Evaluate the Efficacy of MEDI4736 in Immunological Subsets of Advanced Colorectal Cancer
Condition: Advanced Colorectal Cancer
MeSH terms: Colorectal Neoplasms
Intervention: MEDI4736
Intervention description: Patients will be seen the day of administration of MEDI4736. A medical history, with particular reference to toxicities, including medication review, and physical examination will be conducted at each treatment visit.
Intervention MeSH terms: Durvalumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 16.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: MEDI4736; 14-109

Summary:

      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.
    

Eligibility criteria:

        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