The purpose of this study is to determine the safety and tolerability, describe the dose-limiting toxicities (DLTs), and determine the maximum tolerated dose (MTD) (or the highest protocol-defined dose level in the absence of establishing an MTD) of ibrutinib in combination with pembrolizumab in participants with advanced, refractory colorectal cancers.

On this study, one treatment cycle equals 21 days. On the first day of each study treatment cycle, 200 milligrams of pembrolizumab will be given through an IV (intravenously) for about thirty minutes. In addition, participants will begin taking the ibrutinib capsules every day starting on cycle 1, day 1. Participants will have a follow-up visit every 3 weeks, on about the first day of each cycle with laboratories drawn to make sure that the study drugs are not causing any side effects. In addition, participants will have a computed tomography (CT) scan every 6 to 7 weeks to determine whether your cancer is getting better or worse.

Inclusion Criteria:

• Histologically confirmed diagnosis of colorectal adenocarcinoma.

• Measurable or non-measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Stage IV or recurrent disease is required.

• Participants must have received and progressed through or become intolerant to fluoropyrimidine, irinotecan, oxaliplatin, and bevacizumab. If RAS wild type, participants should have received and progressed or become intolerant to the above as well as cetuximab or panitumumab containing therapies. Prior therapy with Regorafenib and/or TAS 102 is allowed.

• Eastern Cooperative Oncology Group (ECOG) Performance Score 0 or 1.

• Estimated life expectancy > 3 months.

• Adequate bone marrow, liver and renal function as assessed by the following:

  • Hemoglobin > 8.0 g/dl
  • Absolute neutrophil count (ANC) > 1,000/mm^3 independent of growth factor support
  • Platelet count > 100,000/mm^3
  • Total bilirubin < 1.5 times upper limit of normal (ULN) unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin
  • AST, ALT and Alkaline Phosphatase ≤2.5 times the ULN ( ≤5 x ULN for potential participants with liver involvement)
  • Creatinine clearance ≥ 30 ml/min

• Must not have had chemotherapy, major surgery, monoclonal antibody therapy or experimental therapy within the 21 days prior to the start of ibrutinib administration

• Women of childbearing potential must have a negative serum or urine pregnancy test performed within 7 days prior to the start of study drug. Post-menopausal women and surgically sterilized women are not required to undergo a pregnancy test.

• Men and women of childbearing potential must agree to use adequate contraception beginning at the signing of the informed consent form (ICF) until at least 4 months for both females and males after the last dose of study drug. The definition of adequate contraception will be based on the judgment of the principal investigator or a designated associate.

• Must agree to not donate sperm (males) or eggs (females) during and up to 120 days after the last dose of study treatment.

• Must be able to understand and be willing to sign the written informed consent form. A signed informed consent form must be appropriately obtained prior to the conduct of any trial-specific procedure. Must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other study requirements.

Exclusion Criteria:

• Active central nervous system (CNS) metastases. If CNS metastases are treated and patients are at neurologic baseline for at least 2 weeks prior to enrollment, they will be eligible but will need a Brain MRI prior to enrollment. Must be off corticosteroids or on a dose of less than 10mg per day.
• Active, known or suspected autoimmune disease. Patients with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
• A condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of enrollment. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
• Prior therapy with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell costimulation or checkpoint pathways).
• Prior therapy with ibrutinib or other BTK inhibitors.
• Previous or concurrent cancer within 3 years prior to treatment start EXCEPT for curatively treated cervical cancer in situ, non-melanoma skin cancer, superficial bladder tumors [Ta (non-invasive tumor), Tis (carcinoma in situ) and T1 (tumor invades lamina propria)].
• Known history of human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS).
• Serologic status reflecting active hepatitis B or C infection. Patients who are hepatitis B core antibody positive and who are antigen negative, will need to have a negative PCR result prior to enrollment. Those who are hepatitis B antigen positive or PCR positive, will be excluded.
• Child Pugh B or C cirrhosis.
• History of severe hypersensitivity reactions to other monoclonal antibodies.
• Substance abuse, medical, psychological or social conditions that may interfere with participation in the study or evaluation of the study results.
• History or concurrent condition of interstitial lung disease of any grade or severely impaired pulmonary function.
• Unresolved toxicity higher than CTCAE grade 1 attributed to any prior therapy or procedure, excluding alopecia.
• Clinically significant cardiovascular disease such as uncontrolled or symptomatic 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 the small bowel, or poorly controlled inflammatory bowel disease affecting the small intestine.
• Requires anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon).
• Requires treatment with a strong CYP3A4/5 and/or CYP2D6 inhibitor.
• History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
• Any illness or medical conditions that are unstable or could jeopardize the safety of the participant and his/her compliance in the study.
• Major surgery or a wound that has not fully healed within 4 weeks of enrollment.
• Vaccinated with live, attenuated vaccines within 4 weeks of enrollment.
• History of (non-infectious) pneumonitis that required steroids or current pneumonitis within 6 months.

All participants who consented to study.

1 year, 5 months

Includes only participants who received at least one dose of study drugs.