Pembrolizumab in Combination With Ibrutinib for Advanced, Refractory Colorectal Cancers

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 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.