A Phase 1/2 interventional study of sirolimus in Autoimmune Pancytopenia, Autoimmune Lymphoproliferative Syndrome (ALPS) and Evans Syndrome, sponsored by Children's Hospital of Philadelphia. Completed at 1 site in United States. Open to participants aged 1 Year to 30 Years. Per ClinicalTrials.gov, last updated 2019-11-19.
Sponsored by Children's Hospital of Philadelphia · Phase 1/2, Interventional, and Treatment
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.
503 studies on the registry are indexed under Purpura, Thrombocytopenic, Idiopathic; 158 are open to participants now.
This study's enrollment of 30 is below the median of 58 across 376 interventional studies indexed under Purpura, Thrombocytopenic, Idiopathic.
Browse Purpura, Thrombocytopenic, Idiopathic studies →Children's Hospital of Philadelphia is the lead sponsor of 489 studies on the registry; 90 are open to participants now.
Of its 28 completed or terminated interventional studies of FDA-regulated products, 22 (79%) have results posted.
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Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
A condition in which the immune system attacks the body’s own tissues, such as rheumatoid arthritis, lupus, psoriasis, type 1 diabetes or inflammatory bowel disease.
Immunotherapy studies often leave out active autoimmune disease, and some name exceptions, such as thyroid disease on replacement hormone. Check the exceptions this study lists.
Blood cells that help blood clot. Too few raises the risk of bleeding and bruising. A usual adult range is about 150–400 × 10⁹/L (150,000–400,000 per µL); each lab has its own reference range.
A weakened immune system. It can come from an illness, such as HIV or some blood cancers, or from medicines that turn the immune system down, for example after an organ transplant or for an autoimmune disease; steroids at higher doses count.
Read whether the line is about a condition or about medicines, and which medicines and doses it means.
Relapsed: the illness came back after treatment had worked. Refractory: it did not respond to treatment, or stopped responding while still on it.
Anti-inflammatory medicines such as prednisone, prednisolone and dexamethasone — not the anabolic steroids used for muscle.
Studies differ in what they allow: check which steroid medicines, routes (tablets, injections, creams, inhalers, eye drops) and doses this study accepts.
A line of therapy is one course of treatment, which may combine several drugs. First-line is the first course given; second-line follows when that stops working or is not tolerated.
“Two prior lines” means two courses that count separately under the study’s rules — not simply two drugs. Ask the study team if you are unsure how yours are counted.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Malignancy means cancer. Criteria about another or earlier malignancy ask whether you have had a different cancer, usually within a set number of years.
Some are commonly allowed, such as treated skin cancers other than melanoma and early cancers removed completely — check the exceptions this study lists.
The human immunodeficiency virus, which weakens the immune system.
Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.
Autoimmune disease
A condition in which the immune system attacks the body’s own tissues, such as rheumatoid arthritis, lupus, psoriasis, type 1 diabetes or inflammatory bowel disease.
Immunotherapy studies often leave out active autoimmune disease, and some name exceptions, such as thyroid disease on replacement hormone. Check the exceptions this study lists.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Platelets
Blood cells that help blood clot. Too few raises the risk of bleeding and bruising. A usual adult range is about 150–400 × 10⁹/L (150,000–400,000 per µL); each lab has its own reference range.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Immunosuppression
A weakened immune system. It can come from an illness, such as HIV or some blood cancers, or from medicines that turn the immune system down, for example after an organ transplant or for an autoimmune disease; steroids at higher doses count.
Read whether the line is about a condition or about medicines, and which medicines and doses it means.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Relapsed and refractory
Relapsed: the illness came back after treatment had worked. Refractory: it did not respond to treatment, or stopped responding while still on it.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Corticosteroids (steroids)
Anti-inflammatory medicines such as prednisone, prednisolone and dexamethasone — not the anabolic steroids used for muscle.
Studies differ in what they allow: check which steroid medicines, routes (tablets, injections, creams, inhalers, eye drops) and doses this study accepts.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Line of therapy
A line of therapy is one course of treatment, which may combine several drugs. First-line is the first course given; second-line follows when that stops working or is not tolerated.
“Two prior lines” means two courses that count separately under the study’s rules — not simply two drugs. Ask the study team if you are unsure how yours are counted.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Cancer (malignancy)
Malignancy means cancer. Criteria about another or earlier malignancy ask whether you have had a different cancer, usually within a set number of years.
Some are commonly allowed, such as treated skin cancers other than melanoma and early cancers removed completely — check the exceptions this study lists.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
HIV
The human immunodeficiency virus, which weakens the immune system.
Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Sirolimus treatment
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)
Also known as: rapamycin, rapamune
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).
Time frame: 6 months
Number of Participants With Autoimmune Disease Response to Oral Sirolimus
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.
Time frame: 6 months
Trough Levels Produced by Administration of Oral Sirolimus
Pharmacokinetic levels produced by administration of oral sirolimus
Time frame: Within first 5 days of starting sirolimus
Effect of Sirolimus on Intracellular Targets
Needs more specific information
Time frame: 6 months
Number of Participants With Lymphoproliferation Response to Oral Sirolimus
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).
Time frame: 6 months
| Milestone | Sirolimus Treatment |
|---|---|
| Started | 30 |
| Completed | 30 |
| Not completed | 0 |
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).
| participants | Sirolimus Treatment |
|---|---|
| Number of Participants With Grade 3 and 4 Toxicities of Administration of Oral Sirolimus | 1 |
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.
| Participants | Sirolimus Treatment |
|---|---|
| Response in patients w/ ALPS — Complete Response (CR) | 11 |
| Response in patients w/ ALPS — Partial Response (PR) | 1 |
| Response in patients w/ ALPS — No Response (NR) | 0 |
| Response in patients w/ ALPS — Progressive Disease (PD) | 0 |
| Response in patients w/ multilineage cytopenias — Complete Response (CR) | 7 |
| Response in patients w/ multilineage cytopenias — Partial Response (PR) | 1 |
| Response in patients w/ multilineage cytopenias — No Response (NR) | 2 |
| Response in patients w/ multilineage cytopenias — Progressive Disease (PD) | 2 |
| Resp pts w/ single-lineage autoimmune cytopenias — Complete Response (CR) | 1 |
| Resp pts w/ single-lineage autoimmune cytopenias — Partial Response (PR) | 2 |
| Resp pts w/ single-lineage autoimmune cytopenias — No Response (NR) | 3 |
| Resp pts w/ single-lineage autoimmune cytopenias — Progressive Disease (PD) | 0 |
Pharmacokinetic levels produced by administration of oral sirolimus
| nanograms/dL | Sirolimus Treatment |
|---|---|
| Trough Levels Produced by Administration of Oral Sirolimus | 8.5 (2.9 to 20) |
Needs more specific information
No measurements were reported for this outcome.
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).
| Participants | Sirolimus Treatment |
|---|---|
| Response in patients w/ ALPS — Complete Response (CR) | 11 |
| Response in patients w/ ALPS — Partial Response (PR) | 1 |
| Response in patients w/ ALPS — No Response (NR) | 0 |
| Response in patients w/ ALPS — Progressive disease (PD) | 0 |
| Response in patients w/ ALPS — Not Applicable (N/A) | 0 |
| Response in patients w/ multilineage cytopenias — Complete Response (CR) | 3 |
| Response in patients w/ multilineage cytopenias — Partial Response (PR) | 0 |
| Response in patients w/ multilineage cytopenias — No Response (NR) | 1 |
| Response in patients w/ multilineage cytopenias — Progressive disease (PD) | 1 |
| Response in patients w/ multilineage cytopenias — Not Applicable (N/A) | 7 |
| esp pts w/ single-lineage autoimmune cytopenias — Complete Response (CR) | 1 |
| esp pts w/ single-lineage autoimmune cytopenias — Partial Response (PR) | 0 |
| esp pts w/ single-lineage autoimmune cytopenias — No Response (NR) | 0 |
| esp pts w/ single-lineage autoimmune cytopenias — Progressive disease (PD) | 0 |
| esp pts w/ single-lineage autoimmune cytopenias — Not Applicable (N/A) | 5 |
Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Sirolimus Treatment | — | 1/30 (3.3%) | 15/30 (50%) |
| Event | Sirolimus Treatment |
|---|---|
| VasculitisNervous system disorders | 1/30 |
| Event | Sirolimus Treatment |
|---|---|
| MucositisGastrointestinal disorders | 10/30 |
| Elevated triglycerides and cholesterolCardiac disorders | 2/30 |
| AcneSkin and subcutaneous tissue disorders | 1/30 |
| Sun sensitivitySkin and subcutaneous tissue disorders | 1/30 |
| Gastro-esophageal reflux diseaseGastrointestinal disorders | 1/30 |
| Age, Categorical(Participants) | Sirolimus Treatment |
|---|---|
| <=18 years | 12 |
| Between 18 and 65 years | 18 |
| >=65 years | 0 |
| Age, Continuous(years) | Sirolimus Treatment |
|---|---|
| Median | 11 (1.8 to 21) |
| Sex: Female, Male(Participants) | Sirolimus Treatment |
|---|---|
| Female | 10 |
| Male | 20 |
| Race and Ethnicity Not Collected(Participants) | Sirolimus Treatment |
|---|
| Region of Enrollment(Participants) | Sirolimus Treatment |
|---|---|
| United States | 30 |
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Studies of the drug tested here: Sirolimus
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