Clinical Trial Finder

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  INCLUSION CRITERIA:

  Individuals must meet all of the following criteria to be eligible for study participation: 1.

Age 8-65 years. 2. Documented CTLA4 mutation (requires documentation of confirmed mutation via Sanger sequencing at a laboratory approved by the Clinical Laboratory Improvement Amendments [CLIA]). 3. At least one of the following established hematologic abnormalities during the past 6 months (including results from outside CLIA-certified laboratories) prior to screening:

• - ANC < 750 cells/microL.

• - Platelet count < 75,000 cells/microL.

• - Hemoglobin < 7.5 g/dL.

4. The above mentioned hematologic abnormalities should require active treatment with steroids, immunomodulatory agents (e.g., mycophenolate mofetil, cyclosporine, tacrolimus, mercaptopurine, methotrexate, sirolimus, high dose intravenous immunoglobulin [IVIG]), and/or other agents (e.g., TPO agonists) for at least 60 days prior to screening. 5. The dose of any concomitant medication(s) aimed at treating cytopenia should be stable in the 60 days prior to screening. Stable is defined as:

• - No new concomitant medications for cytopenia were initiated.

• - No dose increase of the medication was required.

6. Did not receive blood product transfusions within 30 days prior to screening. 7. Did not receive abatacept within 60 days prior to screening. 8. Did not receive rituximab within 3060 days of screening. 9. Did not receive alemtuzumab at any time. 10. Has access to healthcare provider at home. 11. Able to provide informed consent. 12. Willing to allow storage of biological specimens for future use in medical research. 13. Females of childbearing potential must agree to use appropriate birth control methods when engaging in sexual activities that can result in pregnancy, beginning Day -30 through 30 days after the last dose of study agent. Appropriate methods should include 2 forms of contraception, one from each of the following categories:

• - Hormonal contraception or placement of an intrauterine device or intrauterine system.

• - Barrier method: Condom or occlusive cap (diaphragm or cervical/vault cap) with a spermicide.

EXCLUSION CRITERIA:

Patients meeting any of the following criteria are not eligible for this study: 1. History of hypersensitivity to abatacept. 2. Any live vaccines (including attenuated live vaccines) within 6 weeks of screening. 3. History of acquired immunodeficiency diseases, including a positive HIV polymerase chain reaction (PCR) test result. 4. Untreated chronic hepatitis B (positive PCR) or hepatitis C (positive PCR) infection. Patients with chronic hepatitis must be on medical treatment for at least 3 months before screening and have evidence of decreased viral loads after starting treatment. 5. EBV viral load > 4log on 2 or more laboratory checks greater than 1 month apart and within 6 months of screening. 6. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of evidence of local recurrence or metastases. 7. Current active infectious disease (bacterial or fungal) including evidence of tuberculosis (TB) infection as defined by a positive QuantiFERON TB-Gold test. Test results within the past 6 months will be accepted. If presence of latent TB is established, then treatment must be completed before the patient can be considered for enrollment. The patient may also be considered for enrollment after completing treatment of any other active bacterial or fungal infection. 8. Contraindication to PFT or CT scan. 9. Pregnancy or breastfeeding. 10. Any condition that, in the opinion of the investigator, contraindicates participation in this study.

Rare heterozygous mutations in cytotoxic T-lymphocyte antigen-4 (CTLA4) lead to a monogenetic defect that presents with a heterogeneous clinical phenotype of recurrent infections, lymphoproliferation, autoimmunity, and lymphocytic infiltration of target organs. Management is challenging and focuses on treating infections, autoimmune complications, and end organ damage due to lymphocytic infiltrates. Experience with the natural history of the disease and therapies for underlying complications are limited. There is no established standard of care for these patients. Abatacept is a biologically engineered CTLA4-mimetic that is approved as an intravenous (IV) infusion to treat adult rheumatoid arthritis, adult psoriatic arthritis, and juvenile idiopathic arthritis. Given that abatacept mimics CTLA4 function, we hypothesize that the drug will prevent T-cell hyper-activation, restore regulatory T-cell function, and thereby treat the autoimmune and immune dysregulatory manifestations of CTLA4 deficiency. This study is a phase 1/2, double-blind, randomized, intra-patient dose-escalation, placebo-controlled trial designed to evaluate the safety and efficacy of abatacept in participants with CTLA4 deficiency and cytopenia. Participants will come to the NIH Clinical Center monthly for 210 days to receive infusions of study agent or placebo and to undergo safety and research evaluations, including blood draw for cytopenia evaluation and scoring of disease severity. Before and after the treatment period, participants will also have imaging, pulmonary function testing, bone marrow biopsy, and endoscopy (symptomatic participants only). Primary endpoints will be evaluated at Day 210. After completing the blinded treatment trial, participants will be offered the option to enroll in a 6-month open-label extension study for long-term safety evaluation of abatacept.

Arms

Experimental: abatacept

Adult and pediatric dosing will be based on weight per protocol

Placebo Comparator: placebo

will be given as the same IV volume as abatacept

Interventions

Drug: - abatacept

Double-blind, placebo-controlled, intra-patient dose-escalation trial of abatacept for treating cytopenia in CTLA4 deficiency. Abatacept or placebo will be administered for 3 doses over 30 days, followed by 5 more months of administration at double the initial dose. If the participant s hematologic parameters normalize at Day 120 or onwards, the investigator may taper or discontinue concomitant medications aimed at treating cytopenia.

Other: - Placebo

Saline packaged identically to abatacept, with volume matching that of the abatacept dosing by weight, and will be administered via IV infusion identically to abatacept