Sirolimus for Autoimmune Disease of Blood Cells

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00392951
Recruitment Status : Active, not recruiting
First Posted : October 26, 2006
Results First Posted : December 6, 2017
Last Update Posted : December 6, 2017
Information provided by (Responsible Party):
Children's Hospital of Philadelphia

October 24, 2006
October 26, 2006
June 1, 2017
December 6, 2017
December 6, 2017
December 2006
February 2016   (Final data collection date for primary outcome measure)
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).

To define the toxicities of administration of oral sirolimus in children with ALPS
Complete list of historical versions of study NCT00392951 on Archive Site
  • 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.
  • 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
  • Effect of Sirolimus on Intracellular Targets [ Time Frame: 6 months ]
    Needs more specific information
  • 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).
  • To evaluate the efficacy of oral sirolimus in children with ALPS
  • To characterize the trough levels produced by administration of oral sirolimus in children with ALPS.
  • To evaluate the effect of sirolimus on intracellular targets
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Sirolimus for Autoimmune Disease of Blood Cells
Sirolimus for Patients With Chronic and/or Refractory Autoimmune Cytopenias: A Pilot Series
Treatment for patients with autoimmune destruction of blood cells is poor. The part of the body that fights infections is called the immune system and white blood cells (WBCs) are part of the immune system. Normally, a person's body creates WBCs to fight infections and eliminates WBCs which have stopped helping the body function. Patients with autoimmune destruction of blood cells have difficulty eliminating old WBCs. The abnormal WBCs build up and can damage other healthy cells, which can lead to anemia, fatigue, jaundice, internal bleeding, infection, and cancer. Few effective medications exist for treatment for patients with autoimmune cytopenias and those commonly used are fraught with side effects. Nevertheless, as scientific understanding of autoimmune diseases has improved, more directed and less toxic therapies are becoming available. A number of groups have been studying the efficacy of a medication called sirolimus in patients with autoimmune diseases. This medicine has been FDA-approved for over 20 years. Sirolimus is a medicine used in children with other diseases. Sirolimus works, in part, by eliminating old and abnormal WBCs. Our group and others have shown that sirolimus is effective in mice with autoimmunity and in children with a rare condition called Autoimmune Lymphoproliferative Syndrome (ALPS). We believe sirolimus will help children with autoimmune cytopenias. We believe it will improve their symptoms and make them less sick. We propose to study sirolimus in children with chronic and/or refractory autoimmune cytopenias.

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.

Phase 1
Phase 2
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
  • Autoimmune Pancytopenia
  • Autoimmune Lymphoproliferative Syndrome (ALPS)
  • Evans Syndrome
  • Idiopathic Thrombocytopenic Purpura
  • Anemia, Hemolytic, Autoimmune
  • Autoimmune Neutropenia
  • Lupus Erythematosus, Systemic
  • Inflammatory Bowel Disease
  • Rheumatoid Arthritis
Drug: sirolimus
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:
  • rapamycin
  • rapamune
Experimental: Sirolimus treatment
Sirolimus treatment
Intervention: Drug: sirolimus

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Active, not recruiting
February 2020
February 2016   (Final data collection date for primary outcome measure)

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)
Sexes Eligible for Study: All
1 Year to 30 Years   (Child, Adult)
Contact information is only displayed when the study is recruiting subjects
United States
Not Provided
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Children's Hospital of Philadelphia
Children's Hospital of Philadelphia
Not Provided
Principal Investigator: David T. Teachey, MD Children's Hospital of Philadelphia
Children's Hospital of Philadelphia
November 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP