Lapatinib in Stage IV Melanoma With ERBB4 Mutations

* INCLUSION CRITERIA:
* Patients must have histologically confirmed stage IV cutaneous melanoma.
* Patients must have measurable disease defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded). Each lesion must be greater than 10 mm when measured by computed tomography (CT), magnetic resonance imaging (MRI) or caliper measurement by clinical exam; or greater than 20 mm when measured by chest x-ray. Lymph nodes must be greater than 15 mm in short axis when measured by CT or MRI.
* Patients must have no more than two oncogenic somatic ERBB4 mutations detected in one of the 28 exons of the ERBB4 gene analyzed from the tumor and which is not present in the matched normal deoxyribonucleic acid (DNA) as confirmed by sequence analysis of tumor genomic DNA derived from any biopsy specimen obtained at the participating clinical sites. Sequence analysis will be performed at the National Institutes of Health (NIH) Clinical Molecular Profiling Core, a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory.

Note: Patients with 3 or more mutations in their ERBB4 gene may have an increased resistance to lapatinib and are not eligible for lapatinib treatment

* Patients must not have had chemotherapy, molecular therapy with B-RAF, mouse embryonic fibroblast (MEK), or c-kit inhibitors, hormonal therapy, radiation therapy, or biological therapy for at least 4 weeks prior to starting study medication. Patients who received mitomycin C, nitrosoureas, anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4), or carboplatin must be 6 weeks from the last administration of therapy. Patients must have recovered from any acute toxicity related to prior therapy or surgery, to a grade 1 or less unless specified.
* Patients with no more than 3 intracranial metastases, which have been definitively treated by surgery or radiation therapy may be eligible for study provided there is no evidence of active disease for at least 2 months and no requirement for anticonvulsant therapy or steroids following treatment.
* Age greater than or equal to 18 years.

Note: Because no dosing or adverse event data are currently available on the use of lapatinib in patients less than 18 years of age, children are excluded from this study but will be eligible for future pediatric single-agent trials, if applicable.

* Life expectancy of greater than 3 months.
* Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1 (Karnofsky greater than or equal to 70%).
* Patients must have normal organ and marrow function as defined below:

  * absolute neutrophil count greater than or equal to 1,500/mcL
  * platelets greater than or equal to 100,000/mcL
  * total bilirubin within normal institutional limits
  * Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase (SGOT))/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase (SGPT)) less than or equal to 3 times institutional upper limit of normal
  * creatinine less than or equal to institutional upper limit of normal

OR

--creatinine clearance greater than or equal to 60 mL/min/1.73 m\^2 for patients with creatinine levels above institutional normal.

* Patients must be willing to return to the Clinic for follow-up visits.
* Women of childbearing potential must have a negative beta-human chorionic gonadotropin (HCG) (serum or urine) within 14 days prior to study treatment and must be willing to practice effective birth control to prevent pregnancy while receiving treatment and for four months after treatment is discontinued. All males of child fathering potential must also be willing to practice effective birth control.

Note: Lapatinib is a tyrosine kinase inhibitor with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with lapatinib, breastfeeding should be discontinued if the mother is treated with lapatinib. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, the patient should inform the treating physician immediately.

* Ability to understand and the willingness to sign the Informed Consent Document.
* Patients who agree to participate in the pharmacokinetics (PK) portion of the study must be able to swallow lapatinib tablets for the duration of the PK studies.

EXCLUSION CRITERIA:

* Patients may not be currently receiving any other investigational agents.
* Patients may not have received prior treatment with tyrosine kinase inhibitors (e.g., lapatinib erlotinib, or gefitinib).
* Patients currently receiving any medication known to induce/inhibit cytochrome P450 3A4 (CYP3A4) as listed in Appendix D, which in the opinion of the principal investigator, would make the administration of study drug hazardous. Note: patients receiving any strong or moderate CYP3A4 inhibitors will be excluded.
* Patients with active hepatic or biliary disease (with exception of patients with Gilberts syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment)
* Patients with 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.
* Human immunodeficiency virus (HIV)-positive patients on antiretroviral therapy are excluded because most antiretrovirals are strong or moderate CYP3A4 inhibitors.
* Any underlying medical condition which, in the opinion of the principal investigator, will make the administration of study drug hazardous or obscure the interpretation of adverse events
* Patients with any other concurrent malignancy, except for the following:

  * adequately treated basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix, or any other cancer from which the patient has been disease-free for five (5) years or more.

INCLUSION OF WOMEN AND MINORITIES:

Both men and women and members of all races and ethnic groups are eligible for this trial.