Clinical Trial - NCT01494662

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

Recruiting

Sponsor: Dana-Farber Cancer Institute

Collaborators: Translational Breast Cancer Research Consortium, Puma Biotechnology, Inc.

Information provided by (Responsible party): Principal Investigator Dana-Farber Cancer Institute Rachel Freedman, MD, MPH Principle Investigator

ClinicalTrials.gov Identifier: NCT01494662

Protocol Info

Short Description: Phase II of HKI-272 in HER2+ Breast Cancer and Brain Mets
Long Description: A Phase II Trial of HKI-272 (Neratinib) for Patients With Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Breast Cancer and Brain Metastases
MGH Status: Open
Sponsor: NO DATA
Disease Program: Breast

Next Steps


If you are interested in this protocol or in other treatment options at Massachusetts General Hospital, please Request a Consultation.




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.
Condition Title Intervention Phase
Breast Cancer HKI-272 Surgical Resection Capecitabine HKI-272 Ado-Trastuzumab Emtansine Phase 2
Study Type Interventional
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

Primary Outcome Measures

Objective Response Rate [Time Frame: 2 years] [Designated as safety issue: ]


Secondary Outcome Measures

Progression-Free Survival [Time Frame: 2 years] [Designated as safety issue: ]

Overall Survival [Time Frame: 2 years] [Designated as safety issue: ]

CNS response by Macdonald criteria [Time Frame: 2 years] [Designated as safety issue: ]

First site of disease progression [Time Frame: 2 years] [Designated as safety issue: ]

Safety and Tolerability [Time Frame: 2 years] [Designated as safety issue: ]

Association of CTC count and OS [Time Frame: 2 years] [Designated as safety issue: ]

Clinical outcomes [Time Frame: 2 years] [Designated as safety issue: ]

Estimated Enrollment: 168
Study Start Date: February 2012
Estimated Study Completion Date: December 2023
Estimated Primary Completion Date: December 2022
Arms Assigned Interventions

Active Comparator:Cohort 1

Patients With Progressive Brain Metastases Intervention: HKI-272 (Neratinib)340 mg orally, once daily.
Drug:HKI-272
240 mg orally, once daily

Active Comparator:Cohort 2

Patients 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.
Procedure:Surgical Resection
Neratinib concentrations from craniotomy specimen, CSF, plasma Neratinib.

Active Comparator:Cohort 3a/3b

Cohort 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.
Drug:Capecitabine
750 mg/m2 orally, twice daily (1,500 mg/m2 daily) for 14 days followed by 7 days off

Active Comparator:Cohort 4a/4b/4c

Cohort 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.
Drug:Ado-Trastuzumab Emtansine
3.6 mg/kg IV every 3 weeks

Eligibility

Ages Eligible for Study: N/A-N/A

Genders Eligible for Study: All

Accepts Healthly Volunteers: No

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01494662

Locations

  • United States, California
    • University of California, San Francisco Medical Center San Francisco, California, United States, 94115
  • United States, District of Columbia
    • MedStar Georgetown Univeristy Hospital Washington, District of Columbia, United States, 20007
  • United States, Maryland
    • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore, Maryland, United States, 21231
  • United States, Massachusetts
    • Beth Israel Deaconess Medical Center Boston, Massachusetts, United States, 02215
    • Dana-Farber Cancer Institute Boston, Massachusetts, United States, 02215
    • Massachusetts General Hosptial Boston, Massachusetts, United States, 02215
  • United States, Michigan
    • University of Michigan Comprehensive Cancer Center Ann Arbor, Michigan, United States, 48109
  • United States, Minnesota
    • Mayo Clinic Rochester, Minnesota, United States, 55905
  • United States, North Carolina
    • University of North Carolina at Chapel Hill - Lineberger Comprehensive Cancer Center Chapel Hill, North Carolina, United States, 27599
    • Duke University Medical Center Durham, North Carolina, United States, 27710
  • United States, Pennsylvania
    • UPMC Cancer Centers - Magee-Womens Hospital of UPMC Pittsburgh, Pennsylvania, United States, 15213
  • United States, Texas
    • Baylor College of Medicine Lester and Sue Smith Breast Center Houston, Texas, United States, 77030
    • MD Anderson Cancer Center Houston, Texas, United States, 77030

Sponsors and Collaborators

Dana-Farber Cancer Institute

Translational Breast Cancer Research Consortium

Puma Biotechnology, Inc.

More Information

No publications provided

Responsible Party: Principal Investigator Dana-Farber Cancer Institute Rachel Freedman, MD, MPH Principle Investigator
ClinicalTrials.gov Identifier: NCT01494662
Other Study ID Numbers: TBCRC 022
Study First Received:
Last Updated:
Health Authority:

Keywords provided by Dana-Farber Cancer Institute:

HER2 Positive

BrCa

Additional relevant MeSH terms:

Breast Neoplasms

Capecitabine

Trastuzumab

Maytansine

Ado-trastuzumab emtansine

Next Steps


If you are interested in this protocol or in other treatment options at Massachusetts General Hospital, please Request a Consultation.







ClinicalTrials.gov processed this data on August 15, 2019