Clinical Trials /

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

NCT01305941

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Completed

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: LCCC 1025
  • SECONDARY ID: 11-0242
  • NCT ID: NCT01305941

Conditions

  • HER-2 Positive Breast Cancer

Interventions

DrugSynonymsArms
EverolimusRAD001Everolimus +Vinorelbine + trastuzumab
VinorelbineNavelbineEverolimus +Vinorelbine + trastuzumab
TrastuzumabHerceptinEverolimus +Vinorelbine + trastuzumab

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Everolimus +Vinorelbine + trastuzumabExperimentaldaily everolimus plus weekly (Days 1, 8, and 15) vinorelbine and trastuzumab
  • Everolimus
  • Vinorelbine
  • Trastuzumab

Eligibility Criteria

        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 brain metastases (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 intracranial Response (ICR) may be included
             unless ICR is emergently indicated (in consultation with a local therapist, ie
             neurosurgeon or radiation oncologist)

          -  Eastern Cooperative Oncology Group (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 adverse events (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 multigated
             acquisition scan (MUGA) scan) performed within 4 weeks prior to study initiation,
             showing a Left ventricular ejection fraction (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.

          -  international normalized ratio (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
             Low-molecular-weight (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)

          -  aspartate aminotransferase (AST) or Alanine transaminase (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, institutional review board (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
             Cerebrospinal fluid (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 left ventricular (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,
             Bacillus Calmette-Guérin (BCG), yellow fever, varicella, and Typhoid Vaccine Live Oral
             (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. Hepatitis B Virus (HBV) DNA and hepatitis C Virus (HCV) RNA
        polymerase chain reaction (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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:21 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Intracranial Objective Response Rate- Modified RECIST Criteria
Time Frame:3 years
Safety Issue:
Description: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

Measure:Intracranial Response Rate- MacDonald Criteria
Time Frame:3 years
Safety Issue:
Description: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.
Measure:Toxicity
Time Frame:24 weeks
Safety Issue:
Description: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.
Measure:Time to Intracranial Progression.
Time Frame:3 years
Safety Issue:
Description: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.
Measure:Extracranial Response
Time Frame:3 years
Safety Issue:
Description: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.
Measure:Extracranial Time to Progression
Time Frame:3 years
Safety Issue:
Description: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.
Measure:Overall Survival
Time Frame:3 years
Safety Issue:
Description:Overall survival (OS) after administration of everolimus in combination with trastuzumab and vinorelbine
Measure: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
Time Frame:9 weeks
Safety Issue:
Description: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.
Measure: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
Time Frame:9 weeks
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:UNC Lineberger Comprehensive Cancer Center

Trial Keywords

  • everolimus
  • trastuzumab
  • vinorelbine
  • RAD001
  • Breast Cancer
  • Herceptin
  • Navelbine
  • Lineberger Comprehensive Cancer Center
  • Brain Metastases

Last Updated

September 14, 2017