Clinical Trials /

HKI-272 for HER2-Positive Breast Cancer and Brain Metastases

NCT01494662

Description:

The purpose of this research study is to determine how well neratinib works in treating breast cancer that has spread to the brain. Neratinib is a recently discovered oral drug that may stop breast cancer cells from growing abnormally by inhibiting (or blocking) members of a family of proteins that include Human Epidermal Growth Factor Receptor 2 (HER2). In this research study, the investigators are looking to see how well neratinib works to decrease the size of or stabilize breast cancer that has spread to the brain. The investigators are also looking at how previous treatments have affected your thinking (or cognition) and how much neratinib reaches the central nervous system.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: HKI-272 for HER2-Positive Breast Cancer and Brain Metastases
  • Official Title: A Phase II Trial of HKI-272 (Neratinib), Neratinib and Capecitabine, and Ado-Trastuzumab Emtansine for Patients With Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Breast Cancer and Brain Metastases

Clinical Trial IDs

  • ORG STUDY ID: 11-344
  • SECONDARY ID: TBCRC 022
  • NCT ID: NCT01494662

Conditions

  • Breast Cancer

Interventions

DrugSynonymsArms
HKI-272NeratinibCohort 1
CapecitabineXelodaCohort 3a/3b
HKI-272NeratinibCohort 4a/4b/4c
Ado-Trastuzumab EmtansineT-DM1Cohort 4a/4b/4c

Purpose

The purpose of this research study is to determine how well neratinib works in treating breast cancer that has spread to the brain. Neratinib is a recently discovered oral drug that may stop breast cancer cells from growing abnormally by inhibiting (or blocking) members of a family of proteins that include Human Epidermal Growth Factor Receptor 2 (HER2). In this research study, the investigators are looking to see how well neratinib works to decrease the size of or stabilize breast cancer that has spread to the brain. The investigators are also looking at how previous treatments have affected your thinking (or cognition) and how much neratinib reaches the central nervous system.

Detailed Description

      Subjects will receive neratinib and a drug-dosing calendar for each treatment cycle. This
      drug is given orally on a daily basis, continuously. Each treatment cycle will last for 4
      weeks during which time the subject will be taking neratinib every day.

        -  Physical Exams and vital signs: At the start of each cycle, you will have a physical
           exam. You will be asked questions about your general health and specific questions about
           any problems that you might be having and any medications you may be taking. You will
           also have a neurological examination to assess for neurological symptoms.

        -  Scans (or Imaging tests): We will assess your tumor by brain MRI every 2 cycles ( 6 to 8
           weeks) and then every 3 cycles (9 to 12 weeks). CT or MRI scans of your chest, abdomen,
           and pelvis will be performed every other cycle, at the same time points as the brain
           MRI. Your research doctor may ask you to have a bone scan at the same time points if
           this is clinically indicated.

        -  Photographs: Photographs may be taken of your tumor to assess the response of your tumor
           to the treatment. Care will be taken to ensure these do not reveal your identity.

        -  MUGA or Echo: You will have a MUGA or ECHO done every 12 weeks, so every 3 or 4
           treatment cycles, depending on which cohort you are on.

        -  Blood tests: You will have blood tests done at the beginning of each treatment cycle to
           check your blood cell counts and how well your organs are functioning. In addition to
           regular blood tests, we will be collecting 2-3 tablespoons of blood for research prior
           to your study treatment start.

        -  Neurocognitive Function: If you have previously received treatment for cancer that has
           spread to your brain (prior to enrollment on this study), you will be asked to take a
           battery of tests that assess your cognition (thinking) at the start of the study, after
           2 cycles of treatment, and possibly at the end of the study. With these tests, we are
           trying to better understand how your previous treatments and ongoing treatments affect
           your memory, attention, learning, and other related skills. These tests will be
           administered to you by a trained research assistant and may take 30-45 minutes to
           complete.

        -  For preoperative patients only: If you are a patient who is planning to have an
           operation to remove the cancer in your brain, you will have your surgery between 7-21
           days after starting neratinib. These tests will allow us to measure of how much drug
           (neratinib) reaches the central nervous system and will help us understand how well
           neratinib does this.

        -  At surgery, a part of your tumor cerebrospinal fluid will be collected to test for
           levels of neratinib. For the cerebrospinal fluid collection, this may require a lumbar
           puncture just before your surgery begins (spinal tap) if your neurosurgeon feels he/she
           cannot collect this fluid easily during your surgery. A lumbar puncture is a test often
           used to detect tumor cells in your cerebrospinal fluid. In this case, we will collect
           fluid for testing of cancer cells and will also examine the fluid for neratinib
           concentrations. This will provide information on how much drug (neratinib) reaches the
           central nervous system. There will be a separate consent form for this procedure given
           to you by your neurosurgeon (when applicable). This procedure will be done while you are
           already under general anesthesia for your surgery. If you have a contraindication to
           having this procedure or if you wish to refuse to undergo this procedure, you may do so.

        -  You will also have a blood test on day of surgery to test for levels of neratinib

        -  You will then resume neratinib once you have recovered from your surgery

      After the final dose of the study drug:

      You will have a follow-up visit one month after coming off study treatment. During that
      visit, you will have a physical examination, functional assessment, assessment of any
      toxicities and current medications, and a neurological examination. If you continue to have
      ongoing toxicity related to your study treatment, we will continue to follow you until this
      toxicity resolves. In addition, we will collect about 5-6 tablespoons of blood for research
      and to measure if a marker for your particular breast cancer exists.

      We would like to keep track of your medical condition for up to two years after you stop the
      study treatment. If you are not seen in follow-up at your participating center (where you
      enrolled on the study), we would like to follow you by calling you on the telephone or by
      sending you a letter once a year to see how you are doing. We may also contact your doctor
      once every 6 months to see how you are doing. Keeping in touch with you and checking your
      condition every year helps us look at the long-term effects of the research study. If you do
      not wish to be contacted after you stop the study treatment, you must notify the research
      study staff of your withdrawal of consent for follow-up
    

Trial Arms

NameTypeDescriptionInterventions
Cohort 1Active ComparatorPatients With Progressive Brain Metastases Intervention: HKI-272 (Neratinib)340 mg orally, once daily.
  • HKI-272
Cohort 2Active ComparatorPatients Who Are Candidates For Craniotomy. Intervention: HKI-272 (Neratinib) 240 mg orally, once daily. Surgical resection (biopsy). Neratinib concentrations from craniotomy specimen, CSF, plasma Neratinib.
    Cohort 3a/3bActive ComparatorCohort 3a will be made up of participants with No Prior Lapatinib Treatment. They will receive Neratinib 240mg Orally daily and 750mg/m2 Capecitabine twice per day for 14 days followed by 7 days rest. Cohort 3b will be made of of participants with Prior Lapatinib Treatment. Cohort 3b participants will receive Neratinib 240mg Orally daily and 750mg/m2 Capecitabine twice per day for 14 days followed by 7 days rest.
    • Capecitabine
    Cohort 4a/4b/4cActive ComparatorCohort 4a will be made up of participants with previously untreated brain metastases. They will receive Neratinib 160mg Orally daily and T-DM1 3.6mg/kg IV every 3 weeks. Cohort 4b will be made up of participants with progressive brain metastases. They will receive Neratinib 160mg Orally daily and T-DM1 3.6mg/kg IV every 3 weeks. Cohort 4c will be made up of participants with progressive brain metastases and prior T-DM1. They will receive Neratinib 160mg Orally daily and T-DM1 3.6mg/kg IV every 3 weeks.
    • HKI-272
    • Ado-Trastuzumab Emtansine

    Eligibility Criteria

            Inclusion Criteria:
    
              -  Patients (men or women) must have histologically or cytologically confirmed invasive
                 breast cancer, with metastatic disease. Patients without pathologic or cytologic
                 confirmation of metastatic disease should have unequivocal evidence of metastasis by
                 physical exam or radiologic study.
    
              -  Invasive primary tumor or metastatic tissue confirmation of HER2-positive status
    
              -  Over-expression by immunohistochemistry (IHC) with score of 3+ (in > 30% of invasive
                 tumor cells) AND/OR HER2 gene amplification (> 6 HER2 gene copies per nucleus or a
                 FISH ratio [HER2 gene copies to chromosome 17 signals] of ≥ 2.0)
    
              -  Note: Patients with a negative or equivocal overall result (FISH ratio of < 2.0 or ≤
                 6.0 HER2 gene copies per nucleus) and IHC staining scores of 0, 1+, 2+ are not
                 eligible for enrollment
    
              -  No increase in corticosteroid dose in the week prior to baseline brain MRI
    
              -  Prior trastuzumab and lapatinib therapy are allowed.
    
              -  There is no limit to the number of previous lines of therapy (including chemotherapy,
                 trastuzumab, and endocrine therapies)
    
              -  No prior therapy with neratinib is allowed
    
              -  At least 2 weeks washout period post chemotherapy, any prior protocol therapy,
                 lapatinib, other targeted or biologic therapy, or radiation therapy is required prior
                 to study entry
    
              -  No washout is required for hormonal therapy but concurrent hormonal therapy is not
                 allowed for patients on study
    
            Patients with progressive disease (Cohort 1):
    
              -  For cohort 1, patients must have new or progressive CNS lesions, as assessed by the
                 patient's treating physician.
    
              -  In cohort 1, patients must have measurable CNS disease, defined as at least one
                 parenchymal brain lesion that can be accurately measured in at least one dimension
                 with longest dimension ≥10 mm by local radiology review. Note: measurable non-CNS
                 disease is NOT required for study participation
    
              -  It is anticipated that some patients may have multiple progressive CNS lesions, one or
                 several of which are treated with SRS or surgery with residual untreated lesions
                 remaining. Such patients are eligible for enrollment on this study providing that at
                 least one residual (i.e. non-SRS-treated or non-resected) lesion is measurable (≥10
                 mm).
    
              -  Patients who have had prior cranial surgery are eligible, provided that there is
                 evidence of measurable residual or progressive lesions, and at least 2 weeks have
                 passed since surgery. If a patient has surgical resection followed by WBRT, then there
                 must be evidence of progressive CNS disease after the completion of WBRT.
    
              -  Patients who have had prior WBRT and/or SRS and then whose prior treated lesions have
                 progressed thereafter are also eligible. In this case, lesions which have been treated
                 with SRS may be considered as target lesions if there is unequivocal evidence, in the
                 opinion of the treating physician, of progression.
    
            Patients with with operable disease (Cohort 2):
    
              -  In cohort 2, eligible patients will include those who have CNS disease that is
                 amenable for surgery (typically < 3 brain metastases and with planned resection by
                 neurosurgery). These patients may include those who have received or not received
                 previous treatment(s) for their CNS.
    
              -  It is anticipated that that patients who have intracranial disease amenable to surgery
                 will have measurable CNS disease prior to study entry and to resection. However, this
                 is not an eligibility requirement. Measurable disease is also not required to continue
                 on protocol subsequent to surgical resection.
    
              -  For patients who undergo surgery, postoperative whole brain radiation therapy will not
                 be allowed while patients are on study (concurrent neratinib and radiation therapy has
                 not been studied and toxicity of this is unknown). Patients will require
                 discontinuation of neratinib if radiation therapy will be administered.
    
            Patient Cohort 3:
    
            -In cohort 3, eligible patients must have measurable Central Nervous System disease. Cohort
            3a will have participants with no prior lapatinib therapy. Cohort 3b will have had prior
            lapatinib therapy.
    
            Exclusion Criteria:
    
              -  Not pregnant or breastfeeding
    
              -  Participants who have had chemotherapy or radiotherapy (including investigational
                 agents) within 2 weeks prior to entering the study or those who have not recovered
                 adequately from adverse events due to agents administered more than 4 weeks earlier
                 (excluding alopecia). Washout from trastuzumab is not required.
    
              -  Participants who are currently receiving any other investigational agents
    
              -  History of allergic reactions attributed to compounds of similar chemical or biologic
                 composition to neratinib
    
              -  Concurrent use of enzyme-inducing antiepileptic drugs (EIAEDs), including phenytoin,
                 carbamazepine, oxcarbazepine, fosphenytoin, phenobarbital, pentobarbital, or primidone
    
              -  Patients who are receiving any cancer-directed concurrent therapy, such as concurrent
                 chemotherapy, radiotherapy, or hormonal therapy while on study. Concurrent treatment
                 with bisphosphonates is allowed but should be started before the first dose of
                 neratinib.
    
              -  Uncontrolled intercurrent illness including, but not limited to ongoing or active
                 infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
                 arrhythmia, or psychiatric illness/social situations that would limit compliance with
                 study requirements
    
              -  More than two seizures over the last 4 weeks prior to study entry
    
              -  Patients with known contraindication to MRI, such as cardiac pacemaker, shrapnel, or
                 ocular foreign body
    
              -  Those with leptomeningeal metastases as the only site of CNS disease
    
              -  Significant malabsorption syndrome or inability to tolerate oral medications
    
              -  Any predisposing chronic condition resulting in baseline grade 2 or higher diarrhea
    
            Patient Cohort 4:
    
            - In cohort 4, eligible patients must have measurable Central Nervous System disease.
            Cohort 4a will have participants with previously untreated brain metastases. Cohort 4b will
            have participants with progressive brain metastases. Cohort 4c will have participants will
            have progressive brain metastases and prior T-DM1
    
            Exclusion Criteria:
    
              -  Participants who are currently receiving any other investigational agents.
    
              -  Participants who have had chemotherapy or radiotherapy (including investigational
                 agents) within 2 weeks prior to entering the study or those who have not recovered
                 adequately from adverse events due to agents administered more than 4 weeks earlier
                 (excluding alopecia). Washout from trastuzumab or hormonal therapy is not required.
    
              -  History of severe allergic reactions or intolerability attributed to compounds of
                 similar chemical or biologic composition to neratinib and T-DM1 for Cohorts 4A-4C
                 Concurrent use of enzyme-inducing antiepileptic drugs (EIAEDs), including phenytoin,
                 carbamazepine, oxcarbazepine, fosphenytoin, phenobarbital, pentobarbital, or primidone
    
              -  Patients who are receiving any cancer-directed concurrent therapy, such as concurrent
                 chemotherapy, radiotherapy, or hormonal therapy while on study. Concurrent treatment
                 with bisphosphonates and denosumab is allowed for bony metastases but should be
                 started before the first dose of neratinib.
    
              -  Any prior treatment with T-DM1 for Cohorts 4A-4B.
    
              -  For Cohorts 4A, 4B, and 4C: Patients with myocardial infarction or cardiomyopathy
                 onset within the last 6 months are excluded
    
              -  Uncontrolled intercurrent illness including, but not limited to ongoing or active
                 infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
                 arrhythmia, or psychiatric illness/social situations that would limit compliance with
                 study requirements
    
              -  Active hepatitis B or hepatitis C with abnormal liver function tests
    
              -  Active liver disease from autoimmune disorders or sclerosing cholangitis
    
              -  Lung disease from etiology other than metastatic breast cancer resulting in dyspnea at
                 rest (4A-4C)
    
              -  More than two seizures over the last 4 weeks prior to study entry
    
              -  Patients with known contraindication to MRI, such as cardiac pacemaker, shrapnel, or
                 ocular foreign body. However, Head CT with contrast is allowed in place of MRI at
                 baseline and throughout the study if MRI is contraindicated and a participant's CNS
                 lesions are clearly measurable on the head CT.
    
              -  Those with leptomeningeal metastases as the only site of CNS disease
    
              -  Significant malabsorption syndrome or inability to tolerate oral medications
    
              -  Any predisposing chronic condition resulting in baseline grade 2 or higher diarrhea
    
              -  Inability to comply with study and/or follow-up procedures
    
              -  Individuals with a history of a different active malignancy are ineligible.
    
              -  Pregnant women are excluded from this study because neratinib (and other agents on
                 study) is an agent with the potential for teratogenic or abortifacient effects
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Objective Response Rate
    Time Frame:2 years
    Safety Issue:
    Description:To evaluate the objective response rate in the Central Nervous System by composite response criteria in Cohort 1

    Secondary Outcome Measures

    Measure:Progression-Free Survival
    Time Frame:2 years
    Safety Issue:
    Description:Progression Free Survival
    Measure:Overall Survival
    Time Frame:2 years
    Safety Issue:
    Description:Overall survival
    Measure:CNS response by Macdonald criteria
    Time Frame:2 years
    Safety Issue:
    Description:CNS response by Macdonald criteria
    Measure:First site of disease progression
    Time Frame:2 years
    Safety Issue:
    Description:First site of disease progression
    Measure:Safety and Tolerability
    Time Frame:2 years
    Safety Issue:
    Description:Safety and Tolerability of therapy - number and type and severity of adverse events related to the therapy.
    Measure:Association of CTC count and OS
    Time Frame:2 years
    Safety Issue:
    Description:Explore the association of CTC count and OS
    Measure:Clinical outcomes
    Time Frame:2 years
    Safety Issue:
    Description:Assess clinical outcomes for subjects who opt to receive trastuzumab and neratinib at the time of non-CNS progression (i.e. toxicity, CNS and non-CNS response, site of first progression, OS)

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:Dana-Farber Cancer Institute

    Trial Keywords

    • HER2 Positive
    • BrCa

    Last Updated

    November 26, 2019