Neratinib in Treating Older Patients With Metastatic HER2-Positive Breast Cancer

PRIMARY OBJECTIVES:

I. To estimate the safety and tolerability of neratinib in adults age 60 or older with
locally advanced or metastatic HER2 over-expressing breast cancer.

SECONDARY OBJECTIVES:

I. To describe the full toxicity profile including all grade toxicities measured by National
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.0.

II. To estimate the rate of all grades of gastrointestinal (GI) toxicities such as diarrhea,
nausea, and vomiting.

III. To estimate the rate of dose reduction, delays and discontinuation related to study
drug.

IV. To describe pharmacokinetic parameters of neratinib in adults 60 and older. V. To
estimate overall response rate (ORR) and clinical benefit rate (CBR) defined by Response
Evaluation Criteria in Solid Tumors (RECIST) 1.1.

VI. To estimate event free survival (EFS), progression-free survival (PFS) and overall
survival (OS).

VII. To evaluate the role of cancer-specific geriatric assessment tool in predicting
treatment toxicities.

VIII. To estimate adherence rate to neratinib in older adults (percentage of doses of
neratinib taken).

IX. To explore the association of pharmacokinetic (PK) parameters and geriatric assessment
findings.

X. To explore if serum biomarkers of aging (interleukin [IL]-6, C-reactive protein [CRP], and
D-dimer) are associated with treatment toxicities.

OUTLINE:

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

After completion of study treatment, patients are followed up for 30 days and then
periodically thereafter.

Inclusion Criteria:

- Eastern Cooperative Oncology Group (ECOG) performance 0-2

- Life expectancy of greater than 12 weeks

- Histologically or cytologically proven metastatic breast cancer (metastases can be
proven with imaging results in certain circumstances provided that the initial tumor
was demonstrated histologically)

- Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2
targeted therapies

- HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of
American Pathologists (CAP) guidelines

- If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization
(FISH), but activating somatic mutations of HER2 gene identified through genomic
sequencing including but not limited to the following (Clinical Laboratory Improvement
Act [CLIA] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y,
S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V,
G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions
(A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC, G776 insertions,
G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) and/or HER3 activating
mutations; there is no limitation on the number of prior lines of systemic therapy or
HER2-targeted therapies (prior neratinib not allowed)

- Both measurable as well as non-measurable disease will be allowed

- Hemoglobin >= 9 g/dL (after transfusion, if necessary) within 4 weeks of
pre-registration

- Total bilirubin within normal institutional limits within 4 weeks of pre-registration

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration

- Creatinine clearance >= 30 mL/min as calculated by Cockcroft-Gault formula within 4
weeks of pre-registration

- Baseline left ventricular ejection fraction LVEF >= 50% as evaluated by echocardiogram
(ECHO) or multiple-gated acquisition scan (MUGA)

- All grade >= 2 toxicities other than alopecia from prior therapy have resolved by the
time of study commencement

- Patient must have completed radiation therapy with adequate recovery of bone marrow
and organ functions, before starting neratinib

- Patient with stable or treated brain metastases are eligible; asymptomatic patients
with metastatic brain disease who have been on a stable dose of corticosteroids for
treatment of brain metastases for at least 14 days are eligible to participate in the
study

- Provide written, informed consent to participate in the study and follow the study
procedures

Exclusion Criteria:

- Prior treatment with neratinib

- Concurrent usage of other investigational agents, chemotherapy, or hormone therapy;
prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are
allowed but all toxicities grade >= 2 must have resolved by the time of study
commencement (except alopecia)

- Any major surgery =< 28 days prior to the initiation of investigational products

- Received chemotherapy or biologic therapy =< 3 weeks prior to the start of neratinib

- Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart
failure (New York Heart Association functional classification of >= 2, including
individuals who currently use digitalis specifically for congestive heart failure),
unstable angina, myocardial infarction within 12 month of enrollment or ventricular
arrhythmia

- Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval >= 450
milliseconds in men and >= 470 milliseconds in women within 2 weeks of registration or
known history of QTc prolongation or Torsades de Pointes

- Inability to take oral medication

- Other malignancy within the past 3 years with the exception of: a) adequately treated
basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva
carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to
impact survival during the duration of the study, such as localized transitional cell
carcinoma of the bladder, or benign tumors of the adrenal or pancreas

- Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g.,
Crohn's disease, malabsorption, or grade >= 2 NCI CTCAE v.4.0 diarrhea of any etiology
at baseline)

- Known clinically active infection with hepatitis B or hepatitis C virus

- Evidence of significant medical illness, abnormal laboratory finding or psychiatric
illness/social situations that would, in the Investigator's judgment, makes the
patient inappropriate for this study