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• Adults ≥ 18 years of age.
• Post-Fontan palliative surgery and who currently have heart failure, or are at a high risk for heart failure post Fontan surgery.
• Patients with post-Fontan palliative surgery status, heart failure and able to provide informed consent.

• Individuals < 18 years of age.
• Inability to speak English.
• Inability or unwilling to provide informed consent.

Inclusion Criteria- Aim 1 and Aim 2:

• Adults older than 18 years.
• Any gender/race/ethnicity, diagnosed with heart failure (HF) at any time and New York Heart Association (NYHA) II-IV, who are being followed-up at the Mayo Clinic Heart Failure Clinic.
• Who are able to attend outpatient follow-up in person or virtually.
• Willing and able to provide informed consent.
• Speak English.

Exclusion Criteria
•Aim 1 and Aim 2:

• Patients who do not read, write, or speak English or who cannot verbally communicate.
• Patients with active substance abuse, diagnosis of dementia, traumatic brain injury, stroke with residual symptoms, acute psychosis, or mania.

Inclusion Criteria
•Aim 3:

• Adults older than 18 years.
• Any gender/race/ethnicity.
• Have received an left ventricular assist devices (LVAD) as destination therapy.
• Able to attend outpatient follow-up in person or virtually.
• Willing and able to provide informed consent.
• Speak English.

Exclusion Criteria -  Aim 3:

• Patients who have had an LVAD in the past but has been removed.
• Patients with LVAD as bridge to transplant.
• Patients who do not read, write, or speak English and who cannot verbally communicate.
• Patients with active substance abuse.
• Diagnosis of dementia.
• Traumatic brain injury.
• Stroke with residual symptoms.
• Acute psychosis or mania.

Eligibility last updated 11/1/21. Questions regarding updates should be directed to the study team contact.

• Written Informed Consent (mentally competent patient, able to understand and willing to sign the informed consent form).
• Male or non-pregnant female, age ≥ 18 years.
• Histologically confirmed unresectable metastatic cancer (adenocarcinomas and squamous cell carcinomas allowed).
• Able to comply with the study protocol, as per Investigator’s judgment.
• Life expectancy > 3 months according to Investigator’s judgement.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
• Coronavirus SARS-CoV-2 (COVID-19) negative patients (by real time quantitative polymerase chain reaction [RT-qPCR]) at the time of enrollment (test done within 72 h prior to enrollment).
• Patient able and willing to undergo pre- and on/post-treatment biopsies. According to the Investigator’s judgement, the planned biopsies should not expose the patient to substantially increased risk of complications. Every effort will be made that the same lesion is biopsied on repeat biopsies. If the patient is eligible according to all other criteria but declines to consent to a biopsy or there are other medical reasons precluding biopsy, this will be discussed with the sponsor.
• Measurable disease, according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Note that lesions intended to be biopsied should not be target lesions.
• Vaccination for COVID-19 and common flu is allowed before or during the study period. Information on timing and type of vaccine must be recorded.
• Adequate hematologic and end organ function, defined by the following laboratory results obtained prior to first dose of study drug treatment, provided no anti-cancer treatment was administered within the last 7 days:
  • neutrophil count ≥ 1 x 10^9/L;
  • platelet count ≥ 100 x 10^9/L; for hepatocellular carcinoma (HCC) in Part 1 ≥ 50 x 10^9/L;
• • hemoglobin ≥ 8.5 g/dL without transfusion in the previous week;
  • creatinine ≤ 1.5 x upper limit of normal (ULN);
  • aspartate aminotransferase AST (SGOT) ≤ 3 x ULN (≤ 5 x ULN when HCC or hepatic metastases are present);
  • alanine aminotransferase (ALT [SGPT]) ≤ 3 x ULN (≤ 5 x ULN when HCC or hepatic metastases present);
  • bilirubin ≤ 1.5 x ULN (patients with known Gilbert’s disease may have a bilirubin ≤ 3.0 x ULN);
  • albumin ≥ 3.0 g/dL;
  • international normalized ratio (INR) and partial thromboplastin time (PTT);
  • ≤ 1.5 x ULN;
  • amylase and lipase ≤ 1.5 x ULN.
• No evidence of active infection or infections requiring parenteral antibiotics, and no serious infection within 4 weeks before study start.
• Women of child-bearing potential must have a negative pregnancy test within 72 h prior to start of treatment. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or to use contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 180 days after the last study treatment.
• A woman is of childbearing potential if she is post-menarche, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus).
• Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices and copper intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (eg, calendar, ovulation, symptom-thermal, or post ovulation methods) and withdrawal are not acceptable methods of contraception. Fertile men must practice effective contraceptive methods during the study, unless documentation of infertility exists.
• Four (4) weeks or 5 half-lives (whichever is shorter) since the last dose of anti-cancer therapy before the first LYT-200 administration.
• Continuation of bisphosphonate treatment (e.g., zoledronic acid) or denosumab for bone metastases, which have been stable for at least 6 months before C1D1, is allowed...
• Biliary or gastric outlet obstruction allowed, provided it is effectively drained by endoscopic, operative, or interventional means.
• Pancreatic, biliary, or enteric fistulae allowed, provided they are controlled with an appropriate non-infected and patent drain (if any drains or stents are in situ, patency needs to be confirmed before study start).

• Additionally, for Part 1 only:

Patients:

• for whom there are no available standard of care options; or 
•  
• who have declined available and indicated standard of care therapy; or
• who are not eligible for available and indicated standard of care therapy.

Additionally, for Part 2 only:

• PDAC expansion cohort: 1st line metastatic patients who are either gemcitabine-containing regimen naïve or at least 3 months out of having been treated using a gemcitabine-containing regimen previously in a neoadjuvant or adjuvant/locally advanced setting.
• CRC and CCA expansion cohorts – patients who have received at least one prior line of therapy in the metastatic setting.

• Patient unwilling or unable to follow protocol requirements.
• Patient diagnosed with metastatic cancer of an unknown primary.
• Prior or current illicit drug addiction (medical and recreational marijuana/cannabidiol [CBD]/ tetrahydrocannabinol [THC] would not be considered "illicit").
• Clinically significant, active uncontrolled bleeding, and any patients with a bleeding diathesis (e.g., active peptic ulcer disease). Prophylactic or therapeutic use of anticoagulants is allowed.
• Pregnant and/or lactating females.
• Receiving any other investigational agents or participating in any other clinical trial involving another investigational agent for treatment of solid tumors within 4 weeks or 5 half-lives of the administered drug.(whichever is shorter) prior to Cycle 1, Day 1 of the study, or other investigational therapy or major surgery within 4 weeks of the date of consent, or planned surgery within 4 weeks of envisaged study start (this includes dental surgery).
• Radiation therapy within 4 weeks of the first dose of study drug, except for palliative radiotherapy to a limited field, such as for the treatment of bone pain or a focally painful tumor mass, and which does not jeopardize required measurable lesions for response assessment (RECIST v1.1).
• Patients with fungating tumor masses.
• Patients with locally advanced PDAC without distant organ metastatic deposits.
• Grade 4 immune-mediated toxicities with a prior checkpoint inhibitor. Grade 2 or Grade 3 pneumonitis or any other Grade 3 checkpoint inhibitor-related toxicity that led to immunotherapy treatment discontinuation. Low-grade (< Grade 3) toxicities, such as neuropathy from prior treatments, manageable electrolyte abnormalities and lymphopenia, alopecia and vitiligo are allowed.
• History of second malignancy, except those treated with curative intent more than five years previously without relapse or low likelihood of recurrence (for example, non-melanotic skin cancer, cervical carcinoma in situ, early (or localized) prostate cancer, or superficial bladder cancer).
• Active brain or leptomeningeal metastases. Patients with brain metastases are eligible provided they have shown clinically and radiographically stable disease for at least 4 weeks after definitive therapy and have not used steroids (> 10 mg/day of prednisone or equivalent) for at least 4 weeks prior to the first dose of study drug.
• Evidence of severe or uncontrolled systemic diseases, congestive heart failure > New York Heart Association (NYHA) class 2, myocardial infarction (MI) within 6 months, or laboratory finding that in the view of the Investigator makes it undesirable for the patient to participate in the trial.
• Any medical condition that the Investigator considers significant to compromise the safety of the patient or that impairs the interpretation of LYT-200 toxicity assessment.
• Serious non-healing wound, active ulcer, or untreated bone fracture.
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures.
• History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins.
• Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months of Cycle 1, Day 1.
• History of pulmonary embolism, stroke or transient ischemic attack within 3 months prior to Cycle 1, Day 1.
• History of abdominal fistula or gastrointestinal perforation within 6 months prior to Cycle 1, Day 1.
• Active auto-immune disorder (except type I/II diabetes, hypothyroidism requiring only hormone replacement, vitiligo, psoriasis, or alopecia areata).
• Requires systemic immunosuppressive treatment, including, but not limited to cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor (anti-TNF) agents. Patients who have received or are receiving acute, low dose systemic immunosuppressant medications (e.g., ≤ 10 mg/day of prednisone or equivalent) may be enrolled. Replacement therapy (e.g., thyroxine, insulin, physiologic corticosteroid replacement therapy [e.g., ≤ 10 mg/day of prednisone equivalent] for adrenal or pituitary insufficiency) is not considered a form of systemic treatment. The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone), topical steroids, intranasal steroids, intra-articular, and ophthalmic steroids is allowed.
• Severe tumor-related pain (Grade 3, Common Terminology Criteria for Adverse Events [CTCAE] v.5.0) unresponsive to broad analgesic interventions (oral and/or patches).
• Uncontrolled hypercalcemia, despite use of bisphosphonates.
• Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk of treatment complications.
• Received organ transplant(s).
• Patients undergoing dialysis.
• For patients enrolled into anti-PD-1 mAb combination cohorts, no prior exposure to any anti-PD-1 agent in any prior lines of therapy.
• For Part 1, hormonal androgen deprivation therapy is allowed to continue for patients with metastatic castration-resistant prostate cancer.
• Any ablative therapy (Radio Frequency Ablation or Percutaneous Ethanol Injection) for HCC < 6 weeks prior trial entry.
• Hepatic encephalopathy or severe liver adenoma.
• Child-Pugh score ≥ 7.

• Age 45 years and greater.
• Receiving primary care services at any of the 3 main Mayo Clinic sites and Mayo Clinic Health system in Northwest Wisconsin.

• Lack of consent for use of medical records for research.

• Patient and caregiver willing to participate as a dyad (patients will need a legally authorized representative to consent on their behalf given the requirement for at least moderate dementia, but patients who resists participating in the study will not be enrolled).
• U.S. residents (i.e., individuals accessing the LBDA from outside the U.S. will be excluded).
• Patient with a clinical diagnosis of Dementia with Lewy Bodies (DLB).
• Patient with moderate severity dementia as assessed by the Quick Dementia Rating System (QDRS, with a score of > 12 suggestive of moderate dementia), and caregiver modified telephone interview for cognitive status (TICS-m) score of > 31 to ensure that the caregiver is able to reliably complete study visits. Diagnosis of DLB will be confirmed using the Lewy Body Composite Risk Score (LBCRS, score ≥ 3 consistent with DLB). The QDRS and LBCRS were chosen for inclusion criteria as they are validated caregiver-reported scales and can be used for both the clinical and the virtual cohorts.
• The participating caregiver must be the person providing the majority of the patient’s informal care (whether the individual with DLB is living at home or in a facility) and attending the majority of the patient’s clinical visits.
• The carepartner can represent any relationship with the individual with DLB (e.g., spouse, child).
• The type of relationship will be captured in demographic details to assess the impact of this relationship/role on end of life for the individual with DLB and the caregiver.
• The participating caregiver must remain the same throughout the study.
• If the primary caregiver changes (e.g., due to caregiver death), that dyad will drop out of the study.
• The location of the person with DLB (e.g., home, facility) will be monitored throughout the study for its influence on outcomes and its relationship with informal caregiver responsibilities.

• Individuals < 18 years of age.

• Male or female adults, ≥ 18 years of age.
• Patients with unilateral or bilateral cochlear implants that were implanted at Mayo Clinic, Rochester.

• Not able to provide consent for self to participate.
• Patients that declined MN research authorization.
• Additional handicap that would limit the patient from being able to follow study instructions.

• Postmenopausal women with or without history of BSO.
• Willing and able to complete informed consent for this study.
• Already enrolled in IRB#18-008476.

• Ongoing exogenous glucocorticoid therapy.

Parents (of children meeting the following inclusion/exclusion criteria) will be sent surveys.  Per IRB, "To encompass all the participants, the age range should reflect the minimum age of 11 years of age and no maximum age listed. This encompasses the data that will be obtained on the 11 and 12 year olds as well as from the providers (who were/are subjects) and the parents."

• Empaneled in one of the six participating primary care practices.
• 11 to 12 years of age at the first day of each of the 12-month-long steps.
• Due during that 12-month-long step for at least one dose of the HPV vaccine. For immunocompetent children (the overwhelming majority), for children less than 15 years of age, the newly revised ACIP recommendations call for two doses at zero- and six-months with the minimum interval being five months between the first and second dose. Some eligible patients may have received two doses too close together for this because of the previous three-dose recommendation was in effect until December 16, 2016, making the ACIP recommendations official. In these cases where the second dose is less than five months after the first, the individual should receive a third dose of HPV vaccine 12 weeks after the second dose and at least 24 weeks after the first dose. Thus, patients who are eligible and due comprise of three groups: those having received no valid HPV vaccine; those having received one valid HPV dose AND it has now been five calendar-months or more; and those having received two valid doses but Dose 2 was given less than five months after the first. Valid doses include doses given at nine years or older (the minimum age per ACIP) and meet the minimum intervals.

• Not empaneled in one of the six participating practices.
• Empaneled in one of the six participating practices but less than 11 years of age or more than 12 years of age on the first day of each 12 month long step.
• Not due during that 12-month-long step for a dose of HPV vaccine.

• Scholars and former scholars of the Mayo Clinic Cancer Center’s “Paul Calabresi Clinical Oncology (K12) Training Program.”

• None.

• Females and males.
• Between the ages of 18 and 65 years.
• Body mass index between 18 and 35 kg/m^2. 

•  Heartburn, regurgitation, or symptoms suggestive of gastroparesis such as nausea, early satiety, postprandial bloating, and upper abdominal pain.
•  Pregnant.

• Patients with a reoperation within 12 weeks following a primary total knee arthroscopy (TKA).

Patients who/with:

• Were missing synovial fluid analysis data.
• Did not have culture data.
• Previous revision surgery on the same knee.
• Sameday (postoperative day (POD) 0) re-operation.
• Superficial (extraarticular) irrigation and debridement.
• Diagnosis of acquired immunodeficiency syndrome (AIDS) or malignancy.
• Received antibiotics within 2 weeks of synovial fluid aspiration.

Patients must have any one of the following diagnosis:

• Monoclonal B-cell lymphocytosis.
• Chronic lymphocytic leukemia/small lymphocytic lymphoma.
• B-cell Non-Hodgkin’s lymphoma:
  • Follicular lymphoma;
  • Mantle cell lymphoma;
  • Diffuse large B-cell lymphoma;
  • Marginal zone lymphoma;
  • Burkitt lymphoma;
  • Double hit/triple hit lymphoma;
  • Lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia;
• Hodgkin lymphoma.
• Individuals who are a participant of the Mayo Clinic Biobank.

• First diagnosis of malignant neoplasm (International Classification of Diseases for Oncology [ICD-O] behavior code of "3") in first and continuous remission at the time of enrollment.
• Curative cancer treatment must have included chemotherapy and/or radiation.
  • Note: Childrens Oncology Group (COG) therapeutic trial participation is not required.
• All cancer treatment must have been completed within 3-36 calendar months prior to enrollment .
• Patients must have a life expectancy of > 1 year.
• Self-report of < 420 minutes of moderate-to-vigorous physical activity per week as assessed via the study-specific Physical Activity Worksheet.
  • Note: COG Study Web Page for the Godin-Shephard Leisure Time Physical Activity Questionnaire or link to online calculator.
• Ambulatory and no known medical contraindications to increasing physical activity.
• No known significant physical or cognitive impairment that would prevent use of the electronic devices used for the protocol intervention (e.g., Fitbit, smartphone, tablet, or computer).
• Able to read and write English -All patients and/or their parents or legal guardians must sign a written informed consent.
  • Note: Informed consent may be obtained electronically/online if allowed by local site policy and Institutional Review Board (IRB)/Research Ethics Board (REB) of record.
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met.

• Post-menarchal female patients who are pregnant or planning to become pregnant in the next year are excluded.
  • Note: Pregnancy status can be established by clinical history with patient.
• Post-menarchal female patients are eligible as long as they agree to use an effective contraceptive method (including abstinence) during study participation.
• Patients with previous hematopoietic stem cell transplant (HSCT).

PSC

• Patients diagnosed with Primary Sclerosing Cholangitis (PSC) between the age of 18 and 85.
• The diagnosis of PSC will be based on standard PSC criteria including clinical and biochemical evidence of chronic cholestasis of at least six months duration, positive cholangiographic findings and compatible liver biopsies if available.
• Women with PSC of childbearing potential and pregnant women will be offered enrollment because there is no risk to an unborn child in this investigation. Patients with PSC and Cholangiocarcinoma will be included.

Controls

• Controls without history of PSC or evidence of other chronic liver disease of either gender that will participate in this study should be between the ages of 18-85. 

• Patients unable to provide inform consent.
• Prisoners and institutionalized individuals.
• PSC with orthotopic  liver transplantation.
• History of Roux En Y procedure.

Inclusion Criteria -
Patients with Untreated High Risk Prostate Cancer:

Patients with prostate cancer, who have not received anticancer therapy and who meet at least one of the following criteria for high-risk prostate cancer are eligible for inclusion in this expanded access IND study:

• Serum prostate-specific antigen (PSA) concentration of 20 ng/mL or more.
• Pathologic criteria of International Society of Uropathology (ISUP) grade group 3–5: ISUP grades 3-5 are equivalent to pathologic Gleason scores of 4+3, 8, 9 or 10.
• Local staging of T3 or worse, indicating that cancer has invaded into tissues outside of the prostate gland, as seen at either CT or MRI.

Inclusion Criteria - 
Patients with Biochemically Recurrent Prostate Cancer:

Patients with prostate cancer, who have undergone initial anticancer therapy in the form of surgery or radiation and who meet at least one of the following criteria are eligible for inclusion in this expanded access IND study:

• In patients who are post prostatectomy, a PSA > 0.2ng/mL on 2 consecutive tests;
• In patients who have undergone definitive prostate radiation, a PSA rise ≥ 2.0 ng/mL above nadir PSA.

• Patients unable to provide informed consent.
• Patients with a life expectancy less than 6 months.
• Additional exclusion criteria may be added based on demand.

• Adults ≥ 18 years old.
• DLMP employees who work on-site at SDSC.
• Plan to complete the two dose SARS-CoV-2 vaccination schedule.

• Children < 18 years old.
• Subjects who have previously been diagnosed with SARS-CoV-2 infection.
• Subjects who test SARS-CoV-2 antibody positive on the pre-vaccination sample indicating prior infection.

• Patients (≥ 18 years of age) with a solid pancreas tumor requiring a clinical endoscopic ultrasound for diagnostic and staging purposes. 
• Freely of their own will, able to complete a written informed consent.

• Patients under 18 years of age.
• Pregnant.

• Rheumatologist confirmed diagnosis of one of the following diagnoses:
  • Systemic lupus erythematosus;
  • Sjogren syndrome;
  • Inflammatory myositis;
  • Psoriatic arthritis;
  • Osteoarthritis;
  • Gout;
  • Ankylosing spondylitis;
  • IBD-related arthritis.

• Active infection or untreated malignancy (other than skin cancer) at enrollment.
• Pregnancy.

Inclusion Criteria
•Patients:

• Patient of Mayo Clinic, Dialysis Units.
• 18 years of age or over.
• Not pregnant.
• Patient in MCHS.

Exclusion Criteria
•Patients:

• Patients of FLA or ARZ Dialysis Unit.

Inclusion Criteria
•Providers:

• Mayo Clinic employee.
• Involved in Telenephrology.
• Inpatient telenephrology consults.
• Within MCHS and RST.

Exclusion Criteria
•Providers:

• Providers in ARZ or FLA.
• Non-Mayo Clinic providers.
• Providers not involved in telenephrology.

Inclusion Criteria
•Patients:

• Patient of Mayo Clinic, Dialysis Units.
• 18 years of age or over.
• Not pregnant.
• Patient in MCHS.

Exclusion Criteria
•Patients:

• Patients of FLA or ARZ Dialysis Unit.

Inclusion Criteria
•Providers:

• Mayo Clinic employee.
• Involved in Telenephrology.
• Inpatient telenephrology consults.
• Within MCHS and RST.

Exclusion Criteria
•Providers:

• Providers in ARZ or FLA.
• Non-Mayo Clinic providers.
• Providers not involved in telenephrology.

Inclusion Criteria
•Patients:

• Patient of Mayo Clinic, Dialysis Units.
• 18 years of age or over.
• Not pregnant.
• Patient in MCHS.

Exclusion Criteria
•Patients:

• Patients of FLA or ARZ Dialysis Unit.

Inclusion Criteria
•Providers:

• Mayo Clinic employee.
• Involved in Telenephrology.
• Inpatient telenephrology consults.
• Within MCHS and RST.

Exclusion Criteria
•Providers:

• Providers in ARZ or FLA.
• Non-Mayo Clinic providers.
• Providers not involved in telenephrology.

Inclusion Criteria
•Patients:

• Patient of Mayo Clinic, Dialysis Units.
• 18 years of age or over.
• Not pregnant.
• Patient in MCHS.

Exclusion Criteria
•Patients:

• Patients of FLA or ARZ Dialysis Unit.

Inclusion Criteria
•Providers:

• Mayo Clinic employee.
• Involved in Telenephrology.
• Inpatient telenephrology consults.
• Within MCHS and RST.

Exclusion Criteria
•Providers:

• Providers in ARZ or FLA.
• Non-Mayo Clinic providers.
• Providers not involved in telenephrology.

• Adults, age ≥ 18 years old.
• Have already received a cochlear implant.
• Must be able to provide consent to participate.

• Individuals < 18 years old.
• Additional handicap that would limit the patient from being able to follow study instructions.

PRE-REGISTRATION

• Pathology from the resected brain metastasis must be consistent with a non-central nervous system primary site. Patients with or without active disease outside the nervous system are eligible (including patients with unknown primaries), as long as the pathology from the brain is consistent with a non-central nervous system primary site.
• Three or fewer (i.e., 0 to 3) unresected brain metastases (as defined on the post operative magnetic resonance imaging [MRI]) at the time of screening.
  • Note: Dural based metastases (e.g., commonly seen in breast cancer) are eligible.
• Unresected lesions must measure < 4.0 cm in maximal extent on the contrasted post-operative treatment MRI brain scan. The unresected lesions will be treated with SRS as outlined in the treatment section of the concept. 
  • Note: The metastases size restriction does not apply to the resected brain metastasis. 
• One brain metastasis must be completely (gross total resection) resected ≤ 30 days prior to pre-registration. 
  • NOTE: May not have had resection of more than one brain metastasis. 
• The resected brain metastasis must measure 2 cm or larger on the pre-operative MRI. 
• Resection cavity must measure < 5.0 cm in maximal extent and the resection must be complete (gross total resection) on the post-operative MRI obtained ≤ 30 days prior to pre-registration. 
• Karnofsky performance status of ≥ 60.
• For women of childbearing potential only, a negative urine or serum pregnancy test done ≤ 7 days prior to pre-registration is required. 
• Men and women of childbearing potential must be willing to employ adequate contraception throughout the study and for men for up to 3 months after completing treatment. 
• A female of childbearing potential is a sexually mature female who:
  • has not undergone a hysterectomy or bilateral oophorectomy; or 
  • has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months). 
• Ability to complete an MRI of the head with contrast.
• The brain metastasis must be located > 5 mm of the optic chiasm and outside the brain stem.
• Must be fluent in English, Spanish, or French.

REGISTRATION

• Completion of all baseline electronic patient-reported outcome (ePRO) quality of life measures (or booklet quality of life measures) and Montreal Cognitive Assessment (MoCA).

• Must not have any prior whole brain radiation therapy.  Past radiosurgery to other lesions is allowed. 
  • NOTE: The surgically resected lesion cannot be the same location treated in the past with radiosurgery (i.e., repeat radiosurgery to the same location/lesion is not allowed on this protocol). 
• May not have primary germ cell tumor, small cell carcinoma, or lymphoma. 
• No evidence of leptomeningeal metastasis (LMD). 
  • NOTE: For the purposes of exclusion, LMD is a clinical diagnosis, defined as positive cerebrospinal fluid (CSF) cytology and/or equivocal radiologic or clinical evidence of leptomeningeal involvement. Patients with leptomeningeal symptoms in the setting of leptomeningeal enhancement by imaging (MRI) would be considered to have LMD even in the absence of positive CSF cytology, unless a parenchymal lesion can adequately explain the neurologic symptoms and/or signs. In contrast, an asymptomatic or minimally symptomatic patient with mild or nonspecific leptomeningeal enhancement (MRI) would not be considered to have LMD. In that patient, CSF sampling is not required to formally exclude LMD, but can be performed at the investigator's discretion based on level of clinical suspicion.

• Women and minorities may be included.
• Measurable stage III, measurable stage IVA, stage IVB (with or without measurable disease) or recurrent (with or without measurable disease) endometrial cancer.
• Pathology report showing results of institutional MMR IHC testing.
• Histologic confirmation of the original primary tumor is required (submission of pathology report[s] is required). Patients with the following histologic types are eligible:
  • Endometrioid adenocarcinoma, serous adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial carcinoma, adenocarcinoma not otherwise specified (N.O.S.). 
• Submission of tumor specimens for centralized MMR IHC testing is required after Step 1 and before Step 2 registration.
• In patients with measurable disease (stage III and IVA), lesions will be defined and monitored by RECIST version (v) 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 ≥ 10 mm when measured by computed tomography (CT) or magnetic resonance imaging (MRI). Lymph nodes must be 15 mm in short axis when measured by CT or MRI. 
• Patients may have received:
  • NO prior chemotherapy for treatment of endometrial cancer; OR 
  • Prior adjuvant chemotherapy (e.g., paclitaxel/carboplatin alone or as a component of concurrent chemotherapy and radiation therapy [with or without cisplatin]) provided adjuvant chemotherapy was completed  ≥ 12 months prior to STEP 2 registration. 
• Patients may have received prior radiation therapy for treatment of endometrial cancer. Prior radiation therapy may have included pelvic radiation therapy, extended field pelvic/para aortic radiation therapy, and/or intravaginal brachytherapy. All radiation therapy must be completed at least 4 weeks prior to STEP 2 registration. 
• Patients may have received prior hormonal therapy for treatment of endometrial cancer. All hormonal therapy must be discontinued at least three weeks prior to STEP 2 registration. 
• Age ≥ 18 years.
• Performance status of 0, 1 and 2. 
• Hematologic Function:
  • Platelets ≥ 100,000/mcl;
  • Absolute neutrophil count (ANC) ≥ 1,500/mcl.
• Renal Function:
  • Creatinine ≤ 1.5 x institutional/laboratory upper limit of normal (ULN).
• Hepatic Function:
  • Total serum bilirubin level ≤ 1.5 x upper limit of normal (ULN) (patients with known Gilbert's disease who have bilirubin level ≤ 3 x ULN may be enrolled);
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x ULN. 
• Thyroid stimulating hormone (TSH) within normal limits (TSH < ULN allowed in euthyroid patients on thyroid replacement therapy). 
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of Step 2 registration are eligible for this trial. 
• For patients of child bearing potential: negative urine or serum pregnancy test within 72 hours prior to Step 2 registration. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test is required. 
• Administration of study drugs (pembrolizumab, paclitaxel, carboplatin) may have an adverse effect on pregnancy and poses a risk to the human fetus, including embryo-lethality. Women of childbearing potential (WOCBP) must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) from up to 14 days prior to Step 2 registration (for oral contraceptives), during treatment, and for 120 days after the last dose of study medication. Should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately. Patients will be considered of nonreproductive potential if they are either: 
  • Postmenopausal (defined as at least 12 months with no menses without an alternative medical cause; in women < 45 years of age, a high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy;In the absence of 12 months of amenorrhea, a single FSH measurement is insufficient); OR 
  • Have a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral tubal ligation/occlusion, at least 6 weeks prior to Step 2 registration; OR 
  • Have a congenital or acquired condition that prevents childbearing. 
• Patients with a prior or current malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessent of the investigational regimen are eligible for this trial
• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information.

• Patients with prior treatment with anti-PD-1, anti-PD-L1 or anti-CTLA-4 therapeutic antibody or other similar agents.
• Patients who have a history of a severe hypersensitivity reaction to monoclonal antibody or pembrolizumab (MK-3475) and/or its excipients.
• Patients who are currently participating and receiving cancer-directed study therapy or have participated in a study of an investigational agent and received cancer-directed study therapy within 4 weeks prior to Step 2 registration.
• Patients who have a diagnosis of immunodeficiency or are receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to Step 2 registration:
  • Patients who have received steroids as CT scan contrast premedication may be enrolled;
  • The use of inhaled or topical corticosteroids is allowed;
  • The use of mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency is allowed;
  • The use of physiologic doses of corticosteroids may be approved after consultation with the study chair.
• Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression, and they have been off steroids for at least 4 weeks prior to Step 2 registration and remain clinically stable.
• Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids. This includes, but is not limited to, patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome because of the risk of recurrence or exacerbation of disease.
• Patients with vitiligo, endocrine deficiencies including type I diabetes mellitus, thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible.
• Patients with rheumatoid arthritis and other arthropathies, Sjogren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible.
• Patients who have a history of (non-infectious) pneumonitis that required steroids, or current pneumonitis.
• Uncontrolled intercurrent illness including, but not limited to: ongoing or active infection (except for uncomplicated UTI), interstitial lung disease or active, non-infectious pneumonitis, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; and cirrhosis:
  • For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated;
  • Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
• Pregnant or lactating patients.

• All patients must be ≥ 12 years of age.
• All patients must have histologically confirmed newly diagnosed, previously untreated stage III or IV classical Hodgkin lymphoma (nodular sclerosing, mixed cellularity, lymphocyte-rich, or lymphocyte-depleted, or not otherwise specified [NOS]). Nodular lymphocyte predominant Hodgkin lymphoma is not eligible. 
• Patients must have bidimensionally measurable disease (at least one lesion with longest diameter ≥ 1.5 cm) documented on the Lymphoma Baseline Tumor Assessment Form in Rave. 
• Patients must have a whole body or limited whole body PET-CT scan performed within 42 days prior to registration. (A contrast-enhanced [diagnostic] CT, magnetic resonance imaging [MRI] or MRI-PET is acceptable in event that PET-CT is contraindicated, however the same modality must be utilized through the trial.) NOTE: All images from PET-CT, CT, MRI or MR-PET scans performed as standard of care to assess disease (within 42 days prior to registration) must be submitted and associated radiology reports must be submitted.
• Patients must not have received any prior chemotherapy, radiation, or antibody-based treatment for classical Hodgkin lymphoma. Steroid pre-treatment is permitted. 
• Patients must not have had prior solid organ transplant. 
• Patients must not have had prior allogeneic stem cell transplantation. 
• Patients must not have received a live vaccine within 30 days prior to planned day 1 of protocol therapy (e.g., measles, mumps, rubella, varicella, yellow fever, rabies, Bacillus Calmette-Guerin [BCG], oral polio vaccine, and oral typhoid).
• At registration, investigator must declare intent-to-treat with residual PET radiation therapy (residual PET RT- RPRT) to be administered after patient completes 6 cycles of therapy if, after end of treatment, the patient meets criteria specified for receiving RT). Patients will be stratified by investigator's intent-to-treat with residual PET RT. 
• All patients enrolled by Children's Oncology Group (COG) investigators will be considered intent-to-treat with residual PET RT. 
• Patients must have a performance status corresponding to Zubrod scores of 0, 1 or 2. Use Lansky for patients ≤ 17 years of age. *The conversion of the Lansky to Eastern Cooperative Oncology Group (ECOG) scales is intended for National Cancer Institute (NCI) reporting purposes only. 
• Adults (age 18 or older):
  • Creatinine clearance ≥ 30 mL/min, as estimated by the Cockcroft and Gault formula. The creatinine value used in the calculation must have been obtained within 28 days prior to registration. Estimated creatinine clearance is based on actual body weight.
  • Estimated creatinine clearance = (140
    •age) x weight in kg † 72 x creatinine* (mg/dl).
  • Multiply this number by 0.85 if the participant is a female.

† The kilogram weight is the participant weight with an upper limit of 140% of the ideal body weight (IBW).

* Actual lab serum creatinine value with a minimum of 0.7 mg/dL.

• Pediatric Patients (age 12-17), the following must have been obtained within 14 days prior to registration:
  • Measured or calculated creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 70 ml/min/1.73 m^2; or 
  • Serum creatinine ≤ 1.5 x institutional upper limit of normal (IULN), or a serum creatinine (SCr) based on age/gender as follows:
  • Age < 13 maximum serum creatinine:
    • Male 1.2 mg/dL;
    • Female 1.2 mg/dL.
  • Age 13 to < 16 maximum serum creatinine:
    • Male 1.5 mg/dL;
    • Female 1.4 mg/dL.
  • Age 16-17 maximum serum creatinine:
    • Male 1.7 mg/dL;
    • Female 1.4 mg/dL.
  • Total bilirubin ≤ 2 x IULN (must be documented within 28 days prior to registration for adults [age 18 or older]; must be documented within 14 days prior to registration for pediatric patients [age 12-17]).
• Unless due to Gilbert's disease, lymphomatous involvement of liver or vanishing bile duct syndrome.
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x IULN (must be documented within 28 days prior to registration for adults [age 18 or older]; must be documented within 14 days prior to registration for pediatric patients [age 12-17]). 
• Unless due to Gilbert's disease, lymphomatous involvement of liver or vanishing bile duct syndrome
  • Patients must have an echocardiogram (ECHO), multigated acquisition (MUGA), or functional cardiac imaging scan with a left ventricular ejection (LVEF) fraction ≥ 50% or a shortening fraction of ≥ 27%.
• For adults (age 18 or older), the ECHO or MUGA be performed within 42 days prior to registration.
• For pediatric patients (age 12-17), the ECHO, MUGA, or functional cardiac imaging scan must be performed within 14 days prior to registration. 
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable or unquantifiable viral load within 6 months prior to registration are eligible for this trial.
• Patients must not have known active hepatitis B (HBV) or hepatitis C virus (HCV) at date of registration. Patients with previously treated HBV or HCV that have an undetectable viral load and no residual hepatic impairment are eligible. 
• Patients must not have any known central nervous system lymphoma. 
• Patients must not have a history of or active interstitial pneumonitis or interstitial lung disease.
• Patients must not have had a diagnosis of inherited or acquired immunodeficiency. 
• Patients must not have any known uncontrolled intercurrent illness including, but not limited to symptomatic congestive heart failure, unstable angina pectoris, hemodynamically unstable cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. 
• Patients must not have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days prior to registration. Inhaled or topical steroids, and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. Steroid use for the control of Hodgkin lymphoma symptoms is allowable, but must be discontinued prior to cycle 1, day 1. 
• Patients with peripheral neuropathy must have < grade 2 at date of registration. 
• Patients must not have active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, immunosuppressive drugs, or corticosteroids with doses higher than prednisone 10 mg or equivalent). Autoimmune diseases include but are not limited to autoimmune hepatitis, inflammatory bowel disease (including ulcerative colitis and Crohn's disease), as well as symptomatic disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [e.g., Wegener's granulomatosis]); central nervous system (CNS) or motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre syndrome and myasthenia gravis, multiple sclerosis or glomerulonephritis). Vitiligo, alopecia, hypothyroidism on stable doses of thyroid replacement therapy, psoriasis not requiring systemic therapy within the past 2 years are permitted.
• No second prior malignancy is allowed except for adequately treated basal (or squamous cell) skin cancer, any in situ cancer or other cancer for which the patient has been disease free for two years. 
• Females of childbearing potential must not be pregnant or nursing, and have a negative pregnancy test within 28 days prior to registration. Women/men of reproductive potential must have agreed to use an effective contraceptive method while receiving study drug and for women until 6 months after receiving the last dose of study drug or, for men, until 7 months after receiving the last dose of study drug. A woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation. However, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures. 

• Written Informed Consent and HIPAA Authorization:
  • Subjects must have the nature of the study explained to them;
  • Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests, pharmacokinetic collections, and other requirements of the study;
  • Subjects must provide a signed and dated IRB/IEC approved written informed consent form (ICF) in accordance with regulatory and institutional guidelines;
  • Subjects must provide a signed and dated Health Insurance Portability and Accountability Act (HIPAA) authorization;
  • The ICF and HIPAA authorization must be obtained before conducting any procedures that do not form a part of the subject’s normal care;
  • After signing the ICF and HIPAA Authorization, subjects will be evaluated for study eligibility during the Screening Period (no more than 28 days before study drug administration).
• Histologically confirmed unresectable Stage III or Stage IV melanoma as per AJCC staging system (mucosal melanoma is acceptable).
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
• Prior disease progression on anti-PD1 therapy (i.e., anti-PD1 or anti-PD-L1, including prior adjuvant). Prior anti-PD1 therapy must have been completed prior to first dose of SX-682, and all adverse events related to prior therapy have either returned to baseline or stabilized (other than endocrine toxicity for which medical replacement therapy is in place).
• Must have at least measurable non-CNS disease with at least 1 unidimensional measurable lesion per RECIST v1.1.
• Pre-treatment tumor tissue (i.e., archived paraffin-embedded) obtained in the metastatic setting or from an unresectable site of disease must be available for biomarker analyses. Biopsy should be excisional, incisional punch or core needle. Fine needle aspirates or other cytology samples are insufficient.
• Prior radiotherapy must have been completed at least 2 weeks prior to study drug administration.
• Screening laboratory values must meet the following criteria and should be obtained within 14 days prior to first dose:
  • WBC ≥ 3000/μL;
  • Neutrophils ≥ 1500/ μL;
  • Platelets ≥ 100,000/μL;
  • Hemoglobin ≥ 9.0 g/dL (may have been transfused);
  • Creatinine ≤ 1.5 mg/dL;
  • AST/ALT ≤ 2.5 X ULN for subject with no liver metastases;
  • ≤ 5 X ULN for subjects with liver metastases;
  • Bilirubin ≤ 1.5 mg/dL (unless diagnosed with Gilbert’s syndrome who can have total bilirubin < 3.0 mg/dL);
  • INR or PT ≤ 1.5 X ULN unless the subject is receiving anticoagulant therapy;
  • aPTT or PTT  ≤ 1.5 X ULN unless the subject is receiving anticoagulant therapy;
  • No known positivity for human immunodeficiency virus (HIV) (no laboratory testing is required), no active infection with Hepatitis B or Hepatitis C.
• Life expectancy > 12 weeks.
• Subject Re-enrollment: This study permits the re-enrollment of a subject that has discontinued the study as a pre-treatment failure (i.e., subject has not been treated withSX-682) after obtaining agreement from the medical monitor prior to re-enrolling a subject. If re-enrolled, the subject must be re-consented.
• Men and women, ages ≥ 18 years of age.
• Women of childbearing potential (WOCBP) must use method(s) of contraception while on study and for 4 months after the last dose of SX-682 or pembrolizumab. A WOCBP is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or is not postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman over age 45 in the absence of other biological or physiological causes.
• Women under the age of 62 with a history of being postmenopausal must have a documented serum follicle stimulating hormone, (FSH) level > 40 mIU/mL.
• Women must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug.
• Women must not be breastfeeding.
• Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year while on study and for a period at least 6 months after the last dose of study drug.
• Women who are not of childbearing potential and azoospermic men do not require contraception.

• Active brain metastases or leptomeningeal metastases are eligible if the treating physician determines that immediate CNS specific treatment is unlikely to be required before trial screening/enrollment. Subjects with treated/stable brain metastases are also eligible. An MRI is not required to rule out brain metastases or leptomeningeal metastases. There must also be no requirement for high doses of systemic corticosteroids that could result in immunosuppression (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration.
• Ocular melanoma is excluded (mucosal melanoma is acceptable).
• Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results. Specifically:
  • Subjects with active, non-infectious pneumonitis;
  • Subjects with interstitial lung disease or a history of pneumonitis that required oral or intravenous glucocorticoids to assist with management;
  • Subjects with clinically significant heart disease that affects normal activities.
• Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.
• Subjects with active, known or suspected autoimmune disease.
• Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
• Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids, and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
• Use of other investigational drugs (drugs not marketed for any indication) within 30 days before study drug administration.
• Subjects who have had major surgery in the past 4 weeks.
• Subjects who have received a live-virus vaccine within 30 days before study drug administration.
• Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection.
• Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
• ECG demonstrating a QTc interval > 470 msec or patients with congenital long QT syndrome.
• History of allergy to study drug components.
• History of severe hypersensitivity reaction to any monoclonal antibody.
• Women of Childbearing Potential (WOCBP) who are pregnant or breastfeeding.
• Women with a positive serum or urine pregnancy test at enrollment or prior to administration of study medication.
• Prisoners or subjects who are involuntarily incarcerated, or other vulnerable populations (study is exempt from 45 CFR 46 Subparts B, C, and D).
• Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness
• Use of QT prolonging drugs must be stopped at least two (2) weeks before the start of SX-682 dosing and suspended for the length of the trial.
• Subjects who have had major surgery in the past 4 weeks.
• Subjects who have received a live-virus vaccine within 30 days before study drug administration.

Eligibility last updated 9/22/21. Questions regarding updates should be directed to the study team contact.

• Diagnosis of unresectable stage III or metastatic melanoma (stage IV) not amenable to local therapy.
• At least one non-nodal lesion considered measurable by Response Evaluation Criteria in Solid Tumors (RECIST) criteria (that is, a lesion whose longest diameter can be accurately measured as ≥ 1.0 cm with computed tomography [CT] scan, CT component of a positron emission tomography [PET]/CT, or magnetic resonance imaging [MRI]) or at least one malignant lymph node is considered measurable by RECIST criteria (that is, its short axis is ≥ 1.5 cm when assessed by CT scan).
• NOTE: tumor lesions in a previously irradiated area are not considered measurable disease.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2.
• Provide informed written consent.
• Patient is willing to undergo treatment and monitoring at the enrolling institution.
• Willing to provide tissue and blood samples for correlative research purposes.

Inclusion Criteria
•Registration:

• Histologic or cytologic confirmation of unresectable stage III or metastatic melanoma (stage IV) not amenable to local therapy.
• Only if patient has had previous exposure to anti-PD-1 or anti-PD-L1 therapy:
  • Patient had disease progression on or within 6 months after anti-PD-1/anti-PD-L1 therapy in the metastatic setting; OR
  • Patient had disease progression within 6 months after the last dose of adjuvant/neoadjuvant anti-PD-1/anti-PD-L1 treatment.
• The following laboratory values obtained ≤ 14 days prior to registration:
  • Absolute neutrophil count (ANC) ≥ 1000/mm^3;
  • Platelet count ≥ 75,000/mm^3*;
  • Hemoglobin ≥ 9.0 g/dL;
  • Total bilirubin ≤ 1.5 X upper limit of normal (ULN); if total bilirubin > 1.5 X ULN then direct bilirubin ≤ ULN;
  • Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x ULN OR ≤ 5 X ULN for patients with liver metastases;
  • Creatinine ≤ 1.5 X ULN and CrCL ≥ 30 ml/min per Cockcroft Gault formula:
  • (140-Age) x Mass (in kilograms) x (0.85 if Female
    72 x Serum Creatinine (in mg/dL)
  • *Criteria must be met without a transfusion ≤ four weeks prior to registration.
• Patients of childbearing potential only: negative urine pregnancy test done ≤ 7 days prior to study registration.
• Absolute neutrophil ildbearing potential, negative urine pregnancy test done ≤ 7 days prior to study registration.

• 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 an anti-PD-1, or PD-L1 or PD-L2 agent or ipilimumab in the metastatic setting.
• Current use of warfarin or other vitamin K antagonists.
• Current use of a strong cytochrome P450 (CYP) 3A4/5 inhibitor or inducer.
• 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:
    • On ≤ 10 mg/day prednisone or equivalent for at least 28 days prior pre-registration;
    • Inactive (without evidence of progression which is documented by CT or MRI within 90 days prior to registration); AND
    • 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 Wilebrand?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 B or C according to the Child Pugh classification.

Exclusion Criteria
•Registration:

• 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]) within 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 days prior to registration.