Phase II Trial of Combination Immunotherapy in Subjects With Advanced Small Bowel and Colorectal Cancers

-INCLUSION CRITERIA:

• Subjects with cytologically or histologically confirmed locally advanced or metastatic small bowel or colorectal adenocarcinoma
• Subjects must have received two prior lines of systemic therapy unless the subject is not eligible to receive standard therapy or declines standard treatment
• Subjects must have measurable disease
• Eastern Cooperative Oncology Group (ECOG) performance status =1 x 10^9/L
• Hemoglobin >= 9 g/dL
• Platelets >= 75,000/microliter
• Adequate renal and hepatic function at screening, as follows:
• Serum creatinine = 40 mL/min for participant with creatinine levels > 1.5 X institutional ULN (glomerular filtration rate (GFR) can also be used in place of creatinine or creatinine clearance (CrCl);
• Bilirubin = 200 cells per cubic millimeter at enrollment, be on stable antiretroviral therapy for at least 4 weeks and have no reported opportunistic infections or Castleman s disease within 12 months prior to enrollment.
• Ability of subject to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA

• Participants with prior investigational drug, chemotherapy, immunotherapy or any prior radiotherapy (except for palliative bone directed therapy) within the past 28 days prior to the first drug administration except if the investigator has assessed that all residual treatment-related toxicities have resolved or are minimal and feel the participant is otherwise suitable for enrollment. Additionally, current therapies (e.g., maintenance capecitabine) may be continued where in the opinion of the investigator stopping such therapies may increase the risk of disease progression. Also, participants may continue adjuvant hormonal therapy in the setting of a definitively treated cancer (e.g., breast).
• Participants with microsatellite unstable or mismatch repair deficient disease.
• Major surgery within 28 days prior to the first drug administration (minimally invasive procedures such as diagnostic biopsies are permitted).
• Known life-threatening side effects resulting from prior checkpoint inhibitor therapy (e.g., colitis, pneumonitis, fulminant hepatitis which led to permanent discontinuation of prior checkpoint therapy). Autoimmune toxicity which was not life threatening (e.g., arthritis) or did not lead to discontinuation of prior checkpoint therapy is allowed.
• Known active brain or central nervous system metastasis (less than a month out from definitive radiotherapy or surgery), seizures requiring anticonvulsant treatment ( 14 days). In addition, the use of corticosteroids as premedication for contrast-enhanced studies is allowed prior to enrollment and on study.
• Subjects with a history of serious intercurrent chronic or acute illness, such as cardiac or pulmonary disease, hepatic disease, bleeding diathesis or recent (within 3 months) clinically significant bleeding events or other illness considered by the Investigator as high risk for investigational drug treatment.
• Subjects unwilling to accept blood products as medically indicated.
• History of second malignancy within 3 years of enrollment except for the following: adequately treated localized skin cancer, cervical carcinoma in situ, superficial bladder cancer, or other localized malignancy which has been adequately treated or malignancy which does not require active systemic treatment (e.g., low risk chronic lymphocytic leukemia (CLL).
• Subjects with a known severe hypersensitivity reaction to a monoclonal antibody (grade >= 3 National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE v5) will be evaluated by the allergy/immunology team prior to enrollment.
• Receipt of any organ transplantation requiring ongoing immunosuppression.
• Receipt of prior lymphodepleting chemotherapy (e.g., cyclophosphamide or fludarabine at standard lymphodepleting doses).