Neratinib in Metastatic HER2 Non-amplified But HER2 Mutant Breast Cancer

• PFS of patients treated with neratinib [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  The time to progression or death will be listed, and the progression-free survival (PFS) will be estimated using Kaplan-Meier product limit method. For all the enrolled patients, the number and percentage of patients with HER2 mutation will be presented, and its 95% CI will also be calculated. The agreement for the occurrence of HER2 mutation in paired primary and metastatic sites will be described using contingency tables and assess by McNemar test. The association of the presence of HER2 mutation with histology subtype (invasive lobular vs invasive ductal cancer), tumor grade, tumor staging at initial diagnosis (I vs II or III vs IV), and progression-free survival (PFS) will be assessed using Fisher's exact test, Mann-Whitney rank sum test, or log-rank test as appropriate.
• Correlate the presence of HER2 mutation with histology subtype (invasive lobular vs. invasive ductal cancer), tumor grade (grade 1-2 vs 3), tumor staging at initial diagnosis (I vs. II or III vs. IV), disease free survival in HER2- breast cancer. [ Time Frame: Baseline ] [ Designated as safety issue: No ]
  Assessed using RECIST guidelines version 1.1
• Compare the occurrence of HER2 mutation in paired primary and metastatic sites. [ Time Frame: Baseline ] [ Designated as safety issue: No ]

This phase II study will test cancer to see if it has a HER2 mutation and, if so, see how HER2 mutated cancer responds to treatment with neratinib.

Inclusion Criteria for Pre-registration:

• Histologically or cytologically confirmed stage IV breast cancer that is HER2-negative (0 or 1+ by IHC or non-amplified by FISH).
• Administration of at least one line of prior systemic therapy for metastatic breast cancer.
• Presence of measurable or non-measurable disease by RECIST 1.1.
• At least 18 years of age.
• ECOG performance status < or = 2.

• Adequate organ function as defined below within 2 weeks of pre-registration:

  • Serum creatinine < or = 1.5 x ULN
  • Total bilirubin < or = 1.5 x ULN )in case of known Gilbert's syndrome, < 2 x ULN is allowed)
  • AST and ALT < or = 3 x ULN
• Patient (or legally authorized representative if applicable) must be able to understand and willing to sign an IRB approved written informed consent document.

Note: HER2 mutation testing may be performed while the patient is receiving active systemic therapy for metastatic breast cancer so that the result can be used to determine eligibility for study drug therapy in the future.

Exclusion Criteria for Pre-registration:

• Testing for LVEF is not required for pre-registration, but patient must not have a recent LVEF < LLN or have symptoms of congestive heart failure.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Acute or currently active hepatic or biliary disease requiring antiviral therapy (with the exception of Gilbert's syndrome, asymptomatic gallstones, liver metastases, or stable chronic liver disease per investigator assessment).
• History of significant cardiac disease, cardiac risk factors, or uncontrolled arrhythmias.
• Symptomatic intrinsic lung disease or extensive tumor involvement of the lungs resulting in dyspnea at rest.

Inclusion Criteria for Registration

• Tumor tissue tested positive for HER2 mutation.
• ECOG performance status < or = 2.

• Adequate organ function as defined below within 2 weeks of registration:

  • ANC > or = 1.5 x 10^9/L
  • Platelet count > or = 100 x 10^9/L
  • Serum creatinine < or = 1.5 x ULN
  • Total bilirubin < or = 1.5 x ULN (in case of known Gilbert's syndrome, < 2 x ULN is allowed)
  • AST and ALT < or = 3 x ULN
• The patient must have completed radiation therapy and be at least 1 week from the last systemic chemotherapy administration, with adequate recovery of bone marrow and organ functions, before starting neratinib.
• Presence of disease that progressed on the most recent treatment regimen.
• Patients with known brain metastasis are eligible, but must have received radiation and be off steroids and stable (without evidence of disease progression by imaging or exam) for 3 months.
• QTc interval < or = 0.450 seconds within 2 weeks of registration.
• LVEF > or = institutional ILLN within 4 weeks of registration.
• Women of childbearing 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 must inform her treating physician immediately
• Patient (or legally authorized representative if applicable) must be able to understand and willing to sign an IRB approved written informed consent document.

Exclusion Criteria for Registration:

• Currently receiving any other investigational agents or systemic cancer therapy.
• Currently taking medications and herbal or dietary supplements that are strong cytochrome P450 (CYP) 3A4 inducers or inhibitors. The washout period must have been completed prior to the start of neratinib if the patient was taking any of these agents.
• 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.
• Acute or currently active/requiring antiviral therapy hepatic or biliary disease (with the exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases, or stable chronic liver disease per investigator assessment).
• Pregnant and/or breastfeeding.
• History of significant cardiac disease, cardiac risk factors, or uncontrolled arrhythmias.
• Symptomatic intrinsic lung disease or extensive tumor involvement of the lungs resulting in dyspnea at rest.