Pembrolizumab and Ibrutinib in Treating Patients With Stage III-IV Melanoma That Cannot Be Removed by Surgery

Any of the following:

* Pregnant women

* Nursing women

* Men or women of childbearing potential who are unwilling to employ adequate contraception within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study medication; adequate contraception is defined as 2 methods of birth control (e.g., hormonal contraceptives, intrauterine device, diaphragm with spermicide, cervical cap with spermicide, male condoms, or female condom with spermicide) or prior surgical sterilization, or abstinence from heterosexual activity

Prior treatment with ibrutinib or prior exposure to BTK inhibitors

Uveal melanoma

Current use of warfarin or other vitamin K antagonists

Require continuous treatment with a strong CYP3A inhibitor

Currently participating or has participated in a study of an investigational cancer therapy agent or using an investigational device within 28 days prior to study registration

Live vaccines within 28 days prior to study pre-registration

Invasive surgical procedure within 28 days prior to study pre-registration

History of clinically severe (e.g., requires chronic immunosuppressive therapy, \[e.g., cyclosporine A, tacrolimus\]) autoimmune disease (e.g., ulcerative colitis, lupus), or history of organ transplant

Known history of human immunodeficiency virus (HIV) infection, active infection with hepatitis B virus or hepatitis C virus, or any uncontrolled active systemic infection

Gastrointestinal disease that might inhibit ibrutinib absorption (e.g., malabsorption syndrome, resection of the stomach or a large portion of small bowel, or partial/complete bowel obstruction), or unable to swallow capsules

Active central nervous system metastases and/or carcinomatous meningitis

* Note: Patients with untreated brain metastasis will be excluded; patients with previously treated brain metastases may participate provided they meet the following criteria:

* Inactive (without evidence of progression which is documented by CT or MRI within 90 days prior to registration), AND

* On =\< 10 mg/day prednisone or equivalent for at least 28 days prior pre-registration

Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens

Clinically significant cardiovascular disease such as unstable angina, myocardial infarction, or acute coronary syndrome within =\< 180 days prior to registration, symptomatic or uncontrolled arrhythmia, congestive heart failure, or any class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification

Other active malignancy =\< 3 years prior to pre-registration; note: if there is a history of prior malignancy, the patient must not be receiving other specific treatment for cancer

* EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix

Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome =\< 6 months prior to pre-randomization

Known bleeding disorders (von Willebrand's disease or hemophilia)

History of ischemic stroke or intracranial hemorrhage =\< 180 days prior to pre-registration

Currently active, clinically significant hepatic impairment Child-Pugh class A, B or C according to the Child Pugh classification

REGISTRATION- EXCLUSION

Failure to confirm histologically or cytologically unresectable stage III or metastatic melanoma (stage IV) not amenable to local therapy

Prior chemotherapy, immunotherapy, radioactive, or biological cancer therapy (including monoclonal antibody \[mAb\]) =\< 28 days prior to registration

Received a strong cytochrome P450 (CYP) 3A inhibitor =\< 7 days prior to registration

Concurrent systemic immunosuppressant therapy =\< 21 days prior to registration

Recent infection requiring systemic antibiotic treatment that was completed =\< 14 prior to registration

What this study is about