Sirolimus for Autoimmune Disease of Blood Cells

NCT00392951 | Completed Phase 1 Results

• 1 other identifier: 2006-7-4873
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Autoimmune Pancytopenia; Autoimmune Lymphoproliferative Syndrome (ALPS); Evans Syndrome; Idiopathic Thrombocytopenic Purpura; Anemia, Hemolytic, Autoimmune; Autoimmune Neutropenia; Lupus Erythematosus, Systemic; Inflammatory Bowel Disease; Rheumatoid Arthritis

Keywords

ALPS; Autoimmune; Cytopenias; Treatment; Sirolimus; Rapamycin; Lymph Nodes; Spleen; Hemolytic Anemia; Immune Thrombocytopenia; Neutropenia; ITP; Lupus

Outcome Measures

Primary Outcomes (1)

• Number of Participants With Grade 3 and 4 Toxicities of Administration of Oral Sirolimus

  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 Outcomes (4)

• Number of Participants With Autoimmune Disease Response to Oral Sirolimus

  6 months

• Trough Levels Produced by Administration of Oral Sirolimus

  Within first 5 days of starting sirolimus

• Effect of Sirolimus on Intracellular Targets

  6 months

• Number of Participants With Lymphoproliferation Response to Oral Sirolimus

  6 months

Study Arms (1)

Sirolimus treatment

EXPERIMENTAL

Sirolimus treatment

Drug: sirolimus

Interventions

sirolimus DRUG

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)

Also known as: rapamycin, rapamune

Sirolimus treatment

Eligibility Criteria

• Age: 1 Year - 30 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Children's Hospital of Philadelphia: lead

Study Sites (1)

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

Related Publications (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.

  PMID: 16757690 BACKGROUND

• 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.

  PMID: 15542578 BACKGROUND

• 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.

  PMID: 19208097 RESULT

• 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.

  PMID: 26504182 RESULT

MeSH Terms

Conditions

Autoimmune Lymphoproliferative Syndrome; Evans Syndrome; Purpura, Thrombocytopenic, Idiopathic; Anemia, Hemolytic, Autoimmune; Lupus Erythematosus, Systemic; Inflammatory Bowel Diseases; Arthritis, Rheumatoid; Cytopenia; Anemia, Hemolytic; Neutropenia

Interventions

Sirolimus

Condition Hierarchy (Ancestors)

Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Autoimmune Diseases; Immune System Diseases; Immunoproliferative Disorders; Purpura, Thrombocytopenic; Purpura; Blood Coagulation Disorders; Hematologic Diseases; Thrombotic Microangiopathies; Thrombocytopenia; Blood Platelet Disorders; Hemorrhagic Disorders; Hemorrhage; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Skin Manifestations; Signs and Symptoms; Anemia; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Intestinal Diseases; Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Agranulocytosis; Leukopenia; Leukocyte Disorders

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals

Results Point of Contact

• Title: David T. Teachey, MD
• Organization: Children's Hospital of Philadelphia

teacheyd@email.chop.edu

267-426-5802

Study Officials

• David T. Teachey, MD

  Children's Hospital of Philadelphia

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 24, 2006
• First Posted: October 26, 2006
• Study Start: December 1, 2006
• Primary Completion: February 1, 2016
• Study Completion: February 1, 2016
• Last Updated: November 19, 2019
• Results First Posted: December 6, 2017

Record last verified: 2019-11

Locations

US (1)