- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00392951
Sirolimus for Autoimmune Disease of Blood Cells
Sirolimus for Patients With Chronic and/or Refractory Autoimmune Cytopenias: A Pilot Series
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Patients with autoimmune destruction of hematopoietic cells frequently have severe and debilitating disease requiring aggressive and frequent medical management. These patients are often treated with non-specific immunosuppressive medications with limited efficacy and untoward side-effect profiles. We have been investigating the use of an immunosuppressive and anti-cancer agent, sirolimus in patients with an autoimmune cytopenias syndrome: Autoimmune Lymphoproliferative Syndrome (ALPS). ALPS is a primary immune deficiency caused by mutations in the Fas apoptotic pathway, leading to abnormal lymphocyte survival. Clinical manifestations in patients with ALPS typically include autoimmune cytopenias, lymphadenopathy, hepatosplenomegaly, and a propensity to develop secondary malignancies. Thus, far we have found excellent results albeit the total number of patients treated is small.
Sirolimus is a signal transduction inhibitor with a tolerable side effect profile. Sirolimus has two properties making it an attractive agent to treat patients with autoimmune cytopenias syndromes, including ALPS. First, sirolimus induces apoptosis in normal and abnormal white blood cells, the cell type dysregulated in patients with autoimmune disease. In addition, sirolimus increases a T cell subset called Regulatory T cells (Tregs). Tregs are a cell population designed to suppress the immune system and control autoimmunity. These combined properties make sirolimus unique as compared with other immunosuppressive agents. Ample preclinical and clinical data exists demonstrating sirolimus in effective in patients with autoimmunity. Accordingly, we hypothesize sirolimus is a safe and efficacious medication for patients with autoimmune destruction of blood cells..
We plan to confirm our hypotheses by performing a pilot series in children with autoimmune cytopenias who are either refractory to standard therapy or have significant toxicity from standard treatments. Our primary aim is to define the toxicities of administration of oral sirolimus in children with autoimmune cytopenias. Our secondary aims are to evaluate the efficacy of sirolimus in children with autoimmune cytopenias, to determine the trough levels of sirolimus when used in these patients, and to evaluate the effects of sirolimus on intracellular targets of mammalian target of rapamycin (mTOR). We intend to enroll 50 children with autoimmune cytopenias and treat for a 6 month period, however, if we find sirolimus is effective, we anticipate these children will continue to take sirolimus for a longer period of time. We anticipate the results of this work will establish sirolimus is an effective and well tolerated medication and will lead directly to a larger national phase II clinical trial.
Study Type
Enrollment (Actual)
Phase
- Phase 2
- Phase 1
Contacts and Locations
Study Locations
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-
Pennsylvania
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Philadelphia, Pennsylvania, United States, 19104
- Children's Hospital of Philadelphia
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Age > 12 months and < 30 years at the time of study entry
- Diagnosis of autoimmune cytopenias requiring treatment with medications
- At least one of the following: Autoimmune Neutropenia, Autoimmune Hemolytic Anemia, and/or Autoimmune Thrombocytopenia
- Must be proven autoimmune by either a documented autoantibody (positive direct anti globulin test, positive anti-neutrophil, and/or anti-platelet antibody) and/or a documented clinical response to immunosuppression
- Autoimmune Cytopenias can be idiopathic (Idiopathic Thrombocytopenic Purpura (ITP), Autoimmune Hemolytic Anemia (AIHA), Autoimmune Neutropenia (AIN), or Evans syndrome) or secondary to one of following conditions: Lupus, Rheumatoid Arthritis (RA), ALPS (Autoimmune Lymphoproliferative Syndrome), or Inflammatory bowel disease (IBD)
- Patients must have chronic disease diagnosed by either a documented cytopenia syndrome (Lupus, ALPS, RA, or IBD), or by having Evans syndrome defined as idiopathic destruction of multiple blood cell types, and/or by having disease >6 months
- Patients must be refractory to or unable to tolerate standard front-line therapies for autoimmune cytopenias (corticosteroids and/or IVIG)
- Patients may be taking second-line agents for autoimmune cytopenias (mycophenolate mofetil, cyclosporine, tacrolimus, mercaptopurine, and/or methotrexate) at time of study entry; however, attempts should be made to wean these agents. Patients may not stay on a combination of sirolimus and a calcineurin inhibitor for greater than 4 weeks
- Informed consent/assent must be obtained prior to initiating treatment
- Patient must be able to consume oral medication in the form of tablets or solution
Exclusion Criteria:
- Pregnancy or breast feeding
- Uncontrolled infection
- Known allergy to Sirolimus or its components
- Patients with a documented malignancy on therapy or not in remission
- Patients who do not meet organ function requirements listed in protocol
- Patients with a documented history of severe combined immunodeficiency or human immunodeficiency virus infection (HIV)
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Sirolimus treatment
|
Tablet or liquid; taken once or twice daily; dosage is based on establishing a serum trough of 5-15 ng/ml by high-performance liquid chromatography (initial loading dose of 3 mg/m2 then 2.5 mg/m2 with adjustment based on serum trough)
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Number of Participants With Grade 3 and 4 Toxicities of Administration of Oral Sirolimus
Time Frame: 6 months
|
Grade 3 toxicities are those that are considered severe or medically equivalent requiring hospitalization or prolonged hospitalization (according to CTCAE criteria 3.0). Grade 4 toxicities are those that are life-threatening (urgent intervention indicated) (according to CTCAE criteria 3.0). |
6 months
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Number of Participants With Autoimmune Disease Response to Oral Sirolimus
Time Frame: 6 months
|
Complete response (CR) is complete resolution in all autoimmune cytopenias (neutropenia, anemia thrombocytopenia) maintained for more than two months, combined with an ability to wean off corticosteroids and/or other immunosuppressive medication.
Partial response (PR) is improvement in any cytopenias by at least one grade, lasting more than two months, without worsening any other cytopenias or stable disease with the ability to wean corticosteroids and/or immunosuppressive medications by at least 50%.
No response (NR) is no change in cytopenias with treatment, and the inability to wean corticosteroids or other immunosuppressive medications.
Progressive disease (PD) refers to obtaining a CR or PR by the 3 month observation and relapsing or progressing by the 6 month observation, leading to cessation of study drug.
|
6 months
|
Trough Levels Produced by Administration of Oral Sirolimus
Time Frame: Within first 5 days of starting sirolimus
|
Pharmacokinetic levels produced by administration of oral sirolimus
|
Within first 5 days of starting sirolimus
|
Effect of Sirolimus on Intracellular Targets
Time Frame: 6 months
|
Needs more specific information
|
6 months
|
Number of Participants With Lymphoproliferation Response to Oral Sirolimus
Time Frame: 6 months
|
Complete response (CR) is complete resolution of any lymphadenopathy and splenomegaly for at least two months.
Partial response (PR) is a reduction in size of at least 50% of lymphadenopathy or splenomegaly for at least two months.
No response (NR) is no change or < 50% reduction in lymphadenopathy or splenomegaly.
Progressive Disease (PD) is obtaining a CR or PR by the 3 month observation and relapsing or progressing by the 6 month observation, leading to cessation of study drug.
Not Applicable (N/A) is there is no evidence of disease (No pathologic lymphadenopathy or splenomegaly at time of enrollment).
|
6 months
|
Collaborators and Investigators
Investigators
- Principal Investigator: David T. Teachey, MD, Children's Hospital of Philadelphia
Publications and helpful links
General Publications
- Bride KL, Vincent T, Smith-Whitley K, Lambert MP, Bleesing JJ, Seif AE, Manno CS, Casper J, Grupp SA, Teachey DT. Sirolimus is effective in relapsed/refractory autoimmune cytopenias: results of a prospective multi-institutional trial. Blood. 2016 Jan 7;127(1):17-28. doi: 10.1182/blood-2015-07-657981. Epub 2015 Oct 26.
- Teachey DT, Greiner R, Seif A, Attiyeh E, Bleesing J, Choi J, Manno C, Rappaport E, Schwabe D, Sheen C, Sullivan KE, Zhuang H, Wechsler DS, Grupp SA. Treatment with sirolimus results in complete responses in patients with autoimmune lymphoproliferative syndrome. Br J Haematol. 2009 Apr;145(1):101-6. doi: 10.1111/j.1365-2141.2009.07595.x. Epub 2009 Feb 4.
- Teachey DT, Obzut DA, Axsom K, Choi JK, Goldsmith KC, Hall J, Hulitt J, Manno CS, Maris JM, Rhodin N, Sullivan KE, Brown VI, Grupp SA. Rapamycin improves lymphoproliferative disease in murine autoimmune lymphoproliferative syndrome (ALPS). Blood. 2006 Sep 15;108(6):1965-71. doi: 10.1182/blood-2006-01-010124. Epub 2006 Jun 6.
- Teachey DT, Manno CS, Axsom KM, Andrews T, Choi JK, Greenbaum BH, McMann JM, Sullivan KE, Travis SF, Grupp SA. Unmasking Evans syndrome: T-cell phenotype and apoptotic response reveal autoimmune lymphoproliferative syndrome (ALPS). Blood. 2005 Mar 15;105(6):2443-8. doi: 10.1182/blood-2004-09-3542. Epub 2004 Nov 12.
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Digestive System Diseases
- Pathologic Processes
- Immune System Diseases
- Lymphoproliferative Disorders
- Lymphatic Diseases
- Immunoproliferative Disorders
- Autoimmune Diseases
- Disease
- Hematologic Diseases
- Gastrointestinal Diseases
- Hemorrhage
- Hemorrhagic Disorders
- Genetic Diseases, Inborn
- Connective Tissue Diseases
- Gastroenteritis
- Intestinal Diseases
- Anemia
- Blood Coagulation Disorders
- Skin Manifestations
- Thrombocytopenia
- Blood Platelet Disorders
- Agranulocytosis
- Leukopenia
- Leukocyte Disorders
- Thrombotic Microangiopathies
- Syndrome
- Lupus Erythematosus, Systemic
- Inflammatory Bowel Diseases
- Purpura
- Purpura, Thrombocytopenic
- Neutropenia
- Purpura, Thrombocytopenic, Idiopathic
- Pancytopenia
- Hemolysis
- Anemia, Hemolytic
- Anemia, Hemolytic, Autoimmune
- Autoimmune Lymphoproliferative Syndrome
- Physiological Effects of Drugs
- Anti-Infective Agents
- Antineoplastic Agents
- Immunosuppressive Agents
- Immunologic Factors
- Anti-Bacterial Agents
- Antibiotics, Antineoplastic
- Antifungal Agents
- Sirolimus
Other Study ID Numbers
- 2006-7-4873
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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