Safety and Efficacy of RAD001 (Everolimus) in Combination With Letrozole in the Treatment of Postmenopausal Women With Locally Advanced or Metastatic Breast Cancer

Study Overview
=================
Brief Summary
-----------------
This was a multi-center, Israeli phase II open label study evaluating treatment with RAD001 (10 mg daily) combined with letrozole (2.5 mg daily) in postmenopausal women after recurrence or progression on Tamoxifen, Anastrozole or Examestane. There were no treatments specifically approved after recurrence or progression on AIs. Available options, based on common clinical practice and several treatment guidelines (e.g. NCCN treatment guidelines 2008), included fulvestrant. Combining RAD001 with letrazole was a rational approach to the treatment of advanced Brest Cancer, offering the potential for inhibition of tumor cell growth\ proliferation and anti angiogenesis while at the same time potentially preventing the development of letrazole resistance.

Detailed Description
-----------------
Screening Period: Postmenopausal women with estrogen receptor positive, locally advanced or metastatic breast cancer whose disease was refractory to hormonal therapy and had a documented recurrence or progression on last therapy for their breast cancer with either tamoxifen, anastrozole, letrozole, fulvestrant or exemestan were screened for eligibility within 28 days prior to treatment Day 1. Treatment Period: Patients started receiving everolimus (10 mg daily oral dose) combined with letrozole (2.5 mg daily oral dose) tablets from treatment Day 1. Study treatment continued until disease progression, intolerable toxicity or consent withdrawal. Dose adjustment (reduction, interruption or possible dose re-escalation to starting dose) could be done based on the safety findings. Tumor assessments were performed every 12 weeks until disease progression. In order to confirm response at least four weeks after first observation, additional scans to determine a complete response (CR) or partial response (PR) or stable disease (SD) were performed. Patients were followed for safety until 28 days after study treatment discontinuation. Post Treatment Follow up for Survival: Patients were followed for survival every 3 months for up to 3 years. Survival information could be obtained via phone and information was documented in the source documents.

Official Title
-----------------
Phase II Open Label Study of RAD001 (Everolimus) in Combination With Letrozole in the Treatment of Postmenopausal Women With Locally Advanced or Metastatic, Estrogen Receptor Positive Breast Cancer, After Failure of Tamoxifen and/or Anastrozole and/or Letrozole and/or Fulvestrant and/or Exemestane

Conditions
-----------------
Postmenopausal Women, Locally Advanced Metastatic Breast Cancer, Metastatic Breast Cancer

Intervention / Treatment
-----------------
* Drug: Everolimus
* Drug: Letrozole


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Postmenopausal women with estrogen receptor positive locally advanced or metastatic breast cancer after documented recurrence or progression on Tamoxifen, Anastrozole or Examestane. Refractory disease to hormonal therapy is defined as: Recurrence while on, or within 12 month of end of, adjuvant treatment with Tamoxifen , Anastrozole, or Exemestane. Recurrence while on, or within 24 month of end of, adjuvant treatment with Letrozole. Progression while on Tamoxifen, Anastrozole or Exemestane treatment for locally advanced or metastatic breast cancer. Exclusion Criteria: Prior use of chemotherapy and letrozole for Advanced Breast Cancer and mTOR inhibitors as the last anticancer treatment prior to study entry. Patients must have radiological evidence of recurrence or progression on last therapy prior to study entry.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Everolimus + Letrozole<br>All patients received 2 tablets (5 mg each) of Everolimus (a total of 10 mg) + 1 tablet of Letrozole (2.5 mg) daily until disease progression or as described in the protocol. | Drug: Everolimus<br>* Everolimus 10 mg (2 tablets of 5 mg) once daily<br>* Other names: RAD001;Drug: Letrozole<br>* Letrozole 2.5 mg once daily<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Overall Response Rate (ORR) | Overall Response Rate (ORR) was defined as the proportion of patients whose best overall response was either complete response (CR) or partial response (PR) according to RECIST 1.0 for target lesions and assessed by CT: Complete Response (CR), disappearance of all target lesions for a period of at least one month; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (ORR) = CR + PR. Only descriptive statistics. | From the date of randomization until the date of the first documented disease progression or date of death from any cause whichever came first, assessed for approximately 15 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Time to Progression-Free Survival (PFS) | Progression Free Survival (PFS) was defined as the time from the date of study entry to the date of first documented tumor progression or death from any cause, whichever occurred first. If a patient did not have an event, PFS was censored at the last date of tumor assessment. For patients with measurable disease at baseline, progression was determined according to the RECIST 1.0 criteria. Only descriptive analysis done. | Date of randomization to the date of first documented tumor progression or death from any cause, whichever occurs first, reported between day of first patient randomized up to 66 months | 
| Median Time to Overall Survival (OS) | Overall Survival (OS) was defined as the time from the date of study entry to date of death due to any cause. If a death had not observed by the date of analysis, then OS was censored at the date of last contact. Distribution of OS was estimated using the Kaplan Meier method. The median OS along with 95% CI was presented. | From Date of randomization up to approximately 66 months | 
| Disease Control Rate (DCR) | Disease Control Rate (DCR) was defined as the proportion of patients whose best overall response was either: Complete Response (CR), Partial Response (PR) or Stable Disease (SD). Disease Control Rate was calculated only for patients with measurable disease at baseline and was summarized using descriptive statistics. | From the date of randomization until the date of the first documented disease progression or date of death from any cause whichever came first, assessed for approximately 66 months | 
| Long-term Safety and Tolerability | The assessment of safety was based mainly on the frequency of AEs and on the number of laboratory values that fell outside of pre-determined ranges. Other safety data (e.g. ECG, vital signs) were considered as appropriate. Only descriptive analysis done. | From Date of first dose up to approximately 66 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
RAD001 (Everolimus), Letrozole, Breast cancer, Metastatic Breast cancer, Estrogen receptor positive, Failure of Tamoxifen, Anastrozole or Examestane