A Phase 1, Open-Label Study of Sirolimus in Eosinophil-Associated Gastrointestinal Disorders

Fecha de inicio: 7 de marzo de 2013

INCLUSION CRITERIA: Individuals will be eligible for study participation if they meet all of the following criteria: Age greater than or equal to18 years and less than or equal to 65 years at the time of Study Visit 1. Presence of the following diagnostic criteria for EGID: Subjects with EoE must have: 1) esophageal symptoms; 2) histologic evidence of esophageal tissue infiltration by eosinophils with a peak greater than or equal to25 eosinophils per high-powered field (while on greater than or equal to 2 months of twice daily proton-pump inhibitor therapy); and 3) no known etiology for the tissue eosinophilia despite careful clinical evaluation. Subjects with EG must have: 1) gastrointestinal symptoms; 2) histologic evidence of stomach or duodenal tissue infiltration by eosinophils with a peak greater than or equal to35 eosinophils per high-powered field; and 3) no known etiology for the tissue eosinophilia despite careful clinical evaluation. Blood AEC greater than or equal to 800 cells/microL at the screening visit. This screening value will not be used to calculate the baseline AEC used in the principal secondary endpoint. Baseline laboratory values within the following ranges: White blood cell count greater than or equal to3,300 cells/microL. Absolute neutrophil count greater than or equal to1,000 cells/microL. Hemoglobin greater than or equal to10 g/dL. Platelet count greater than or equal to100,000 platelets/microL. Three or more positive allergen-specific IgE tests (skin tests or in vitro assay) out of this panel of 10 food and aeroallergens: milk, eggs, wheat, soy, shrimp, cod, corn, peanut, dust mite, cat. Subjects currently on medication for their EGID or for GI symptoms must be on a stable dose for 1 month prior to screening and be willing to continue on that dose for the duration of the study. Other medications (e.g. for hypertension, asthma, or depression) may be adjusted by the subject s physician. Willingness to have samples stored for future research and genetic testing. Women of childbearing potential must have a negative serum beta-hCG. Agree to practice abstinence or effective contraception as detailed below. Contraception: The fetal risks associated with sirolimus are not known, but pre-clinical animal data demonstrate some risk. Subjects must agree not to become pregnant or impregnate a female, accordingly. Females of childbearing potential must have a pregnancy test at each NIH visit. Because of the risk involved, both male and female subjects and their partners must use 2 methods of birth control. As per the sirolimus package insert, subjects must continue to use both methods for 3 months after stopping the study drug. Two methods of birth control may be selected from the list included below: Hormonal contraception. Male or female condoms with or without a spermicidal. Diaphragm or cervical cap with a spermicidal. Intrauterine device. If pregnancy is suspected or should occur, subjects must notify the study staff immediately. EXCLUSION CRITERIA: Individuals will not be eligible to participate in this study if they meet any of the following criteria: Are breast feeding. Are HIV positive or have any other known immunodeficiency. Have used any investigational agent within 6 months of the screening visit. Express the FIP1L1-PDGF-R fusion gene. Have evidence of preexisting proteinuria with urine albumin-to-creatinine ratio >200 mg/g (men) or >300 mg/g (women). Have serum creatinine with estimated GFR <60 mL/min/1.73 m2. Have any chronic liver disease, including hepatitis B or C. Use of medications that have CYP3A4 or P-glycoprotein (P-gp) inhibitor or inducer activity. Are Taking ACE inhibitor medicatons Drug allergy or intolerance to allergies to sirolimus, other rapalogs, or excipients in the preparation. Have any condition that, as determined by the investigator, places the patient at undue risk by participating in the study.