A Study Of Everolimus, Trastuzumab And Vinorelbine In HER2-Positive Breast Cancer Brain Metastases
- Conditions
- HER-2 Positive Breast Cancer
- Interventions
- Registration Number
- NCT01305941
- Lead Sponsor
- UNC Lineberger Comprehensive Cancer Center
- Brief Summary
Purpose: This study is a single-arm, open-label phase II clinical trial testing the hypothesis that daily everolimus plus weekly vinorelbine and trastuzumab will be effective, safe, and tolerable among patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer brain metastases. Once enrolled, patients will receive everolimus PO daily in combination with weekly intravenous (IV) vinorelbine and trastuzumab. Cycles will be repeated every 3 weeks (21 days). At the time of progression, patients will come off study.
Participants: Up to 35 adults over 21 with HER-2 positive breast cancer that has metastasized to the brain.
- Detailed Description
STUDY OBJECTIVES Primary Objective -To determine the intracranial objective response rate of mTOR inhibition (everolimus) in combination with vinorelbine and trastuzumab in the treatment of HER2-positive, progressive breast cancer brain metastases as defined via modified RECIST criteria.
Secondary Objectives
* To determine the intracranial objective response rate of mechanistic target of rapamycin (mTOR) inhibition (everolimus) in combination with vinorelbine and trastuzumab in the treatment of HER2-positive, progressive breast cancer brain metastases as defined by MacDonald criteria.
* To evaluate the safety and tolerability of everolimus in combination with trastuzumab and vinorelbine as assessed via the NCI CTCAE version 4.0
* To evaluate time to intracranial progression after administration of everolimus in combination with trastuzumab and vinorelbine as defined via modified RECIST criteria
* To evaluate the extracranial objective response rate as determined by RECIST 1.1 criteria after administration of everolimus in combination with trastuzumab and vinorelbine.
* To evaluate the extracranial time to progression as determined by RECIST 1.1 criteria after administration of everolimus in combination with trastuzumab and vinorelbine.
* To evaluate progression free survival (PFS) and overall survival (OS) after administration of everolimus in combination with trastuzumab and vinorelbine.
* To evaluate the impact of everolimus in combination with trastuzumab and vinorelbine on quality of life as measured by the Functional Assessment of Cancer Therapy Breast (FACT-B) and Functional Assessment of Cancer Therapy Brain (FACT-Br) questionnaires.
Exploratory Objective
-To evaluate biomarkers in archival tumor tissue samples and correlate with therapeutic response to everolimus in combination with vinorelbine and trastuzumab.
Following Hepatitis B antiviral prophylaxis if required, or following screening and informed consent if antiviral therapy is not needed, treatment will be initiated with everolimus PO daily in combination with weekly intravenous (IV) vinorelbine and trastuzumab (Days 1, 8, and 15)
A cycle is defined as 3 weeks (21 days). Cycles of therapy will be repeated until documented disease progression, unacceptable toxicity, or patient withdrawal from study for other reasons, including death.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 32
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Everolimus +Vinorelbine + trastuzumab Vinorelbine daily everolimus plus weekly (Days 1, 8, and 15) vinorelbine and trastuzumab Everolimus +Vinorelbine + trastuzumab Everolimus daily everolimus plus weekly (Days 1, 8, and 15) vinorelbine and trastuzumab Everolimus +Vinorelbine + trastuzumab Trastuzumab daily everolimus plus weekly (Days 1, 8, and 15) vinorelbine and trastuzumab
- Primary Outcome Measures
Name Time Method Intracranial Objective Response Rate- Modified RECIST Criteria 3 years response will be evaluated via gadolinium-enhanced brain MRI using modified RECIST criteria.
Complete Response (CR) - Disappearance of all target and nontarget lesions
Partial Response (PR) - at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum longest diameter AND an absolute decrease of at least 5mm in at least one target lesion.
Stable Disease (SD) - neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum of the longest diameter since the treatment started.
Progressive Disease (PD) - at least a 20% increase in the sum LD of target lesions, taking as reference the smallest sum of the longest diameter recorded since the treatment started AND an absolute increase in size of at least 5 mm in at least one target lesion OR the appearance of one or more new lesions of at least 6 mm in size.
- Secondary Outcome Measures
Name Time Method Intracranial Response Rate- MacDonald Criteria 3 years Intracranial tumor lesions were evaluated via gadolinium-enhanced brain MRI using the MacDonald criteria. Measurable disease is defined as at least 1 measurable brain lesion accurately measured in at least 2 dimensions (longest diameter) as ≥5.0 mm. Tumor size is the product of the 2 longest bi-dimensional lines.
Complete Response (CR)- Disappearance of all tumor on consecutive CT or MRI scans at least 1 month apart, off steroids for treatment of neurological symptoms, and neurologically stable or improved.
Partial Response (PR)- ≥50% reduction in size of tumor on consecutive CT or MRI scans at least 1 month part, steroids stable or reduced, and neurologically stable or improved.
Progressive Disease (PD)- ≥25% increase in size of tumor or any new tumor on CT or MRI scans, or neurologically worse, and steroids stable or increased due to neurologic symptoms.
Stable Disease (SD)- all other situations Overall Response Rate (ORR) is the sum of partial responses (PRs) and CRs.Toxicity 24 weeks Grade 3 or higher toxicities of interest are reported. Toxicity was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.
The NCI CTCAE is a descriptive terminology which can be utilized for Adverse Event (AE) reporting. A grading (severity) scale is provided for each AE term. Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living (ADL). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE.Time to Intracranial Progression. 3 years Time to intracranial progression after administration of everolimus in combination with trastuzumab and vinorelbine as defined via modified RECIST criteria.
Progressive Disease (PD) - at least a 20% increase in the sum LD of target lesions, taking as reference the smallest sum of the longest diameter recorded since the treatment started AND an absolute increase in size of at least 5 mm in at least one target lesion OR the appearance of one or more new lesions of at least 6 mm in size.Extracranial Response 3 years Extracranial response was measured using RECIST 1.1 criteria and defined as the number of subjects achieving CR or PR.
Complete Response (CR) - Disappearance of all target and nontarget lesions Partial Response (PR) - at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum longest diameter AND an absolute decrease of at least 5mm in at least one target lesion.
Stable Disease (SD) - neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum of the longest diameter since the treatment started.
Progressive Disease (PD) - at least a 20% increase in the sum LD of target lesions, taking as reference the smallest sum of the longest diameter recorded since the treatment started AND an absolute increase in size of at least 5 mm in at least one target lesion OR the appearance of one or more new lesions of at least 6 mm in size.Extracranial Time to Progression 3 years To evaluate the extracranial time to progression as determined by RECIST 1.1 criteria after administration of everolimus in combination with trastuzumab and vinorelbine.
Progressive Disease (PD) - at least a 20% increase in the sum LD of target lesions, taking as reference the smallest sum of the longest diameter recorded since the treatment started AND an absolute increase in size of at least 5 mm in at least one target lesion OR the appearance of one or more new lesions of at least 6 mm in size.Overall Survival 3 years Overall survival (OS) after administration of everolimus in combination with trastuzumab and vinorelbine
Functional Assessment of Cancer Therapy- Brain (FACT-Br) Change From Baseline to Assess Impact of Everolimus in Combination With Trastuzumab and Vinorelbine on Quality of Life 9 weeks The FACT-Br is a 23-question self-report questionnaire subscale administered with the Functional Assessment of Cancer Therapy- General (FACT-G) which contains concerns relevant to patients with brain tumors . Each question has a value 0-4. For some questions a higher indicates better outcome and others are the opposite. The former are summed as is, the latter are reversed in value before adding, such that each domain ranges from 0 to 4 times the number of questions in the domain, with 0 indicating worst and the highest possible value indicating best outcome. Total scores on the FACT-Br subscale range from 0 to 92 with lower scores indicating declining quality of life. The change from baseline is the difference in scores between the baseline and 9 week assessments.
Functional Assessment Cancer Therapy- Breast (FACT-B) From Baseline to 9 Weeks of Treatment to Assess Impact of Everolimus in Combination With Trastuzumab and Vinorelbine on Quality of Life 9 weeks The FACT-B is a 10-question self-report questionnaire subscale administered with the Functional Assessment of Cancer Therapy- General (FACT-G) which contains concerns relevant to patients with breast cancer. Each question has a value 0-4. For some questions a higher indicates better outcome and others are the opposite. The former are summed as is, the latter are reversed in value before adding, such that each domain ranges from 0 to 4 times the number of questions in the domain, with 0 indicating worst and the highest possible value indicating best outcome. Total scores on the FACT-B subscale range from 0 to 40 with lower scores indicating declining quality of life. The change from baseline is the difference in scores between the baseline and 9 week assessments.
Trial Locations
- Locations (4)
UNC Lineberger Comprehensive Cancer Center
🇺🇸Chapel Hill, North Carolina, United States
Carolinas Healthcare System
🇺🇸Charlotte, North Carolina, United States
University Of Alabama at Birmingham
🇺🇸Birmingham, Alabama, United States
Vanderbilt-Ingram Cancer Center
🇺🇸Nashville, Tennessee, United States