Antibody Treatment for Advanced Celiac Disease
Antibody Treatment for Advanced Celiac Disease
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.
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.
-  INCLUSION CRITERIA

 2.1.1.1 Patients must be greater than or equal to 18-years-old.

 2.1.1.2 All patients must have a pathologically confirmed diagnosis of refractory celiac
 disease(RCD) defined by internationally accepted criteria of persistent and 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.

 2.1.1.3 Persistence of the above signs and symptoms despite strict adherence to a
 gluten-free diet for 6-12 months

 2.1.1.4 Patients are to have had circulating antibodies to transglutaminase-1 or similar
 celiac specific serology

 2.1.1.5 Patients must have a life expectancy of > 3 months

 2.1.1.6 Patients must have a creatinine of less than 2.0 mg/dL or if the patient has an
 elevated creatinine measured creatinine clearance (Ccr) must be > 60 mL/min/1.73m(2)

 2.1.1.7 Patients must have a serum alkaline phosphatase, ALT (SGPT) and AST (SGOT) less
 than 3x the upper limits of normal (ULN)

 2.1.1.8 Patients must have a total bilirubin of less than 2.5 x ULN

 2.1.1.9 Women of childbearing potential must have a negative beta HCG pregnancy test at
 initial screening and within 3 days prior to registration

 2.1.1.10 Patients receiving a stable dose (> 4 weeks) of corticosteroid therapy equal to 20
 mg of prednisone per day or less are eligible

 2.1.1.11 Patients with a history of curatively treated basal cell carcinoma or
 intraepithelial neoplasia of the uterine surface will be allowed on the study

 2.1.1.12 Patients must be able to understand and sign an informed consent

 EXCLUSION CRITERIA

 2.1.2.1 Patients enrolled in another therapeutic study

 2.1.2.2 Patients with a history of venous thrombosis

 2.1.2.3 Patients with antibodies to Hu-Mik-Beta-1

 2.1.2.4 A contraindication to monoclonal antibody therapy including adverse events related
 to prior monoclonal antibody therapy. Patients who have received prior antibody therapy
 will have permanent medical records reviewed by the study investigator.

 2.1.2.5 Any uncontrolled or chronic bacterial, mycobacterial or other viral (e.g., herpes
 virus), fungal, parasitic or protozoal infection

 2.1.2.6 History of malignancy (active or within the previous 5 years)

 2.1.2.7 Patients with HIV infection (antibody positive) with positive confirmatory
 molecular tests

 2.1.2.8 Patients who have chronic hepatitis B or chronic hepatitis C

 2.1.2.9 Pregnant or breastfeeding women. Women who not using an acceptable method of
 contraception. Acceptability of various methods of contraception will be determined by the
 investigator. Postmenopausal or surgically sterile women who have documentation of
 postmenopausal status or surgical sterility availability prior to enrollment.

 2.1.2.10 Patients with significant co-morbidities including uncontrolled hypertension
 (diastolic B/P > 115 mm/Hg), unstable angina, congestive heart failure (> N.Y.H.A. Class
 II), poorly controlled diabetes, severe chronic pulmonary disease, coronary angioplasty or
 myocardial infarction within the last 6 months or uncontrolled atrial or ventricular
 cardiac arrhythmias.

 2.1.2.11 Abnormal screening/baseline tests exceeding the limits outlined below:

 -  Total white blood cell count (WBC) <300/mm(3)

 -  Platelet count <85,000/mm(3)

 -  INR greater than or equal to 1.5

 -  Serum creatinine level > 1.5 mg/dL

 -  Serum alanine transaminase, aspartate transaminase or creatinine kinase > 2 x the
 upper limits of normal

 2.1.2.12 Patients with a history of a psychiatric disorder that may interfere with the
 understanding and compliance with this protocol, and the required follow-up

 2.1.2.13 Exclusion at the discretion of the PI or delegate if participation in the study is
 deemed too risky (e.g., clinically significant pleural or pericardial effusion or ascites)

 2.1.2.14 Inability to give informed consent

 2.1.2.15 History of diverticulitis