 weeks	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.