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A Study Of Everolimus, Trastuzumab And Vinorelbine In HER2-Positive Breast Cancer Brain Metastases

This study is ongoing, but not recruiting participants.
Novartis Pharmaceuticals
Information provided by (Responsible Party):
UNC Lineberger Comprehensive Cancer Center Identifier:
First received: February 25, 2011
Last updated: March 10, 2017
Last verified: March 2017

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 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.

Condition Intervention Phase
HER-2 Positive Breast Cancer
Drug: Everolimus
Drug: Vinorelbine
Drug: Trastuzumab
Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: A Phase II Study Evaluating The Efficacy And Tolerability Of Everolimus (RAD001) In Combination With Trastuzumab And Vinorelbine In The Treatment Of Progressive HER2-Positive Breast Cancer Brain Metastases

Resource links provided by NLM:

Further study details as provided by UNC Lineberger Comprehensive Cancer Center:

Primary Outcome Measures:
  • intracranial response rate- modified RECIST Criteria [ Time Frame: 3 years ]
    response will be evaluated via gadolinium-enhanced brain MRI using modified RECIST criteria for all evaluable patients. A responder will be a patient whose best overall response is a CR or PR

Secondary Outcome Measures:
  • Intracranial Response Rate- MacDonald Criteria [ Time Frame: 3 years ]
    intracranial response rate will be evaluated via gadolinium-enhanced MRI using MacDonald criteria

  • Extracranial response [ Time Frame: 3 years ]
    Extracranial response will be measured using RECIST 1.1 criteria.

  • Toxicity [ Time Frame: 3 years ]
    Toxicity will be assessed according to the NCI CTCAE v4.

Estimated Enrollment: 35
Study Start Date: September 2011
Estimated Study Completion Date: May 19, 2017
Primary Completion Date: August 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Everolimus +Vinorelbine + trastuzumab
daily everolimus plus weekly (Days 1, 8, and 15) vinorelbine and trastuzumab
Drug: Everolimus
everolimus 5 mg PO daily as two 2.5-mg tablets
Other Name: RAD001
Drug: Vinorelbine
vinorelbine 25 mg/m2 will be administered via IV infusion over 6-10 minutes weekly.
Other Name: Navelbine
Drug: Trastuzumab
2 mg/kg IV administered over 30 minutes weekly
Other Name: Herceptin

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 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 FACT-B and 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.


Ages Eligible for Study:   21 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria

  • Histologically-confirmed HER2-positive (IHC 3+ or fluorescence in situ hybridization [FISH] amplified; by clinical assay on either primary or metastatic tumor) adenocarcinoma of the breast with at least one progressive and/or new metastatic brain lesion (>/=5 mm on radiographic imaging) after receipt of intracranial radiation therapy (whole brain radiation therapy, stereotactic radiosurgery, gamma knife, or equivalent). Patients in whom BM are asymptomatic and detected during routine brain MRI screening per institutional protocols are eligible.
  • Prior intracranial radiation therapy (whole brain radiation therapy, stereotactic radiosurgery, gamma knife or equivalent) is allowed but not required.
  • Patients with no prior treatment with ICR may be included unless ICR is emergently indicated (in consultation with a local therapist, ie neurosurgeon or radiation oncologist)
  • ECOG performance status of 0-2.
  • Life expectancy >12 weeks.
  • At least 21 years of age.
  • No prior mTOR inhibitors
  • Prior navelbine allowed provided navelbine therapy discontinued >/= 12 months from Day 1 of treatment under this protocol.
  • Last anti-cancer treatment (including any investigational drug) >/= 2 weeks from initiation of protocol based therapy, provided all AEs (other than alopecia) have resolved to ≤grade 1 at baseline.
  • No active serious infection or other comorbid illness which would impair ability to participate in the trial.
  • Left ventricular ejection fraction assessment (echocardiogram or MUGA scan) performed within 4 weeks prior to study initiation, showing a LVEF value ≥ lower limit of normal (LLN).
  • If patient is on dexamethasone, must be on stable or decreasing dose of dexamethasone for ≥7 days. If patient is on different glucocorticoid e.g., prednisone, must be converted to dexamethasone prior to enrollment. Refer to dose modification of everolimus for patients taking dexamethasone.
  • Interval ≥4 weeks between open brain biopsy and initiation of protocol-based therapy.
  • INR ≤2.0. Anticoagulation is allowed if target INR ≤2.0 on a stable dose of warfarin or if patient on a stable dose of LMW heparin for >1 weeks at time of enrollment.
  • Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglycerides ≤2.5 x ULN. NOTE: In case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication.
  • Patients must have adequate organ function as evidenced by:
  • Absolute neutrophil count ≥1.5/µL
  • Platelet count ≥100,000/µL
  • Hg ≥9 g/dL
  • Bilirubin ≤1.5 x upper limit of normal (ULN)
  • AST or ALT ≤2.5 x ULN (≤5 x ULN if liver metastases are present)
  • Serum creatinine ≤1.5 x ULN
  • Archived, paraffin-embedded tissue block (primary or metastatic) available for genomic studies is required.
  • Signed, IRB-approved written informed consent.

Exclusion Criteria

  • Patients who have received prior treatment with an mTOR inhibitor (e.g., sirolimus, temsirolimus, everolimus); patients who have received prior treatment with navelbine within prior 12 months.
  • patients with a known hypersensitivity to everolimus or other rapamycins (e.g. sirolimus, temsirolimus) or to its excipients.
  • Patients requiring treatment with any other systemic glucocorticoid. NOTE: This restriction regarding choice of glucocorticoid does not apply should patient need <2 week course of glucocorticoid for treatment of non-infectious pneumonitis during study (see section 4.5.2).
  • Patients with a known hypersensitivity to vinorelbine or to its excipients.
  • Prior allergic reaction to trastuzumab for the treatment of metastatic breast cancer.
  • Concurrent or planned radiation, hormonal, chemotherapeutic, experimental or targeted biologic therapy.
  • Peripheral neuropathy ≥grade 3.
  • Evidence of frank hemorrhage or impending herniation on baseline brain imaging.NOTE: asymptomatic micro-hemorrhage is allowed.
  • Evidence of diffuse leptomeningeal disease on brain MRI or by previously documented CSF cytology. NOTE: discrete dural metastases are permitted.
  • Active cardiac disease including any of the following:

    • Angina pectoris that requires the use of anti-anginal medication;
    • Ventricular arrhythmias except for benign premature ventricular contractions;
    • Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication;
    • Conduction abnormality requiring a pacemaker;
    • Valvular disease with documented compromise in cardiac function;
    • Symptomatic pericarditis
  • History of cardiac dysfunction including any one of the following:

    • Myocardial infarction documented by elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LV function;
    • History of documented congestive heart failure (New York Heart Association functional classification III-IV);
    • Documented cardiomyopathy
  • Patients who have had a major surgery or significant traumatic injury within 4 weeks of start of study drug, patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia), or patients that may require major surgery during the course of the study.
  • Patients should not receive immunization with attenuated live vaccines within 1 week of study entry or during study period. Close contact with those who have received attenuated live vaccines should be avoided during treatment with everolimus. Examples of live vaccines include intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.
  • Other malignancies within the past 3 years except for adequately treated carcinoma of the cervix or basal or squamous cell carcinomas of the skin.
  • Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:

    • severely impaired lung function, defined as spirometry and diffusion lung capacity for carbon monoxide (DLCO) that is 50% of the normal predicted value and/or 02 saturation that is ≤88% at rest on room air
    • uncontrolled diabetes, defined as fasting serum glucose >1.5 x ULN (Note: Optimal glycemic control should be achieved before starting trial therapy)
    • active (acute or chronic) or uncontrolled severe infections
    • liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh class C).

Note: A detailed assessment of Hepatitis B/C medical history and risk factors must be done at screening for all patients. HBV DNA and HCV RNA PCR testing are required at screening for all patients with a positive medical history based on risk factors and/or confirmation of prior HBV/HCV infection.

  • A known history of HIV seropositivity.
  • Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of everolimus (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
  • Patients with an active, bleeding diathesis or on oral anti-vitamin K medication (except low-dose warfarin and aspirin or equivalent, as long as the INR ≤2.0).
  • Unable or unwilling to discontinue use of prohibited fruit (or its juices) and prohibited medications listed in Appendices II and III for at least 14 days or 5 half-lives of a drug (whichever is longer) prior to the first dose of study drug and for the duration of the study.
  • Female patients who are pregnant or breastfeeding, or adults of reproductive potential who are not using effective birth control methods. Adequate contraception must be used throughout the trial and for 8 weeks after the last dose of study drug, by both sexes. Women of childbearing potential (WOCBP) must have a negative urine or serum pregnancy test within 7 days prior to everolimus initiation.
  • Male patients whose sexual partner(s) are WOCBP who are not willing to use adequate contraception, during the study and for 8 weeks after the end of treatment
  • Contraindication to gadolinium-enhanced MRI imaging.
  • Inability to comply with study and/or follow-up procedures.
  • History of noncompliance to medical regimens.
  Contacts and Locations
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Please refer to this study by its identifier: NCT01305941

United States, Alabama
University Of Alabama at Birmingham
Birmingham, Alabama, United States, 35294
United States, North Carolina
UNC Lineberger Comprehensive Cancer Center
Chapel Hill, North Carolina, United States, 27599
Carolinas Healthcare System
Charlotte, North Carolina, United States, 28203
United States, Tennessee
Vanderbilt-Ingram Cancer Center
Nashville, Tennessee, United States, 37212
Sponsors and Collaborators
UNC Lineberger Comprehensive Cancer Center
Novartis Pharmaceuticals
Principal Investigator: Carey K Anders, MD UNC Lineberger Comprehensive Cancer Center
  More Information

Additional Information:
Responsible Party: UNC Lineberger Comprehensive Cancer Center Identifier: NCT01305941     History of Changes
Other Study ID Numbers: LCCC 1025
11-0242 ( Other Identifier: UNC IRB assigned protocol number )
Study First Received: February 25, 2011
Last Updated: March 10, 2017

Keywords provided by UNC Lineberger Comprehensive Cancer Center:
Breast Cancer
Lineberger Comprehensive Cancer Center
Brain Metastases

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasm Metastasis
Neoplasms by Site
Breast Diseases
Skin Diseases
Neoplastic Processes
Pathologic Processes
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Antineoplastic Agents, Phytogenic
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action processed this record on May 25, 2017