This phase II trial studies how well ibrutinib works in treating patients with stage IV melanoma of the skin that has not responded to previous treatment. Ibrutinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES:

I. Estimate rate of objective response (OR: complete response [CR] + partial response [PR]) to ibrutinib administered as single agent in patients with immune checkpoint inhibitor-refractory, or immune checkpoint inhibitor ineligible and mitogen-activated protein kinase (MAPK) inhibitor-refractory (if B-Raf proto-oncogene, serine/threonine kinase [BRAF]V600-mutant) or MAPK inhibitor-intolerant distant metastatic cutaneous melanoma.

SECONDARY OBJECTIVES:

I. Estimate progression-free survival (PFS) rate at 6 months after initiation of ibrutinib in patients with immune checkpoint inhibitor-refractory or immune checkpoint ineligible and MAPK inhibitor-refractory (if BRAFV600-mutant) or MAPK inhibitor-intolerant distant metastatic cutaneous melanoma.

II. Estimate overall survival (OS) after initiation of ibrutinib in patients with immune checkpoint inhibitor-refractory or immune checkpoint ineligible and MAPK inhibitor-refractory (if BRAFV600-mutant) or MAPK inhibitor-intolerant distant metastatic cutaneous melanoma.

III. Explore the association of ITK protein expression with OR and PFS.

TERTIARY OBJECTIVES:

I. Explore association between other putative targets of ibrutinib (e.g. Tec, ErbB4, Hck, Yes, BTK) in melanoma cells, as assessed by 2-color immunofluorescence (IF) in representative tissue sections obtained from pretreatment archived formalin-fixed paraffin-embedded (FFPE) tumor blocks or FFPE blocks obtained from fresh tissue biopsy from enrolled patients, with overall response (OR) and PFS.

II. Explore ibrutinib-mediated effect(s) on immune cell subsets associated with immunomodulation by performing multiparameter flow cytometric analysis in peripheral blood mononuclear cell (PBMC) obtained prior to treatment, on day 29 (i.e., predose day 1 of cycle 2) following initiation of treatment with ibrutinib, and at the time of disease progression (3 time points).

III. Determine pharmacokinetics (PK) of ibrutinib following daily dosing at 840 mg on day 8 of cycle 1 (Css).

OUTLINE:

Patients receive ibrutinib 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 every 3 months for up to 2 years.

Inclusion Criteria:

• Histologically confirmed melanoma of cutaneous primary; metastatic melanoma from unknown primary are allowed

• Measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 10 mm (>= 1 cm) with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam

• Stage IV disease

• If BRAFV600-mutant, documented refractory disease to at least one BRAF inhibitor (dabrafenib or vemurafenib) and/or a MEK inhibitor (trametinib or cobimetinib), defined as progression of measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) criteria while on treatment; subjects with MAPK inhibitor-intolerance are eligible if they meet criteria

• Documented disease refractory to at least one PD1/PD-L1 inhibitor, defined as disease progression following at least 2 infusions of the same drug; radiographic disease progression will be documented by the institutional radiologist based on any radiographic evidence (magnetic resonance imaging [MRI], computed tomography [CT], positron emission tomography [PET], or other modalities, etc.) of disease progression on two separate radiographic scans assessment obtained at least 4 weeks apart; this minimum 4-week interval is required to define PD-1 inhibitor resistance based on imaging; alternatively, clinical disease progression may be documented on examination by the treating investigator

• Prior treatment-related toxicity resolved to =< grade 1 or baseline with the exception of alopecia and permanent grade =< 2 toxicities related to prior immune checkpoint inhibitor treatment (e.g. PD-1/PD-L1, CTLA-4, CD40, LAG3) treatment with the review and approval by the lead principal investigator (PI)

• Prior radiation allowed (no restriction on amount); measurable lesion(s) may not have been previously irradiated

• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

• Life expectancy of greater than 3 months

• Hemoglobin >= 9.0 g/dL

• Absolute neutrophil count (ANC) > 1,500/uL

• Platelets > 100,000/uL

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2 x upper limit of normal (ULN); =< 5 x ULN, if liver metastasis

• Total bilirubin =< 1.5 x ULN unless Gilbert's syndrome of disease infiltration of the liver is present

• Creatinine clearance estimated glomerular filtration rate (GFR) >= 30 mL/min/1.73 m^2 (Cockcroft-Gault)

• Patients with brain metastases are allowed provided that:

  • No leptomeningeal disease is present
  • Intracranial disease is controlled by prior local therapies (craniotomy, stereotactic radiosurgery, whole brain irradiation), as evidenced by brain MRI 4 weeks post treatment indicating no new intracranial disease
  • Stable or decreasing dose of steroids provided patient on =< 20 mg of prednisone or its equivalent daily

• Ibrutinib should be held at least 3 to 7 days pre- and post-surgery, depending upon the type of surgery and risk of bleeding

• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and for 90 days after completion of ibrutinib administration; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 90 days after completion of ibrutinib administration

• Negative serum pregnancy test within 7 days of treatment initiation with ibrutinib in women of childbearing potential (WOCBP)

• Ability to swallow oral medications

• Patients with autoimmune disease requiring systemic corticosteroid treatment (and previously ineligible to receive systemic immunotherapies for melanoma) are allowed on condition that they do not receive more than 20 mg of daily dose methylprednisolone, prednisone, or its equivalent; this does not include autoimmune diseases caused by previous immunotherapy treatments for melanoma that require ongoing treatment with corticosteroids (e.g. autoimmune colitis or autoimmune hepatitis receiving corticosteroids)

• Willing to consent to allow access to known archival tumor tissue (NOTE: designated pathologist from participating site OR lead principal investigator must sign-off to ensure "sufficient" tumor should be available for support of tumor imaging studies [multi-color immunofluorescence])

• If archival tumor tissue from a metastatic melanoma lesion is unavailable OR designated pathologist from participating site cannot sign-off to ensure that "sufficient" tumor is available from existing archival tumor block for support of tumor imaging studies, patients must be willing to consent to undergo a biopsy to collect metastatic tumor tissue; collection of fresh biopsy tissue does not guarantee enrollment, unless the pathologist from the participating site signs-off that "sufficient" tumor has been collected

• Ability to understand and the willingness to sign a written informed consent document

• Subjects who are unable to tolerate BRAF inhibitor and/or MEK inhibitor therapy due to grade >= 2 toxicity (Common Terminology Criteria for Adverse Events [CTCAE] version [v]4.0) from these agents, irrespective of antitumor response, are eligible on condition that: (a) toxicities persisted despite change from doublet to singlet therapy (i.e. from concurrent BRAF inhibition plus MEK inhibition to BRAF inhibition alone), (b) toxicities are attributed to a class effect, and therefore switch from one drug to another is expected to induce the same type of toxicity (e.g. ocular toxicities or cardiac dysfunction from MEK inhibitor), (c) drug-specific toxicities that do not resolve with switch from one BRAF inhibitor to another (i.e. dabrafenib to vemurafenib, or vice versa), will be eligible for enrollment in 9922; in other words, patients will be allowed to enroll into the NCI9922 study despite lack of progression to MAPK inhibitor treatments, on condition that grade 2 or higher toxicities attributed to MAPK inhibitors resolve to grade 1, or less, at the time of study enrollment

Exclusion Criteria:

• Patients with melanoma of mucosal or ocular primary

• Patients who have had chemotherapy or immunotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) or radiotherapy within 2 weeks prior to cycle 1 day 1; patients who have had tyrosine kinase inhibitors (such as Braf or MEK inhibitors) within 15 days of cycle 1 day 1

• Patients who are receiving any other biologic, cytotoxic or investigational agents

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to ibrutinib (difficulty breathing, lip swelling, itching or rash)

• 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

• Pregnant and breastfeeding women are excluded from this study; breastfeeding should be discontinued if the mother is treated with ibrutinib

• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are eligible; unless the patient's cluster of differentiation (CD)4+ count is below the institutional lower limit of normal

• Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura (ITP) resulting in (or as evidenced by) declining platelet or hemoglobin (Hgb) levels within the 4 weeks prior to first dose of study drug

• Presence of transfusion-dependent thrombocytopenia

• Need for daily corticosteroids at high doses (prednisone >= 20 mg daily, or an equivalent) is prohibited from 28 days prior to first dose and during treatment with ibrutinib; brief (up to 7 days) and episodic use of systemic corticosteroids for other general conditions (e.g. pre-medication for radiographic imaging due to intravenous [IV] contrast allergy, chronic obstructive pulmonary disease [COPD] exacerbation, poison ivy, etc.) is allowed

• Prior exposure to ibrutinib or other ITK inhibitors

• History of prior malignancy, with the exception of the following:

  • Non-melanoma skin cancers, non-invasive bladder cancer, and carcinoma in situ of the cervix
  • Prostate cancer not under active systemic treatment other than hormonal therapy and with documented undetectable prostate-specific antigen (PSA) (< 0.2 ng/mL)
  • Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) provided patient has isolated lymphocytosis (Rai stage O), and does not require systemic treatment (for "B" symptoms, Richter's transformation, lymphocyte doubling time [< 6 months], lymphadenopathy or hepatosplenomegaly)
  • Lymphoma of any type of hairy-cell leukemia provided patient is not on active systemic treatment and is in complete remission, as evidenced by PET/CT scans and bone marrow biopsies for at least 3 months
  • History of malignancy provided that patient has completed therapy and is free of disease for >= 2 years; if patient had other malignancy within the last 2 years from which he may have been completely cured by surgery alone, he may be considered to be enrolled on condition that the risk of development of distant metastatic disease based on American Joint Committee on Cancer (AJCC) staging system is less than 30%

• Currently active clinically significant cardiovascular disease, such as uncontrolled arrhythmia, congestive heart failure, any class 3 or 4 cardiac disease, as defined by the New York Heart Association Functional Classification, or history of myocardial infarction within 6 months prior to first dose with study drug

• Unable to swallow capsules, or disease significantly affecting gastrointestinal function and/or inhibiting small intestine absorption, such as malabsorption syndrome, resection of portions of small bowel larger than 3 feet, or poorly controlled inflammatory bowel disease affecting the small intestine

• Known serologic status reflecting active hepatitis B or C infection; patients that are hepatitis B core antibody positive, but antigen negative, will need a negative polymerase chain reaction (PCR) prior to enrollment (NOTE: hepatitis B antigen or PCR positive patients will be excluded)

• History of stroke or intracranial hemorrhage within 6 months prior to enrollment

• Current life-threatening illness, medical condition, or organ system dysfunction, which, in the investigator's opinion, could compromise the patient's safety, or put the study at risk

• Received anticoagulation therapy with warfarin, or equivalent vitamin K antagonists, within the last 28 days prior to day 1 of ibrutinib; patients with familial coagulopathic diseases (e.g. hemophilia, von Willebrand disease) are also excluded; if applicable, subjects must discontinue fish oil and vitamin E supplements within 7 days prior to initiating ibrutinib therapy

• Subjects with known hepatic insufficiency (i.e. Child-Pugh score A [mild], Child-Pugh score B [moderate] or Child-Pugh score C [severe]) according to Child-Pugh criteria

• Subjects who received a strong cytochrome P450 (CYP) 3A inhibitor within 7 days prior to the first dose of ibrutinib or subjects who require continuous treatment with a strong CYP 450 3A inhibitor