The purpose of this study is to find out what effects, good and/or bad, MEDI4736 has on the patient and cancer.

MEDI4736 is a type of medication called an antibody. Antibodies are normal proteins in the body that help fight infections and possibly cancer. MEDI4736 is a special type of an antibody produced in a laboratory. MEDI4736 works by blocking a specific protein called the Programmed Death Ligand-1 (PDL-1), located on tumor cells.

Inclusion Criteria:

• Written informed consent obtained.
• Histologically- or cytologically- confirmed CRC.
• Microsatelite-high colorectal cancer (also known as MSI-H, DNA mismatch repair deficient, or sometimes Lynch syndrome); or increased Tumor-Infiltrating Lymphocytes in an archived tumor specimen or fresh biopsy.
• Locally advanced or metastatic CRC
• Subjects have received two or more standard available therapies known to prolong survival and for which they would be considered eligible. At a minimum, such therapies should include regimens containing oxaliplatin and irinotecan in combination with a fluoropyrimidine (e.g., FOLFOX and FOLFIRI or their variants).
• Age ≥ 18 years at time of study entry.
• Eastern Cooperative Oncology Group (ECOG) status of 0 or 1
• Adequate organ and marrow function as defined below:
• Absolute neutrophil count ≥ 1,500/mm3.
• Platelet count ≥ 90,000/mm3.
• AST and ALT ≤ 3 × institutional upper limit of normal (ULN) or ≤ 5 × ULN for subjects with liver metastases.
• Bilirubin ≤ 1.5 × ULN or ≤ 3 × ULN for subjects with documented/suspected Gilbert's disease.
• Serum creatinine ≤ 1.5 x ULN;
• Radiographically measurable disease per RECIST 1.1.
• Life expectancy ≥ 16 weeks.
• Willingness to provide consent for use of archived tissue for research purposes.
• Subjects will be required to agree to a biopsy performed at baseline and again at week 8 of the study in order to be eligible for enrollment in stage 1 of the study
• Females of childbearing potential who are sexually active with a nonsterilized male partner must use 2 methods of effective contraception from screening, and must agree to continue using such precautions for 90 days after the final dose of investigational product; cessation of birth control after this point should be discussed with a responsible physician. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control.
• Females of childbearing potential are defined as those who are not surgically sterile (ie, bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or postmenopausal (defined as 12 months with no menses without an alternative medical cause).
• Subjects must use 2 acceptable methods of effective contraception as described in below.
• Nonsterilized males who are sexually active with a female partner of childbearing potential must use 2 acceptable methods of effective contraception from Day 1 and for 90 days after receipt of the final dose of investigational product.

Exclusion Criteria:

• Anticancer therapy, monoclonal antibody or major surgery within 4 weeks prior to the first dose of MEDI4736.
• Concurrent use of hormones for non-cancer-related conditions (e.g., insulin for diabetes and hormone replacement therapy) is acceptable.
• Any prior Grade ≥ 3 irAE while receiving immunotherapy (including anti-CTLA-4 or anti-CD137 MAb) or any unresolved irAE of any grade (controlled irAE endocrinopathies are allowed).
• Prior exposure to any anti-PD-1 or anti-PD-L1 antibody.
• Current or prior use of immunosuppressive medication within 28 days before the first dose of MEDI4736, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid.
• Any unresolved toxicity CTCAE >Grade 2 from previous anti-cancer therapy.
• Active autoimmune disease within the past 2 years, except for mild conditions not requiring systemic treatment, such as vitiligo.
• Any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment. NOTE: Local treatment of isolated lesions, excluding target lesions, for palliative intent is acceptable (e.g., by local ablation, surgery or radiotherapy).
• Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, irritable bowel syndrome, ulcerative colitis).
• Receipt of radiation therapy within 4 weeks prior to starting investigational product, or limited field of radiation for palliation within 2 weeks of the first dose of investigational product.
• Known allergy or reaction to any component of the MEDI4736 formulation or its excipients.
• Known central nervous system (CNS) metastases requiring treatment, such as surgery, radiation or steroids.
• Known history of confirmed primary immunodeficiency.
• History of organ transplant requiring therapeutic immunosuppression.
• Other malignancy within 3 years, except for noninvasive malignancies such as cervical carcinoma in situ (CIS), non-melanomatous carcinoma of the skin or ductal carcinoma in situ (DCIS) of the breast that has/have been surgically cured, or prior malignancy considered by the investigator to be of low likelihood for recurrence.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses including any patient known to have active hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the patient to give written informed consent.
• Women who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control.
• Any other condition(s) that, in the opinion of the investigator, would interfere with evaluation of the investigational product or interpretation of subject safety or study results.
• Subjects who are known to be HIV positive.
• Receipt of live attenuated vaccination within 30 days prior to receiving MEDI4736

2 years