Everolimus in Combination With Trastuzumab and Paclitaxel in the Treatment of HER2 Positive Locally Advanced or Metastatic Breast Cancer

Study Overview
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Brief Summary
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The purpose of this Phase III study was to confirm the value of adding everolimus to weekly paclitaxel and trastuzumab as treatment of HER2-overexpressing metastatic breast cancer.

Official Title
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A Randomized Phase III, Double-Blind, Placebo-Controlled Multicenter Trial of Everolimus in Combination With Trastuzumab and Paclitaxel, as First Line Therapy in Women With HER2 Positive Locally Advanced or Metastatic Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Everolimus
* Drug: Placebo
* Drug: Trastuzumab
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult Women (≥ 18 years old). Histologically or cytologically confirmed invasive breast carcinoma with local recurrence or radiological evidence of metastatic disease. Must have at least one lesion that can be accurately measured or bone lesions in the absence of measurable disease. HER2+ patients by local laboratory testing (IHC 3+ staining or in situ hybridization positive). Prior trastuzumab and/or chemotherapy (taxanes included) as neo-adjuvant or adjuvant treatment is allowed but should be discontinued > 12 months prior to randomization. Prior treatment for breast cancer with endocrine therapy (adjuvant or metastatic settings) is allowed but should be discontinued at randomization. Patients treated with bisphosphonates at entry or who start bisphosphonates during study may continue this therapy during protocol treatment. Documentation of negative pregnancy test. Organ functions at time of inclusion. Exclusion Criteria: Prior mTOR inhibitors for the treatment of cancer. Other anticancer therapy for locally advanced or metastatic breast cancer except for prior hormonal therapy. Patients with only non-measurable lesions other than bone metastasis (e.g. pleural effusion, ascites, etc). Radiotherapy to ≥ 25% of the bone marrow within 4 weeks prior to randomization History of central nervous system metastasis. Impairment of gastrointestinal (GI) function or GI disease or active ulceration of the upper gastrointestinal tract. Serious peripheral neuropathy. Cardiac disease or dysfunction. Uncontrolled hypertension. HIV. Pregnant,

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Everolimus + Paclitaxel + Trastuzumab<br>Everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22 | Drug: Everolimus<br>* Everolimus was administered in a continuous oral daily dosing of 10 mg (two 5-mg tablets).<br>* Other names: RAD001;Drug: Trastuzumab<br>* Trastuzumab, 2 mg/kg weekly was used intravenously.<br>Drug: Paclitaxel<br>* Paclitaxel, 80 mg/m2 weekly was used intravenously.<br>|
| Placebo Comparator: Placebo + Paclitaxel + Trastuzumab<br>Placebo of everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22 | Drug: Placebo<br>* Everolimus placebo was administered in a continuous oral daily dosing of 10 mg (two 5-mg tablets).<br>Drug: Trastuzumab<br>* Trastuzumab, 2 mg/kg weekly was used intravenously.<br>Drug: Paclitaxel<br>* Paclitaxel, 80 mg/m2 weekly was used intravenously.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) Per Investigators' Assessment Based on Local Radiology Review - Full Population | PFS is defined as the time from the date of randomization to the date of first documented tumor progression or death from any cause, whichever occurs first. This was assessed in the full patient population. | 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 about 56 months | 
| Progression-free Survival (PFS) Per Investigators' Assessment Based on Local Radiology Review - (Hormone Receptor (HR)-Negative Population | PFS is defined as the time from the date of randomization to the date of first documented tumor progression or death from any cause, whichever occurs first. This was assessed in the HR-negative patient population. | 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 about 56 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) - Full Population | OS is defined as the time from date of randomization to the date of death due to any cause. For patients with documented progression, survival follow up was performed either by telephone or clinic visit at least every 3 months. Additional survival updates were requested prior to interim or final analysis or prior to providing data to the health authorities. This was assessed in the full patient population. | up to about 76 months | 
| Overall Survival (OS) - HR-negative Population | OS is defined as the time from date of randomization to the date of death due to any cause. For patients with documented progression, survival follow up was performed either by telephone or clinic visit at least every 3 months. Additional survival updates were requested prior to interim or final analysis or prior to providing data to the health authorities. This was assessed in the HR-negative patient population. | up to about 76 months | 
| Overall Response Rate (ORR) - Full Population | ORR is defined as the percentage of participants whose best overall response is either complete response (CR) or partial response (PR) according to RECIST. This was assessed in the full patient population. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit. | up to about 23 months | 
| Overall Response Rate (ORR) - HR-negative Population | ORR is defined as the percentage of participants whose best overall response is either complete response (CR) or partial response (PR) according to RECIST. This was assessed in a subset of patients with Hormone Receptor Negative disease. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit. | up to about 23 months | 
| Clinical Benefit Rate (CBR) Equal to or Greater Than 24 Weeks - Full Population | CBR is defined as the percentage of participants whose best overall response is either complete response (CR), a partial response (PR) or stable disease (SD) lasting for at least 24 weeks, according to RECIST. This was assessed in the full patient population. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit. | up to about 23 months | 
| Clinical Benefit Rate (CBR) Equal to or Greater Than 24 Weeks - HR-negative Population | CBR is defined as the percentage of participants whose best overall response is either complete response (CR), a partial response (PR) or stable disease (SD) lasting for at least 24 weeks, according to RECIST. This was assessed in a subset of patients with Hormone Receptor Negative disease. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit. | up to about 23 months | 
| Time to Overall Response Based on Investigator - Full Population | Time to overall response defined as the time between date of randomization until first documented response Complete reseponse (CR) or partial response (PR) ), according to RECIST. This was assessed in the full patient population and in a subset of patients with Hormone Receptor Negative disease. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit. | up to about 23 months | 
| Time to Overall Response Based on Investigator - HR-negative Population | Time to overall response defined as the time between date of randomization until first documented response Complete reseponse (CR) or partial response (PR) ), according to RECIST. This was assessed in the full patient population and in a subset of patients with Hormone Receptor Negative disease. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit. | up to about 23 months | 
| Overall Response (OR) - Full Population | OR applies only to patients whose best OR was CR or PR. Start date = date of first documented response (CR or PR) and end date = date of documented response (CR or PR) and end date = date of event defined as the first documented progression or death due to underlying cause. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit. | up to about 23 months | 
| Overall Response (OR) - HR-negative Population | OR applies only to patients whose best OR was CR or PR. Start date = date of first documented response (CR or PR) and end date = date of documented response (CR or PR) and end date = date of event defined as the first documented progression or death due to underlying cause. This was assessed in the HR-negative patient population. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit. | up to about 23 months | 
| Everolimus Blood Level Concentrations at Steady States for Everolimus | Blood levels at steady states for everolimus 10 mg/day and 5 mg/day. Only valid samples are included. Some patients had dose reduction to 5 mg daily dose therefore the everolimus blood concentration for them have been summarized separately. Cycle = 28 days | predose, 2 hours post-dose at Cycle 2/Day 1, Cycle 2/Day 15, Cycle 2/ Day 22 | 
| Paclitaxel Plasma Concentrations | Blood levels at steady states for everolimus/placebo | Cycle 2/Day 15 (Pre-infusion and end of infusion) | 
| Trastuzumab Serum Concentrations | Blood levels at steady states for everolimus/placebo | Cycle 4/Day 1 (Pre-infusion and end of infusion) | 
| Time to Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG-PS) Score - Full Population | Time to definitive deterioration of the ECOG PS by one category of the score from baseline will be performed. Baseline is the last available assessment on or before randomization date. A deterioration is considered definitive if no improvements in the ECOG PS status is observed at a subsequent time of measurement during the treatment period following the time point where the deterioration is observed. | up to about 56 months | 
| Time to Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG-PS) Score - HR-negative Population | Time to definitive deterioration of the ECOG PS by one category of the score from baseline will be performed. Baseline is the last available assessment on or before randomization date. A deterioration is considered definitive if no improvements in the ECOG PS status is observed at a subsequent time of measurement during the treatment period following the time point where the deterioration is observed. | up to about 56 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast Cancer, HER2+, mTOR, everolimus, RAD001, first line, metastatic, locally advanced, Trastuzumab, Paclitaxel, First Line Therapy, HER2 Positive, Metastatic Breast Cancer