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

Inclusion Criteria:

• Patients (men or women) must have histologically or cytologically confirmed invasivebreast cancer, with metastatic disease. Patients without pathologic or cytologicconfirmation of metastatic disease should have unequivocal evidence of metastasis byphysical 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 invasivetumor cells) AND/OR HER2 gene amplification (> 6 HER2 gene copies per nucleus or aFISH 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 noteligible 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 (includingchemotherapy, 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 requiredprior to study entry

• No washout is required for hormonal therapy but concurrent hormonal therapy is notallowed for patients on study

Patients with progressive disease (Cohort 1):

• For cohort 1, patients must have new or progressive CNS lesions, as assessed by thepatient's treating physician.

• In cohort 1, patients must have measurable CNS disease, defined as at least oneparenchymal brain lesion that can be accurately measured in at least one dimensionwith longest dimension ≥10 mm by local radiology review. Note: measurable non-CNSdisease is NOT required for study participation

• It is anticipated that some patients may have multiple progressive CNS lesions, oneor several of which are treated with SRS or surgery with residual untreated lesionsremaining. Such patients are eligible for enrollment on this study providing that atleast one residual (i.e. non-SRS-treated or non-resected) lesion is measurable (≥10mm).

• Patients who have had prior cranial surgery are eligible, provided that there isevidence of measurable residual or progressive lesions, and at least 2 weeks havepassed since surgery. If a patient has surgical resection followed by WBRT, thenthere 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 lesionshave progressed thereafter are also eligible. In this case, lesions which have beentreated with SRS may be considered as target lesions if there is unequivocalevidence, 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 isamenable for surgery (typically < 3 brain metastases and with planned resection byneurosurgery). These patients may include those who have received or not receivedprevious treatment(s) for their CNS.

• It is anticipated that that patients who have intracranial disease amenable tosurgery will have measurable CNS disease prior to study entry and to resection.However, this is not an eligibility requirement. Measurable disease is also notrequired to continue on protocol subsequent to surgical resection.

• For patients who undergo surgery, postoperative whole brain radiation therapy willnot be allowed while patients are on study (concurrent neratinib and radiationtherapy has not been studied and toxicity of this is unknown). Patients will requirediscontinuation 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 investigationalagents) within 2 weeks prior to entering the study or those who have not recoveredadequately 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 orbiologic composition to neratinib

• Concurrent use of enzyme-inducing antiepileptic drugs (EIAEDs), including phenytoin,carbamazepine, oxcarbazepine, fosphenytoin, phenobarbital, pentobarbital, orprimidone

• Patients who are receiving any cancer-directed concurrent therapy, such asconcurrent chemotherapy, radiotherapy, or hormonal therapy while on study.Concurrent treatment with bisphosphonates is allowed but should be started beforethe first dose of neratinib.

• Uncontrolled intercurrent illness including, but not limited to ongoing or activeinfection, symptomatic congestive heart failure, unstable angina pectoris, cardiacarrhythmia, or psychiatric illness/social situations that would limit compliancewith 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, orocular 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 investigationalagents) within 2 weeks prior to entering the study or those who have not recoveredadequately 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 ofsimilar chemical or biologic composition to neratinib and T-DM1 for Cohorts 4A-4CConcurrent use of enzyme-inducing antiepileptic drugs (EIAEDs), including phenytoin,carbamazepine, oxcarbazepine, fosphenytoin, phenobarbital, pentobarbital, orprimidone

• Patients who are receiving any cancer-directed concurrent therapy, such asconcurrent chemotherapy, radiotherapy, or hormonal therapy while on study.Concurrent treatment with bisphosphonates and denosumab is allowed for bonymetastases 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 cardiomyopathyonset within the last 6 months are excluded

• Uncontrolled intercurrent illness including, but not limited to ongoing or activeinfection, symptomatic congestive heart failure, unstable angina pectoris, cardiacarrhythmia, or psychiatric illness/social situations that would limit compliancewith 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 dyspneaat 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, orocular foreign body. However, Head CT with contrast is allowed in place of MRI atbaseline and throughout the study if MRI is contraindicated and a participant's CNSlesions 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 onstudy) is an agent with the potential for teratogenic or abortifacient effects