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

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2016 by Dana-Farber Cancer Institute
Translational Breast Cancer Research Consortium
Information provided by (Responsible Party):
Rachel Freedman, Dana-Farber Cancer Institute Identifier:
First received: December 14, 2011
Last updated: May 23, 2016
Last verified: May 2016

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 Intervention Phase
Breast Cancer
Drug: HKI-272
Procedure: Surgical Resection
Drug: Capecitabine
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Trial of HKI-272 (Neratinib) and Capecitabine for Patients With Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Breast Cancer and Brain Metastases

Resource links provided by NLM:

Further study details as provided by Dana-Farber Cancer Institute:

Primary Outcome Measures:
  • Objective Response Rate [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    To evaluate the objective response rate in the Central Nervous System by composite response criteria in Cohort 1

Secondary Outcome Measures:
  • Progression-Free Survival [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    Progression Free Survival

  • Overall Survival [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    Overall survival

  • CNS response by Macdonald criteria [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    CNS response by Macdonald criteria

  • First site of disease progression [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    First site of disease progression

  • Safety and Tolerability [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
    Safety and Tolerability of therapy - number and type and severity of adverse events related to the therapy.

  • Association of CTC count and OS [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    Explore the association of CTC count and OS

  • Clinical outcomes [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    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)

Estimated Enrollment: 105
Study Start Date: February 2012
Estimated Study Completion Date: September 2017
Estimated Primary Completion Date: December 2016 (Final data collection date for primary outcome measure)
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
Other Name: Neratinib
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.

Drug: HKI-272
240 mg orally, once daily
Other Name: Neratinib
Procedure: Surgical Resection
Neratinib concentrations from craniotomy specimen, CSF, plasma Neratinib.
Other Name: Biopsy
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: HKI-272
240 mg orally, once daily
Other Name: Neratinib
Drug: Capecitabine
Other Name: Xeloda

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Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT01494662

Contact: Rachel Freedman, M.D., M.P.H. 6176322335

United States, California
University of California, San Francisco Medical Center Recruiting
San Francisco, California, United States, 94115
Contact: Amy DeLuca    415-353-7288   
Principal Investigator: Michelle Melisko, MD         
United States, District of Columbia
MedStar Georgetown Univeristy Hospital Recruiting
Washington, District of Columbia, United States, 20007
Contact    866-745-2633      
Principal Investigator: Paula R Pohlmann, MD         
United States, Maryland
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Recruiting
Baltimore, Maryland, United States, 21231
Contact: Clinical Trials Line    410-955-8804      
Principal Investigator: Roisin Connolly, MD         
United States, Massachusetts
Beth Israel Deaconess Medical Center Active, not recruiting
Boston, Massachusetts, United States, 02215
Dana-Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Elizabeth Lawler, B.S.    617-632-5928   
Principal Investigator: Rachel Freedman, MD, MPH         
Massachusetts General Hosptial Recruiting
Boston, Massachusetts, United States, 02215
Contact: Meghan Miles    617-726-1070   
Principal Investigator: Beverly Moy, MD         
United States, Michigan
University of Michigan Comprehensive Cancer Center Recruiting
Ann Arbor, Michigan, United States, 48109
Contact    800-865-1125      
Principal Investigator: Cathy VanPoznak, MD         
United States, North Carolina
University of North Carolina at Chapel Hill - Lineberger Comprehensive Cancer Center Recruiting
Chapel Hill, North Carolina, United States, 27599
Contact: Pete McIlwaine    919-609-0915   
Principal Investigator: Carey Anders, MD         
Duke University Medical Center Recruiting
Durham, North Carolina, United States, 27710
Contact: Kimberly Riley    919-660-1278   
Principal Investigator: Kimberly Blackwell, MD         
United States, Pennsylvania
UPMC Cancer Centers - Magee-Womens Hospital of UPMC Recruiting
Pittsburgh, Pennsylvania, United States, 15213
Contact: Brenda Lee Steele, RN    412-641-2261   
Principal Investigator: Shannon Puhalla, MD         
United States, Texas
Baylor College of Medicine Lester and Sue Smith Breast Center Recruiting
Houston, Texas, United States, 77030
Contact: Anne C Pavlick    713-798-7814   
Principal Investigator: Polly Niravath, MD         
MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Aurora G Madrigal    713-745-3888   
Principal Investigator: Nuhad Ibrahim, MD         
Sponsors and Collaborators
Dana-Farber Cancer Institute
Translational Breast Cancer Research Consortium
Principal Investigator: Rachel Freedman, M.D., M.P.H. Dana-Farber Cancer Institute
  More Information

Responsible Party: Rachel Freedman, Principle Investigator, Dana-Farber Cancer Institute Identifier: NCT01494662     History of Changes
Other Study ID Numbers: 11-344  TBCRC 022 
Study First Received: December 14, 2011
Last Updated: May 23, 2016
Health Authority: United States: Food and Drug Administration

Keywords provided by Dana-Farber Cancer Institute:
HER2 Positive

Additional relevant MeSH terms:
Breast Neoplasms
Breast Diseases
Neoplasms by Site
Skin Diseases
Antimetabolites, Antineoplastic
Antineoplastic Agents
Molecular Mechanisms of Pharmacological Action processed this record on May 26, 2016