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Neratinib, Capecitabine, and Trastuzumab Emtansine in Treating Patients with HER2-Positive Breast Cancer That Has Spread to the Brain

Trial Status: Active

This phase II trial studies how well neratinib, capecitabine, and trastuzumab emtansine work in treating patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer that has spread to the brain. Neratinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Trastuzumab emtansine (T-DM1) is a monoclonal antibody, called trastuzumab, linked to a chemotherapy drug called DM1. Trastuzumab attaches to HER2 positive cancer cells in a targeted way and delivers DM1 to kill them. Giving neratinib, capecitabine, and trastuzumab emtansine together may be an effective treatment for breast cancer.

Inclusion Criteria

  • Patients 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, defined as presence of one or more of the following criteria: * Over-expression by immunohistochemistry (IHC) with score of 3+ (in > 30% of invasive tumor cells) AND/OR HER2 gene amplification (average of > 6 HER2 gene copies per nucleus or a FISH ratio [HER2 gene copies to chromosome 17 signals] of >= 2.0), according to guidelines and in keeping with past eligibility for ratio of >= 2.0 rather than the ratio of > 2.2 required by new guidelines * 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 imaging
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-2
  • Absolute neutrophil count >= 1,000/uL
  • Platelets >= 100,000/uL
  • Total bilirubin =< 1.5 x upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN without liver metastases, or =< 5 x institutional ULN with liver metastases
  • Creatinine =< 2.0 mg/dL or creatinine clearance >= 50 mL/min
  • Left ventricular ejection fraction >= 50%, as determined by radionuclide ventriculograms (RVG) (multi-gated acquisition scan [MUGA]) or echocardiogram within 60 days prior to initiation of protocol therapy
  • Prior therapy: * Prior trastuzumab is allowed for all cohorts * Prior capecitabine is NOT allowed for participants enrolled to Cohorts 3A/3B ONLY * Prior lapatinib is allowed for Cohorts 1, 2, and 3B but NOT Cohort 3A * Prior T-DM1 is NOT allowed for Cohorts 4A and 4B, but is required for Cohort 4C; dose reductions on prior T-DM1 for Cohort 4C do not preclude enrollment on Cohort 4C; patients on 4C may have progressed on prior T-DM1 in the CNS or non-CNS sites and had to have tolerated therapy without significant toxicity that would preclude retreatment * No prior therapy with neratinib is allowed on any cohort * There is no limit to the number of previous lines of therapy (including chemotherapy, trastuzumab, and endocrine therapies); at least 2 weeks washout period post chemotherapy, any prior protocol therapy, lapatinib, other targeted or biologic or immunotherapy, 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; the only exception to this is longstanding ovarian suppression in pre-menopausal patients, if this has been started >= 6 months prior to study enrollment; other hormonal therapies are not allowed while patients are on study
  • Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
  • Human immunodeficiency virus (HIV)-positive individuals on combination antiretroviral therapy are eligible for enrollment and will be monitored closely for potential pharmacokinetic interactions with neratinib
  • Concomitant medications should be avoided (when possible) while on study
  • Ability to understand and willingness to sign a written informed consent document
  • For Cohorts 1, 3A/3B, 4B and 4C patients must have new or progressive measurable CNS lesions, as assessed by the patient's treating physician; this includes patients who have progressed after at least one line of standard local treatment for CNS disease (whole brain radiotherapy [WBRT], stereotactic radiosurgery [SRS], or surgical resection as below)
  • 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
  • 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); the location of the measurable lesion should be documented in the patient chart and case report form
  • 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
  • Except for those in Cohort 4A where prior local CNS therapy is not allowed, patients who have had prior WBRT and/or SRS and then whose prior treated lesions have progressed thereafter are also eligible for all other cohorts; 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
  • It is anticipated 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; patients will require discontinuation of neratinib if WBRT will be administered; however, if the treating provider feels that targeted radiosurgery (SRS, gamma knife, etc) would be of benefit postoperatively, patients may proceed with this and then begin neratinib AFTER radiation completes
  • Further eligibility details for patients on Cohort 4A: All patients on Cohort 4A will not have received prior radiation or surgery to their brain; prior systemic therapy aimed to treat disease in the brain is allowed (i.e. prior systemic standard therapy or protocol systemic therapy for brain metastases [mets])
  • Note: laboratory tests required for eligibility must be completed within 4 weeks prior to study entry; baseline measurements in the CNS must be documented from tests up to 21 days prior to planned start of protocol therapy unless not covered by insurance; if insurance coverage is an issue, a case by case approval of testing beyond this window may be approved by the overall study principal investigator (PI); other non-laboratory tests must be performed as indicated
  • Participants must have met all criteria to be enrolled on the main protocol for receipt of neratinib; at the time of enrollment on the extension phase for Cohorts 1 and 3, patients must have experienced progression of non-CNS disease by RECIST 1.1 criteria
  • Cohorts 1 and 3: Participants must have stable disease or be responders (partial response [PR] or complete response [CR]) to neratinib in the CNS at the time of non-CNS progression
  • Cohort 2: Participants must have progressive disease in CNS or non-CNS sites
  • ECOG performance status 0-2 (all cohorts)
  • Absolute neutrophil count > 1,000/uL
  • Platelets > 100,000/uL
  • Total bilirubin =< 1.5 x ULN
  • AST (SGOT)/ALT (SGPT) < 3.0 x institutional upper limit of normal OR =< 5 x institutional upper limit of normal with liver metastases
  • Creatinine =< 2 mg/dL or creatinine clearance >= 50 mL/min
  • The effects of trastuzumab, capecitabine, and neratinib on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
  • Left ventricular ejection fraction >= 50%, as determined by RVG (MUGA) or echocardiogram within 60 days prior to initiation of extension phase therapy (all cohorts)
  • Ability to understand and the willingness to sign a written informed consent document (all cohorts)

Exclusion Criteria

  • 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
  • Participants who are currently receiving any other investigational agents
  • History of severe allergic reactions or intolerability attributed to compounds of similar chemical or biologic composition to neratinib (all cohorts), capecitabine for Cohorts 3A/3B, 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 capecitabine for patients enrolled to Cohorts 3A/3B, prior lapatinib for participants on Cohort 3A, and T-DM1 for Cohorts 4A-4B
  • 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
  • For Cohorts 4A, 4B, and 4C: Patients with myocardial infarction or cardiomyopathy onset within the last 6 months are excluded
  • Active hepatitis B or hepatitis C with abnormal liver function tests (Cohorts 4A-4C); positive hepatitis B (hepatitis B surface antigen and antibody) and/or hepatitis C (hepatitis C antibody test) as indicated by serologies conducted =< 3 months prior to registration if liver function tests are outside of the normal institutional range * Note: Patients with positive hepatitis B or C serologies without known active disease are eligible if they meet all laboratory requirements; patients with laboratory evidence of vaccination to hepatitis B (e.g., positive antibodies) are also eligible
  • 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 magnetic resonance imaging (MRI), such as cardiac pacemaker, shrapnel, or ocular foreign body; however, head computed tomography (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
  • Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with neratinib; negative urine pregnancy test is required for women of childbearing potential within 4 weeks of planned treatment start
  • Individuals with a history of a different active malignancy are ineligible
  • Exclusion criteria will include all criteria listed for the main protocol
  • History of allergic reactions attributed to trastuzumab (Cohorts 1, 3) that were not treatable/preventable with pre-medications or desensitization protocols


San Francisco
UCSF Medical Center-Mount Zion
Status: ACTIVE
Contact: Michelle Elizabeth Melisko
Phone: 877-827-3222

District of Columbia

MedStar Georgetown University Hospital
Status: ACTIVE
Contact: Paula R Pohlmann
Phone: 202-444-0381


Johns Hopkins University / Sidney Kimmel Cancer Center
Status: ACTIVE
Contact: Roisin M Connolly
Phone: 410-955-8804


Beth Israel Deaconess Medical Center
Contact: Nadine Muskatel Tung
Brigham and Women's Faulkner Hospital
Contact: Rachel A. Freedman
Phone: 617-632-6973
Brigham and Women's Hospital
Status: ACTIVE
Contact: Alarice Cheng-Yi Lowe
Phone: 617-525-8696
Dana-Farber Cancer Institute
Status: ACTIVE
Contact: Rachel A. Freedman
Phone: 617-632-6973
Massachusetts General Hospital Cancer Center
Status: ACTIVE
Contact: Beverly Moy
Phone: 617-726-4920


Ann Arbor
University of Michigan Comprehensive Cancer Center
Status: ACTIVE
Contact: Catherine Hall Van Poznak
Phone: 734-936-9209


Mayo Clinic in Rochester
Status: ACTIVE
Contact: Ciara C. O'Sullivan

North Carolina

Chapel Hill
UNC Lineberger Comprehensive Cancer Center
Status: ACTIVE
Contact: Trevor Augustus Jolly
Duke University Medical Center
Contact: Paul Kelly Marcom
Phone: 919-684-3877


UPMC Pinnacle Cancer Center / Community Osteopathic Campus
Status: ACTIVE
Contact: Adam Matthew Brufsky
UPMC Pinnacle West Shore
Status: ACTIVE
Contact: Adam Matthew Brufsky
UPMC-Magee Womens Hospital
Status: ACTIVE
Contact: Adam Matthew Brufsky
University of Pittsburgh Cancer Institute (UPCI)
Status: ACTIVE
Contact: Adam Matthew Brufsky
Phone: 412-641-6500


Baylor College of Medicine / Dan L Duncan Comprehensive Cancer Center
Status: ACTIVE
Contact: Julie Rani Nangia
Phone: 713-798-1999
M D Anderson Cancer Center
Contact: Jeffrey Wefel
Phone: 713-563-0514


I. To evaluate the objective response rate (ORR) in the central nervous system (CNS) by composite response criteria in Cohort 1, Cohort 3A, and Cohort 3B.

II. To evaluate the ORR in the CNS by more modern criteria, namely the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria, separately in Cohorts 4A, 4B, and 4C.


I. ORR in non-CNS sites (by Response Evaluation Criteria in Solid Tumors [RECIST 1.1] criteria). (All Cohorts)

II. Progression-free survival (PFS) and overall survival (OS). (All Cohorts)

III. CNS response by Macdonald criteria. (Cohort 1 only)

IV. CNS response by volumetric/composite criteria. (Secondary endpoint for Cohorts 4A-4C only as this is primary objective for Cohorts 1, 3A-3B)

V. First site of disease progression. (All Cohorts)

VI. Safety and tolerability of therapy. (All Cohorts)

VII. Time to CNS radiation. (Cohort 4A only)

VIII. Association of circulating tumor cell (CTC) count and OS. (Cohort 1 only)

IX. Assess clinical outcomes for patients 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). (Cohort 1 only)


I. PFS and OS in patients who undergo craniotomy. (Cohort 2)

II. PFS from the time of addition of capecitabine for Cohort 2 patients.

III. ORR in the CNS for lapatinib-naive patients versus (vs.) lapatinib-treated patients. (All Cohorts)

IV. Explore the association of MET (hepatocyte growth factor receptor) and HER2 co-amplification (in CTCs) with treatment response. (Cohorts 1, 3A/3B)

V. Explore the relationship between the HER2 status of a patient’s primary breast cancer, metastatic lesions, and CTCs using fluorescence in situ hybridization (FISH) for HER2 gene amplification. (Cohorts 1, 3A/3B)

VI. Explore the possible mechanisms of resistance driven by Epidermal Growth Factor Receptor (EGFR) using FISH for EGFR gene amplification in HER2-positive CTCs. (Cohorts 1, 3A/3B)

VII. Assess neratinib concentrations and concentrations of its metabolites in CNS tumor, cerebrospinal fluid (CSF), and plasma at craniotomy in patients who receive neratinib prior to surgery. (Cohort 2)

VIII. Examine neurocognitive function for patients with varying previous therapies for CNS disease. (Cohort 1)

IX. Explore primary archival samples and metastatic samples when able to evaluate for predictors of response and outcome. (Cohorts 3A/3B)

X. Perform molecular characterization of potential resistance mechanisms, predictive biomarkers, and immunological function by collecting blood and tumor specimens. (Cohort 3A/3B, 4A/4B/4C)

XI. Examine changes in the mutational profiles of one’s disease using circulating tumor (ct) deoxyribonucleic acid (DNA) (all Cohort 4 patients) in blood and in CSF (for any Cohort 4 patient undergoing lumbar puncture).

XII. Evaluate patient-reported gastrointestinal (GI) toxicity and its impact on quality of life for patients receiving neratinib and trastuzumab emtansine (T-DM1). (Cohort 4 patients only, cycles 1-3)

XIII. Compare patient-reported and clinician-reported gastrointestinal adverse events during the first 3 cycles of T-DM1 and neratinib therapy. (Cohort 4 patients)

XIV. Evaluate self-reported adherence using the Voils measure to anti-diarrheal prophylaxis during cycle 1 and anti-diarrheal medication diaries during T-DM1 and neratinib therapy. (All Cohort 4 patients)

XV. Compare (exploratory endpoint) symptom reporting for Patient-Reported Outcomes Measurement Information System (PROMIS) and Systemic Therapy Induced Diarrhea Assessment Tool (STIDAT) measures for diarrhea. (Cohorts 4A-4C)


COHORT I: Patients receive neratinib orally (PO) once daily (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

COHORT II: Patients receive neratinib PO QD for 7-21 days and then undergo craniotomy. Patients resume neratinib within 10 days post-operatively.

COHORTS IIIA/IIIB: Patients receive neratinib PO QD on days 1-21 and capecitabine PO twice daily (BID) on days 1-14. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

COHORTS IVA-IVC: Patients receive neratinib PO QD on days 1-21 and trastuzumab emtansine intravenously (IV) over 30-90 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

EXTENSION PHASE: Patients achieving CNS response or disease stability yet develop disease progression outside of the CNS receive trastuzumab intravenously (IV) over 30-90 minutes every 7 or 21 days. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up approximately every 6 months for up to 2 years.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
Rachel A. Freedman

  • Primary ID 11-344
  • Secondary IDs NCI-2012-00255, TBCRC 022
  • ID NCT01494662