Antibody Treatment for Advanced Celiac Disease
Condition: Celiac Disease; Celiac Sprue; Gluten Enteropathy; Gluten-Sensitive Enteropathy
MeSH terms: Celiac Disease; Intestinal Diseases
Study type: Interventional
Phase: Phase 1

Summary: 
      Background:

      - Celiac disease is a condition where the immune system attacks the cells of the small
      intestine. The intestine becomes inflamed and cannot digest food properly. The disease most
      often causes a reaction to foods that contain gluten. Most people can treat celiac disease
      with a gluten-free diet. However, some people have digestion problems even on a gluten-free
      diet. Researchers want to try a new antibody therapy for celiac disease. The treatment may
      block the immune reaction that causes the disease. They will test this antibody in people who
      have celiac disease that has not responded to a gluten-free diet.

      Objectives:

      - To see if antibody therapy is a safe and effective treatment for celiac disease that has
      not responded to standard treatments.

      Eligibility:

      - Individuals at least 18 years of age who have been on a gluten-free diet for 6 to 12 months
      but still have symptoms of celiac disease.

      Design:

        -  Participants will be screened with a physical exam and medical history. Blood samples
           will be collected. These samples will help determine if the specific antibody treatment
           is likely to work.

        -  Before the start of the study, participants will have a biopsy of the small intestine.

        -  Participants will receive three doses of the study antibody as injections. These doses
           will be given 3 weeks apart.

        -  Treatment will be monitored with blood tests and heart function tests. Participants will
           also have a second small intestine biopsy within a week after the last dose of the
           antibody.
    

Detailed description: 
      Background:

        -  Celiac disease is a complex inflammatory disorder with an autoimmune component
           characterized by a dramatic expansion of intraepithelial cytotoxic T lymphocytes that
           usually regress on a gluten-free diet.

        -  It is estimated that approximately 10% of patients become refractory on a gluten-free
           diet.

        -  A subgroup of refractory celiac disease is characterized by expansion of a highly
           oligoclonal intraepithelial T-lymphocyte population that exhibits a high risk of
           developing enteropathy associated T-cell lymphoma (EATL).

        -  There is presently no effective therapy for refractory celiac disease.

        -  A number of studies indicate that intestinal epithelial derived IL-15 plays a critical
           role in the disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis that
           characterizes refractory celiac disease.

        -  A pivotal role for IL-15 in refractory celiac disease and EATL is further supported by
           the finding that in two murine models of celiac disease the pathognomonic features were
           reversed completely by administration of an antibody to CD122 (IL-2/IL-15R beta) that
           blocks IL-15 transpresentation and action.

        -  A Phase I clinical trial in patients with T-cell LGL and hematocytopenia using the
           monoclonal antibody, Hu-Mik-Beta-1 that blocks IL-15 action produced under cGMP
           conditions by the BDP NCI has been completed in the Metabolism Branch, NCI at the
           Clinical Center NIH.

      Objectives:

      Primary Objectives:

        -  Phase I trial to define the safety of Hu-Mik-Beta-1 infusions to 2 groups of patients
           each with refractory celiac disease at escalating 0.5 (7 patients) and 1.0 (2 patients)
           mg/kg doses.

        -  To define the clinical efficacy of Hu-Mik-Beta-1 infusions in 9 patients with refractory
           celiac disease and to correlate these findings with celiac disease specific tests.

      Secondary Objectives:

        -  Definition of the receptor saturation capacity on CD122 (IL-2/IL-15R beta) of
           intravenously administered Hu-Mik-Beta-1 administered at 0.5 and 1.0 mg/kg body weight
           to 2 groups of patients on three occasions separated by 3 weeks in patients with
           refractory celiac disease.

        -  Determine the immunogenicity of intravenously administered Hu-Mik-Beta-1.

        -  Determine the effects of Hu-Mik-Beta-1 on the phenotype and the state of activation of
           the elements of the cellular immune system in the circulation and in intestinal biopsies
           with special focus on the cells implicated in the pathogenesis of celiac disease.

      Eligibility:

        -  Patients with refractory celiac disease (RCD) defined by the following internationally
           accepted criteria: persistent or recurrent symptoms (diarrhea, weight loss, and
           abdominal pain) associated with intestinal damage characterized by partial to total
           villous atrophy with intraepithelial lymphocytes (defined by >25 intraepithelial
           lymphocytes per 100 epithelial cells) despite strict adherence to a gluten-free diet for
           6-12 months.

        -  Lack of antibodies to Hu-Mik-Beta-1.

        -  Patients are not to have circulating antibodies to tissue transglutaminase that are
           greater than 10 assay units using recombinant human transglutaminase antibodies.

      Design:

        -  Patients will be enrolled and treated at the Mayo Clinic with the University of Chicago
           and the Clinical Center at the NIH involved as laboratory sites. This is a nonrandomized
           openlabel phase I trial.

        -  In this phase I trial initial patients are enrolled to receive 0.5 mg/kg of
           Hu-Mik-Beta-1 (3 patients). Patients receive Hu-Mik-Beta-1 every 3 weeks for a total of
           3 doses (given on day 1, week 3 and week 6). At specific points in time the patients are
           monitored (see below). If 1 or more of the 3 patients receiving 0.5 mg/kg of
           Hu-Mik-Beta-1 experience a NCI CTCAE version 4.0 grade 3 or greater toxicity with the
           exception of fatigue of >4days duration possibly, probably or definitely related to the
           infusion of Hu-Mik-Beta-1, subject enrollment and dosing is stopped.

        -  At the completion of Week 9, the safety data are reviewed by the Principal Investigator
           and DSMB. If the safety data in the 0.5 mg/kg cohort are acceptable, the Sponsor may
           then enroll additional patients in doses greater than 0.5 mg/kg, evaluated in a similar
           manner as the 0.5 mg/kg (e.g., 3 more patients to receive 1 mg/kg Hu-Mik-Beta-1 every 3
           weeks for a total of 3 doses.

        -  Modification: Three subjects completed study dosing with 0.5mg/kg without serious
           adverse events. Two subjects were then randomized to 1.0mg/kg dose and both experienced
           serious adverse events with a possible connection to the agent. Subject 5 experienced an
           event during the study, acute diverticulitis associated with free intraperitoneal air
           treated with antibiotics with resolution. Subject 4 who also received 1.0 mg / kg
           experienced a colon perforation many months after completing dosing associated with
           severe constipation. These events were reviewed by the DSMP. It was determined that even
           though direct cause and effect cannot be established because these occurred in subjects
           treated with the 1.0mg/kg that dose escalation be abandoned and the study completed with
           the lowest dose used 0.5mg/Kg. This modification proposed that any further subjects be
           recruited only at the 0.5mg/kg dose in the remaining 4 subjects.

      Monitoring:

      - At specific points in time the following cardiac tests/studies are obtained, the results
      reviewed prior to subsequent doses (at week 3 and week 6):

      i. EKG at screening (Week -4 to 0), Day 1, Week 3, Week 6 and Week 7.

      ii. CK-MB and troponin I at screening (Week -4 to 0), Day 1, Day 7, Week 3, Week 6, and Week
      7.

      In addition, an echocardiogram at screening (Week -4 to 0) and Week 7.

        -  FACS of peripheral blood mononuclear cells and peroral intestinal biopsies for
           expression of NKG2D, CD94, NKG2C, NKG2A, NKb44, NKb30, CD158 and granzyme.

        -  Immune profiling on intestinal biopsies performed on the first infusion and one week +
           or -3 days following the third infusion to analyze for CD8 T-cells, TCR gamma
           rearrangements by multiplex PCR and fluorescence analysis of CD8 and CD3 expression,
           high-resolution PCR expression for immunoglobulin gene rearrangement and for IEL, ERK
           and JNK phosphorylation reflecting abnormal IEL activation.

        -  Furthermore, IL-15, IL-15R alpha and interferon alpha expression will be assayed in the
           cells of the intestinal biopsy and in the serum.

        -  FACS of PBMCs with Hu-Mik-Beta-1 and Hu-Mik-Beta-3 to define saturation of CD122
           (IL2/IL-15R beta).

      Endpoints:

        -  Complete clinical response and by clinical biochemical results at the 20-week time
           point.

        -  Secondary partial response, duration of response, toxicities, immunogenicity of
           Hu-Mik-Beta- 1.
    

Intervention name(s): Hu-Mik- Beta-1
Intervention type(s): Biological
Intervention description(s): Hu-Mik-Beta-1 every 3 weeks for a total of 3 doses (given on day 1, week 3 and week 6)
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Anti CD 122; Monoclonal Antibody Therapy; Autoimmune Inflammatory Enteropathy