Everolimus in Combination With Trastuzumab and Paclitaxel in the Treatment of HER2 Positive Locally Advanced or Metastatic Breast Cancer
- Conditions
- Breast Cancer
- Interventions
- Registration Number
- NCT00876395
- Lead Sponsor
- Novartis Pharmaceuticals
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- Female
- Target Recruitment
- 719
- 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.
- 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,
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Everolimus + Paclitaxel + Trastuzumab Trastuzumab 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 Everolimus + Paclitaxel + Trastuzumab Paclitaxel 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 Placebo + Paclitaxel + Trastuzumab Placebo 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 Everolimus + Paclitaxel + Trastuzumab Everolimus 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 Placebo + Paclitaxel + Trastuzumab Trastuzumab 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 Placebo + Paclitaxel + Trastuzumab Paclitaxel 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
- Primary Outcome Measures
Name Time Method Progression-free Survival (PFS) Per Investigators' Assessment Based on Local Radiology Review - Full 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 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.
Progression-free Survival (PFS) Per Investigators' Assessment Based on Local Radiology Review - (Hormone Receptor (HR)-Negative 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 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.
- Secondary Outcome Measures
Name Time Method Overall Survival (OS) - Full Population up to about 76 months 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.
Overall Response Rate (ORR) - Full Population up to about 23 months 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.
Time to Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG-PS) Score - Full Population up to about 56 months 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.
Overall Response Rate (ORR) - HR-negative Population up to about 23 months 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.
Clinical Benefit Rate (CBR) Equal to or Greater Than 24 Weeks - Full Population up to about 23 months 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.
Clinical Benefit Rate (CBR) Equal to or Greater Than 24 Weeks - HR-negative Population up to about 23 months 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.
Time to Overall Response Based on Investigator - Full Population up to about 23 months 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.
Overall Response (OR) - Full Population up to about 23 months 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.
Paclitaxel Plasma Concentrations Cycle 2/Day 15 (Pre-infusion and end of infusion) Blood levels at steady states for everolimus/placebo
Overall Survival (OS) - HR-negative Population up to about 76 months 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.
Time to Overall Response Based on Investigator - HR-negative Population up to about 23 months 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.
Overall Response (OR) - HR-negative Population up to about 23 months 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.
Everolimus Blood Level Concentrations at Steady States for Everolimus predose, 2 hours post-dose at Cycle 2/Day 1, Cycle 2/Day 15, Cycle 2/ Day 22 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
Trastuzumab Serum Concentrations Cycle 4/Day 1 (Pre-infusion and end of infusion) Blood levels at steady states for everolimus/placebo
Time to Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG-PS) Score - HR-negative Population up to about 56 months 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.
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Trial Locations
- Locations (27)
Comprehensive Blood and Cancer Center Dept. of CBCC (2)
🇺🇸Bakersfield, California, United States
New York Oncology Hematology NYOH Amsterdam
🇺🇸Albany, New York, United States
Texas Oncology Charles A. Sammons Cancer Ctr
🇺🇸Dallas, Texas, United States
Central Indiana Cancer Centers CICC - East (3)
🇺🇸Indianapolis, Indiana, United States
University of South Alabama / Mitchell Cancer Institute Dept. of Mitchell Cancer Inst.
🇺🇸Mobile, Alabama, United States
Ironwood Cancer and Research Centers
🇺🇸Chandler, Arizona, United States
St. Jude Heritage Medical Group Virginia Crosson Cancer Center
🇺🇸Fullerton, California, United States
University of California at Los Angeles Dept. of UCLA
🇺🇸Los Angeles, California, United States
Cancer Care Associates Medical Group Dept. of CCA
🇺🇸Redondo Beach, California, United States
Ventura County Hematology and Oncology
🇺🇸Oxnard, California, United States
Santa Barbara Hematolgy Oncology Medical Group Dept.ofSantaBarbaraHem/Onc
🇺🇸Santa Barbara, California, United States
Central Coast Medical Oncology Corporation Onc Dept
🇺🇸Santa Maria, California, United States
Florida Cancer Specialists Dept.of FloridaCancerSpec. (2)
🇺🇸Fort Myers, Florida, United States
Florida Cancer Specialists
🇺🇸West Palm Beach, Florida, United States
University of Nebraska Medical Center Unv Nebraska Med Ctr (2)
🇺🇸Omaha, Nebraska, United States
Kansas City Cancer Center Dept. of KCCC
🇺🇸Overland Park, Kansas, United States
Beth Israel Medical Center Dept.ofBeth Israel Med. Ctr(2)
🇺🇸New York, New York, United States
Tyler Cancer Center Dept.ofTylerCancerCtr. (2)
🇺🇸Tyler, Texas, United States
Texas Oncology P A SC-Austin
🇺🇸Dallas, Texas, United States
Virginia Oncology Associates SC
🇺🇸Norfolk, Virginia, United States
Virginia Cancer Institute VCI (3)
🇺🇸Richmond, Virginia, United States
Novartis Investigative Site
🇻🇪Valencia, Estado Carabobo, Venezuela
Rocky Mountain Cancer Centers RMCC - Denver-Midtown (3)
🇺🇸Greenwood Village, Colorado, United States
Sarah Cannon Research Institute Dept.ofSarahCannonCancerCtr(5)
🇺🇸Nashville, Tennessee, United States
Northwest Cancer Specialists Vancouver Cancer Center (3)
🇺🇸Portland, Oregon, United States
San Juan VA Hospital San Juan Hospital
🇵🇷San Juan, Puerto Rico
Highlands Oncology Group
🇺🇸Fayetteville, Arkansas, United States