Trial of Ibrutinib Combined With Nivolumab or Cetuximab to Treat Recurrent/Metastatic HNSCC

Inclusion Criteria: \- To be enrolled in the study, each potential subject must satisfy all of the following inclusion criteria. 1. Histologically or cytologically proven squamous cell carcinoma of the head and neck not amenable to curative intent therapy. P16 or HPV status must be known on all patients with oropharyngeal primaries or unknown primaries. 2. Known p16 and/or HPV status by institutional standard. 3. Presence of measurable tumor lesions per RECIST criteria v1.1 by investigator review 4. Life expectancy greater than 12 weeks 5. Previously archived or newly obtained tumor specimens for correlative analysis 6. Adequate hematologic function independent of transfusion and growth factor support for at least 7 days prior to screening and randomization, with the exception of pegylated G-CSF (pegfilgrastim) and darbepoetin which require at least 14 days prior to screening and randomization defined as: * Absolute neutrophil count \>750 cells/mm3 (0.75 x 109/L). * Platelet count \>50,000 cells/mm3 (50 x 109/L). * Hemoglobin \>8.0 g/dL. 7. Adequate hepatic and renal function defined as: * Serum aspartate transaminase (AST) or alanine transaminase (ALT) ≤ 3.0 x upper limit of normal (ULN). * Estimated Creatinine Clearance ≥30 ml/min (Cockcroft-Gault) * Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin) 8. PT/INR \<1.5 x ULN and PTT (aPTT) \<1.5 x ULN 9. Men and women ≥ 18 years of age. 10. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. 11. Female subjects who are of non-reproductive potential (ie, post-menopausal by history - no menses for ≥1 year; OR history of hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral oophorectomy). Female subjects of childbearing potential must have a negative serum pregnancy test upon study entry. 12. Male and female subjects who agree to use highly effective methods of birth control (eg, , implants, injectables, combined oral contraceptives, some intrauterine devices \[IUDs\], complete abstinence, or sterilized partner) and a barrier method (eg., condoms, vaginal ring, sponge, etc) during the period of therapy and for for 30 days after the last dose of study drug for females and 90 days for males.Ability and willingness to provide written informed consent Exclusion Criteria: \- To be enrolled in the study, potential subjects must meet NONE of the following exclusion criteria: 1. Prior therapy with an EGFR inhibitor in the recurrent or metastatic setting 2. Nasopharyngeal carcinoma histology 3. Known, clinically active central nervous system metastases (stable metastases permitted) 4. Chemotherapy ≤ 28 days prior to first administration of study treatment and/or monoclonal antibody (including immunotherapy) ≤16 weeks prior to first administration of study treatment. 5. Prior exposure to BTK inhibitor, PD-1 inhibitor, or PD-L1 inhibitor 6. History of other malignancies, except: * Malignancy treated with curative intent and with no known active disease present for ≥3 years before the first dose of study drug and felt to be at low risk for recurrence by treating physician. * Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease. * Adequately treated carcinoma in situ without evidence of disease. 7. Concurrent systemic immunosuppressant therapy (eg, cyclosporine A, tacrolimus, etc., or chronic administration \[\>14 days\] of \>10 mg/day of prednisone) within 28 days of the first dose of study drug. 8. Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug. 9. Recent infection requiring systemic treatment that was completed ≤14 days before the first dose of study drug. 10. Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved to Common Terminology Criteria for Adverse Event (CTCAE v4.0), Grade ≤1, or to the levels dictated in the inclusion/exclusion criteria with the exception of alopecia. 11. Known bleeding disorders (eg, von Willebrand's disease) or hemophilia. 12. History of stroke or intracranial hemorrhage within 6 months prior to enrollment. 13. Known history of human immunodeficiency virus (HIV) or active with hepatitis C virus (HCV) or hepatitis B virus (HBV). Subjects who are positive for hepatitis B core antibody, hepatitis B surface antigen, or hepatitis C antibody must have a negative polymerase chain reaction (PCR) result before enrollment. Those who are PCR positive will be excluded. 14. Any uncontrolled active systemic infection. 15. Any history of interstitial lung disease. 16. Active autoimmune disease or other contraindication to PD-1 inhibition. 17. Major surgery within 4 weeks of first dose of study drug. 18. Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator's opinion, could compromise the subject's safety or put the study outcomes at undue risk. 19. 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 within 6 months prior to randomization. 20. Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction. 21. Concomitant use of warfarin or other Vitamin K antagonists. 22. Requires treatment with a strong cytochrome P450 (CYP) 3A inhibitor 23. Currently active, clinically significant hepatic impairment Child-Pugh Class B or C according to the Child-Pugh Classification 24. Lactating or pregnant. 25. Unwilling or unable to participate in all required study evaluations and procedures. 26. Unable to understand the purpose and risks of the study and to provide a signed and dated informed consent form (ICF) and authorization to use protected health information (in accordance with national and local subject privacy regulations).