A Phase II Study of Everolimus in Combination With Exemestane Versus Everolimus Alone Versus Capecitabine in Advance Breast Cancer.

Study Overview
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Brief Summary
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This was a three-arm, randomized, open label, multi-center phase II study investigating the combination of everolimus (10mg daily) with exemestane (25mg daily) versus everolimus (10mg daily) versus capecitabine (1250mg/m2 twice daily for 14 days, 3-week cycle) in patients with estrogen-receptor positive, HER2 negative, advanced breast cancer after recurrence or progression on letrozole or anastrozole.

Detailed Description
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The reference therapy (control arm) used in the course of this trial was the combination arm of everolimus plus exemestane. The investigational therapies in the context of this study were everolimus monotherapy and capecitabine monotherapy. All treatments were taken orally until disease progression, intolerable toxicity or withdrawal of patient's informed consent. Patients were randomly assigned with equal allocation to one of the treatment arms: Exemestane (25mg daily) in combination with everolimus (10mg daily) Everolimus (10mg daily) Capecitabine (1250mg/m2 twice daily) orally for two weeks, followed by a one week rest period in 3-weeks cycles. Treatment assignment was stratified by the presence of visceral disease (yes vs. no). Visceral refered to lung, liver, heart, ovary, spleen, kidney, adrenal gland, malignant pleural or pericardial effusion or malignant ascites. Randomization and Treatment Phase: At Visit 3 all eligible patients were randomized in 1:1:1 ratio to receive everolimus (10mg daily oral tablets) in combination with exemestane (25 mg daily oral tablets), everolimus (10mg daily oral tablets) or capecitabine monotherapy (1250mg/m2 twice daily orally for two weeks followed by a one week rest period in 3-weeks cycles). Assignment was stratified by the presence of visceral disease (yes vs. no). Visceral refered to lung, liver, heart, ovary, spleen, kidney, adrenal gland, malignant pleural or pericardial effusion or malignant ascites. After randomization, study treatment started and continued until progression, intolerable toxicity or consent withdrawal. Further treatment after progression and study treatment discontinuation was at the investigator's discretion. Dose adjustment (reduction, interruption) according to safety findings was allowed. Regular safety and efficacy reviews by Data Monitoring Committee (DMC) were performed. Tumor assessments were performed every 6 weeks until disease progression. Additional evaluation were performed to confirm response at 4 weeks after it was first observed. After at least 150 PFS events had been documented per RECIST 1.1 by local assessment in each of the two following groups: (i) everolimus + exemestane arm plus everolimus monotherapy arm, and (ii) everolimus + exemestane arm plus capecitabine monotherapy arm, the frequency of tumor assessments was changed to every 12 weeks or as clinically indicated. Follow-up phase: Patients were followed for safety for 30 days after study treatment discontinuation. If a patient did not discontinue study treatment due to disease progression, lost to follow-up or consent withdrawal, then tumor assessments continued to be performed every 6 weeks until disease progression, death, lost to follow-up or investigator decision in patient best interest. Survival Data Collection: All patients were followed for survival status at least every 3 months regardless of treatment discontinuation reason and up to two years after randomization of last patient. Survival information could be obtained via phone and information were documented in the source documents and eCRF. Additional survival follow-up might be performed more frequently if a survival update was required for reporting the results or to meet safety or regulatory needs.

Official Title
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A Three-arm, Randomized, Open Label, Phase II Study of Everolimus in Combination With Exemestane Versus Everolimus Alone Versus Capecitabine in the Treatment of Postmenopausal Women With Estrogen Receptor Positive, Locally Advanced, Recurrent, or Metastatic Breast Cancer After Recurrence or Progression on Prior Letrozole or Anastrozole.

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Capecitabine
* Drug: Exemestane
* Drug: Everolimus


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: - Women with locally advanced, recurrent, or metastatic breast cancer along with confirmation of estrogen-receptor positive (ER+). Measurable disease defined as at least one lesion ≥ 10 mm by CT or MRI that can be accurately measured in at least one dimension (CT scan slice thickness ≤ 5 mm) OR • Bone lesions: lytic or mixed (lytic + blastic) in the absence of measurable disease as defined above. Key Exclusion Criteria: - Patients who received more than one chemotherapy line. Patients with only non-measurable lesions other than lytic or mixed (lytic and blastic) bone metastasis.Previous treatment with exemestane, mTOR inhibitors, PI3K inhibitors or AKT inhibitors.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Capecitabine 1250 mg/m2<br>Capecitabine (1250 mg/m2 twice daily) for two weeks, followed by one week rest period in 3-weeks cycles (investigational arm). | Drug: Capecitabine<br>* Capecitabine, tablets for oral use, 1250 mg/m² twice daily for 2 weeks followed by one week rest (3-week-cycle) (locally supplied)<br>* Other names: Capecitabine monotherapy;|
| Experimental: Everolimus 10 mg<br>Everolimus (10 mg daily) (investigational arm). | Drug: Everolimus<br>* Everolimus, 5 mg tablets for oral use, 10 mg (2 x 5 mg) per day (centrally supplied)<br>* Other names: RAD001;|
| Active Comparator: Everolimus 10 mg + Exemestane 25 mg<br>Everolimus (10 mg daily) with Exemestane (25 mg daily) (control arm). | Drug: Exemestane<br>* Exemestane, tablets for oral use, 25 mg per day in (locally supplied)<br>* Other names: Control arm;Drug: Everolimus<br>* Everolimus, 5 mg tablets for oral use, 10 mg (2 x 5 mg) per day (centrally supplied)<br>* Other names: RAD001;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) - Everolimus Plus Exemestane Versus Everolimus Alone | Progression Free Survival (PFS) is defined as the time from date of randomization to the date of first radiologically documented progression or death due to any cause. If a patient did not have an event, PFS was censored at the date of the last adequate tumor assessment. PFS was compared between the everolimus + exemestane combination therapy with the everolimus monotherapy. | 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 39 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) - Everolimus Plus Exemestane Versus Capecitabine Alone | Progression Free Survival (PFS) is defined as the time from date of randomization to the date of first radiologically documented progression or death due to any cause. If a patient did not have an event, PFS was censored at the date of the last adequate tumor assessment. PFS was compared between the everolimus + exemestane combination therapy with the everolimus monotherapy. | 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 39 months | 
| Overall Survival (OS) | Overall Survival (OS) is defined as the time from date of randomization to date of death due to any cause. If a patient was not known to have died by the date of analysis cut-off, OS was censored at the date of last known date patient alive. | Every 3 months following end of treatment visit, assessed for approximately 54 months | 
| Overall Response Rate (ORR) | Overall Response Rate (ORR) as the proportion of patients whose best overall response is either complete response (CR) or partial response (PR) according to RECIST 1.1 This was assessed in the full patient population. Complete response is achieved when all lesions evaluated at baseline are absent at subsequent visit. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = 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 43 months | 
| Clinical Benefit Rate (CBR) | Clinical Benefit Rate (CBR) is defined as the proportion of participants with a best overall response of complete response (CR) or partial response (PR) or stable disease (SD) or Non-CR/non-PD lasting more than 24 weeks based on local investigator's assessment according to RECIST 1.1. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR, Stable disease (SD), neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD; CBR = CR+PR+SD. 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 43 months | 
| Time to Eastern Cooperative Oncology Group (ECOG) Performance Deterioration | The Eastern Cooperative Oncology Group (ECOG) Performance Status is a scale used to assess physical health of subjects,ranging from 0 (most active) to 5 (least active). Definitive deterioration is defined as no improvement in the ECOG status following observation of the deterioration. | Baseline, every 6 weeks up to about 43 months | 
| Time to 10% Definitive Deterioration in the Global Health Status / Quality of Life | The global health status/QoL scale score of the QLQ-C30 is identified as the primary PRO variable of interest. Physical Functioning (PF), Emotional Functioning (EF) and Social Functioning (SF) scale scores of the QLQ-C30. The time to definitive 10% deterioration is the number of days between the date of randomization and the date of the assessment at which definitive deterioration is seen. Definitive 10% (5-point) deterioration is defined as a decrease in score by at least 10% (5-points) compared to baseline, with no later increase above this threshold observed during the course of the study. | Baseline, every 6 weeks up to about 43 months | 
| Mean Change in Treatment Satisfaction Questionnaire for Medication (TSQM) Between Week 3 and 12 | TSQM was used to measure the Patients' self-reported satisfaction or dissatisfaction with the study treatment. The differences in mean scale scores between weeks 3 and 12 comparing treatment satisfaction in the different treatment arms: everolimus + exemestane combination therapy versus everolimus monotherapy, and everolimus + exemestane combination therapy versus capecitabine monotherapy. The TSQM version 1.4 domain scores range from 0 to 100 with higher scores representing a higher satisfaction on that domain. | Week 3, Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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metastatic, breast cancer progression, Everolimus, Exemestane, Capecitabine, locally advanced, breast cancer, breast cancer positive for human epidermal growth factor receptor 2, HER2, HER2 positive, estrogen-receptor positive breast cancer, ER