Phase I/II Thymus Transplantation With Immunosuppression #950

Study Overview
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Brief Summary
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The study purpose is to determine if cultured thymus tissue implantation (CTTI) (previously described as transplantation) with tailored immunosuppression based on the recipient's pre-implantation T cell population is a safe and effective treatment for complete DiGeorge anomaly. This study will also evaluate whether cultured thymus tissue implantation and parathyroid transplantation with immunosuppression is a safe and effective treatment for complete DiGeorge anomaly and hypoparathyroidism.

Detailed Description
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Complete DiGeorge anomaly is a congenital disorder characterized by athymia. Without successful treatment, children remain immunodeficient and usually die by age 2 years. In infants with complete DiGeorge anomaly and no T cells, cultured thymus tissue implantation (CTTI) without immunosuppression resulted in diverse T cell development and good T cell function. Some infants with no thymus have some T cells that presumably developed extrathymically; these T cells can reject a thymus graft. The purpose of this study is to tailor immunosuppression use for complete DiGeorge anomaly subjects who have some T cells and different T cell function levels. This protocol includes tailored immunosuppression regimens to allow subjects with different T cell function levels to be suppressed adequately. Patients with complete DiGeorge often have hypoparathyroidism, a life threatening condition. Successful CTTI does not result in improvement of the hypoparathyroidism. The patients must go to the clinic for frequent calcium levels and to the hospital for calcium infusions. These infants are at risk for seizures from low calcium. This study had a parental parathyroid transplant arm for subjects with hypoparathyroidism who require calcium replacement. Whether or not a subject was enrolled in the parathyroid arm, the immunosuppression regimen the subject received was dependent on the immune findings as stated in the clinical protocol.

Official Title
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Phase I/II Trial of Thymus Transplantation With Immunosuppression, #950

Conditions
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DiGeorge Anomaly, Complete DiGeorge Anomaly, Complete Atypical DiGeorge Anomaly, Complete DiGeorge Syndrome, Complete Atypical DiGeorge Syndrome

Intervention / Treatment
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* Biological: Cultured Thymus Tissue for Implantation (CTTI)
* Other: Cultured Thymus Tissue Implantation and Parental Parathyroid Transplantation
* Procedure: Blood Draw
* Drug: Rabbit anti-thymocyte globulin
* Drug: Cyclosporine
* Drug: Tacrolimus
* Drug: Methylprednisolone or Prednisolone
* Drug: Daclizumab
* Drug: Mycophenolate mofetil


Participation Criteria
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Eligibility Criteria
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Thymus Transplantation Inclusion: Must have 1 of following: 22q11 or 10p13 hemizygosity; hypocalcemia requiring replacement; congenital heart defect; CHARGE association or CHD7 mutation; or abnormal ears plus mother w/diabetes (type I, type II, gestational). <50 CD3+ T cells/cumm or <50 CD3+ T cells/cumm that are CD62L+ CD45RA+ (cluster of differentiation 45RA) (naïve phenotype), or <5% of CD3+ count being CD62L+ CD45RA+ Atypical DiGeorge: Must have, or have had, a rash. If rash present, rash biopsy must show T cells in skin. If rash & adenopathy resolved, must have >50/cumm T cells & naive T cell must be <50/cumm or <5% of T cells. Typical DiGeorge: CD3+ CD45RA+ CD62L+ T cells <50/mm3 or <5% of total T cells Parathyroid Transplantation Additional Inclusion: 2 studies in recipient which PTH<5 pg/ml when ionized calcium <1.1 mmol/L. Can be done anytime pre-tx; 1 must be done while at Duke Hospital. Parent(s) willing & eligible to be donors Thymus Transplantation Exclusion: Heart surgery <4 wks pre-tx Heart surgery anticipated w/in 3 months after proposed tx Rejection by surgeon or anesthesiologist as surgical candidate Lack of sufficient muscle tissue to accept transplant of 4 grams/m2 BSA HIV infection Prior attempts at immune reconstitution, such as bone marrow tx or previous thymus tx CMV(>500 copies/ml blood by PCR on 2 tests) Ventilator dependence Parathyroid Donor Inclusion: >18 years of age Serum calcium in normal range Normal PTH function HLA typing consistent with parentage Not on anticoagulation or can come off Parent chosen will share HLA-DR allele with thymus donor that was not inherited by the recipient. If no HLA matching at all, then either parent is acceptable if the parent meets other criteria. Parathyroid Donor Exclusion: <18 years old Hypoparathyroidism-low PTH in presence of low serum calcium & high serum phosphate Hyperparathyroidism(or history)-elevated PTH in presence of high serum calcium and low serum phosphate. History of cancer Donor only living involved parent/guardian of recipient Evidence of HIV-1, HIV-2, HTLV-1, HTLV-2, syphilis, hepatitis B, hepatitis C, West Nile virus, or Chagas disease Creutzfeldt Jakob disease (CJD) Elevated liver function studies: AST, ALT, alkaline phosphatase >3x upper normal limit Receipt of xenograft or risk factors for SARS, CJD and/or smallpox exposure. {If CJD risk factors but not active disease, parent may give permission for parathyroid use.} Urine CMV positive Positive CMV IgM Positive IgM anti-EBV VCA On blood thinners and cannot stop for parathyroid donation Elevated PT or PTT (>ULN) Platelets<100,000 Positive Toxoplasma IgM Donor will receive a history and physical; may be excluded based on PI's medical judgment. Hemoglobin <9g/dl Infectious head or neck lesion Goiter on ultrasound Abnormal fiberoptic laryngoscopy of vocal cords HLA inconsistent with parentage Pregnancy Positive HSV IgG isn't exclusion; post-tx prophylaxis needed for recipient if donor is HSV IgG+. Positive VZV IgG isn't exclusion; post-tx prophylaxis needed if donor is VZV IgG+. Medical concern of independent otolaryngologist. Concern by medical psychologist/social worker that potential donor isn't competent or does not understand risks. Questionnaire responses can lead to exclusion. Mother of DiGeorge Inclusion: • Provides consent to use blood/buccal sample. No exclusions except unwillingness to consent; or, provide blood/buccal sample.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cultured Thymus Tissue Implantation (CTTI) w/immunosuppression<br>Patients with complete DiGeorge Anomaly (cDGA) undergo cultured thymus tissue implantation (previously described as transplantation) with tailored immunosuppression based on the subject's pre-implantation T cell numbers and function. | Biological: Cultured Thymus Tissue for Implantation (CTTI)<br>* Potential thymus recipient subjects are screened for eligibility. Thymus donor (unrelated donor), and thymus donor's birth mother are screened for safety. CTTI is done under general anesthesia in the operating room. Cultured thymus tissue is implanted into the subject's quadriceps. Two to three months post CTTI, if medically stable, the subject undergoes allograft biopsy. At the time of implantation and biopsy, a skin biopsy is done. Immunosuppression is weaned as per protocol.<br>* Other names: CTTI;Procedure: Blood Draw<br>* Birth mothers of Thymus Recipients are asked to participate in the study and undergo phlebotomy to allow testing of T cell identity in the Complete DiGeorge subjects. If blood is not obtainable then a buccal swab may be done.<br>* Other names: Venipuncture;Drug: Rabbit anti-thymocyte globulin<br>* Three doses of 2 mg/kg IV (through a central venous catheter) prior to CTTI. Each dose of Rabbit anti-thymocyte globulin (RATGAM) is given over 12 hours. RATGAM is usually given on days-5, -4, and -3 prior to CTTI or CTTI and parathyroid transplantation. Medications (diphenhydramine, steroids, and acetaminophen) are given with rabbit anti-thymocyte globulin.<br>* Other names: thymoglobulin;Drug: Cyclosporine<br>* In addition to RATGAM, subjects with typical cDGA with PHA responses >50,000 cpm, or atypical cDGA with PHA response <75,000cpm (when not on immunosuppression) or <40,000 cpm to PHA while on immunosuppression, are started on cyclosporine (Csa) as soon as cDGA is diagnosed. Csa is continued with target trough levels of 180 to 220 ng/ml. If subject cannot tolerate Csa, Csa may be changed to tacrolimus (FK506) with target trough level 7 to 10 ng/ml. When trough levels are outside of range, dosing is modified appropriately. Csa may be given every 8 to 12 hours enterally or IV before and after CTTI. The Csa dose is dependent on T cell numbers and the target Csa trough levels. Csa is weaned as per protocol.<br>* Other names: Csa;Drug: Tacrolimus<br>* If unable to tolerate cyclosporine, then tacrolimus is given. Tacrolimus may be given every 8 to 12 hours enterally or IV before and after the CTTI transplant. Tacrolimus dose is dependent on the T cell numbers and the target tacrolimus trough levels. Tacrolimus is weaned as per protocol.<br>* Other names: FK506;Drug: Methylprednisolone or Prednisolone<br>* Steroids IV or enterally may be given before and after CTTI or CTTI and parathyroid transplantation. Administration and dosage depends on T cell numbers and symptoms. Pre-transplant steroids may be used when pre-transplant T cells >4,000cumm. Steroids are weaned as per protocol.<br>* Other names: Steroids;Drug: Daclizumab<br>* In addition, subjects with Atypical DiGeorge with PHA responses >75,000cpm while on no immunosuppression or PHA responses >40,000cpm while on immunosuppression, Daclizumab 1 mg/kg single dose IV may be given depending on T cell counts. Administration of Daclizumab depends on T cell numbers and T cell activation. A single dose may be given after the administration of rabbit anti-thymocyte globulin and before CTTI. If Daclizumab is not given before CTTI, and, depending on the T cell numbers and T cell activation, a single dose of Daclizumab may be given 3-5 days after CTTI.<br>* Other names: Zenapax;Drug: Mycophenolate mofetil<br>* In addition, subjects with Atypical DiGeorge with PHA responses >75,000cpm while on no immunosuppression or PHA responses >40,000cpm while on immunosuppression, Mycophenolate mofetil 15 mg/kg/dose every 8 hours IV or enterally may be given depending on T cell counts. Mycophenolate mofetil may be given if the T cell count remains elevated 5 days after CTTI. If MMF is given, the dose is 15 mg/kg IV. MMF may be stopped at 35 days after CTTI or continued for up to six months after CTTI.<br>* Other names: CellCept;|
| Experimental: CTTI with Parathyroid Transplantation w/immunosuppression<br>Patients with complete DiGeorge Anomaly (cDGA) undergoes cultured thymus tissue thymus implantation (previously described as transplantation) with tailored immunosuppression based on the subject's pre-implantation T cell numbers and function. If the patient has hypoparathyroidism, and is eligible, the patient may also receive a parathyroid transplant. | Other: Cultured Thymus Tissue Implantation and Parental Parathyroid Transplantation<br>* For subjects w/ hypoparathyroidism, the subject may receive CTTI and parathyroid transplant. For parathyroid transplant, parental parathyroid donors are screened. Parathyroid is harvested from the parent who shares the most Human Leukocyte Antigens (HLA) alleles with the thymus donor. Parathyroid gland is minced and placed in quadriceps muscle; there is no dose. Parathyroid donors are monitored as outpatients until recipients' discharge. Recipients' calcium and PTH levels are monitored indefinitely. Potential thymus recipient subjects are screened for eligibility. Thymus donor (unrelated donor), and thymus donor's birth mother are screened for safety. CTTI is done under general anesthesia in the operating room. Cultured thymus tissue is implanted into the subject's quadriceps. Two to three months post CTTI, if medically stable, the subject undergoes allograft biopsy. At the time of CTTI and biopsy, a skin biopsy is done. Immunosuppression is weaned as per protocol.<br>* Other names: CTTI and Parathyroid Transplant;Procedure: Blood Draw<br>* Birth mothers of Thymus Recipients are asked to participate in the study and undergo phlebotomy to allow testing of T cell identity in the Complete DiGeorge subjects. If blood is not obtainable then a buccal swab may be done.<br>* Other names: Venipuncture;Drug: Rabbit anti-thymocyte globulin<br>* Three doses of 2 mg/kg IV (through a central venous catheter) prior to CTTI. Each dose of Rabbit anti-thymocyte globulin (RATGAM) is given over 12 hours. RATGAM is usually given on days-5, -4, and -3 prior to CTTI or CTTI and parathyroid transplantation. Medications (diphenhydramine, steroids, and acetaminophen) are given with rabbit anti-thymocyte globulin.<br>* Other names: thymoglobulin;Drug: Cyclosporine<br>* In addition to RATGAM, subjects with typical cDGA with PHA responses >50,000 cpm, or atypical cDGA with PHA response <75,000cpm (when not on immunosuppression) or <40,000 cpm to PHA while on immunosuppression, are started on cyclosporine (Csa) as soon as cDGA is diagnosed. Csa is continued with target trough levels of 180 to 220 ng/ml. If subject cannot tolerate Csa, Csa may be changed to tacrolimus (FK506) with target trough level 7 to 10 ng/ml. When trough levels are outside of range, dosing is modified appropriately. Csa may be given every 8 to 12 hours enterally or IV before and after CTTI. The Csa dose is dependent on T cell numbers and the target Csa trough levels. Csa is weaned as per protocol.<br>* Other names: Csa;Drug: Tacrolimus<br>* If unable to tolerate cyclosporine, then tacrolimus is given. Tacrolimus may be given every 8 to 12 hours enterally or IV before and after the CTTI transplant. Tacrolimus dose is dependent on the T cell numbers and the target tacrolimus trough levels. Tacrolimus is weaned as per protocol.<br>* Other names: FK506;Drug: Methylprednisolone or Prednisolone<br>* Steroids IV or enterally may be given before and after CTTI or CTTI and parathyroid transplantation. Administration and dosage depends on T cell numbers and symptoms. Pre-transplant steroids may be used when pre-transplant T cells >4,000cumm. Steroids are weaned as per protocol.<br>* Other names: Steroids;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival at 1 Year Post-CTTI | Survival at 1 year post cultured thymus tissue implantation was assessed using the Kaplan Meier Estimated Survival. This mathematical function estimates the survival for a certain length of time. | 1 year post-CTTI | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival at 2 Years Post-CTTI | Survival at 2 years post cultured thymus tissue implantation was assessed using the Kaplan Meier Estimated Survival. This mathematical function estimates the survival for a certain length of time. | 2 years post-CTTI | 
| Immune Reconstitution Efficacy - Total CD3 T Cells | The development of total CD3 T cells at one year as measured using flow cytometry | 1 year post-CTTI | 
| Immune Reconstitution Efficacy - Total CD4 T Cells | The development of total CD4 T cells at one year as measured using flow cytometry | 1 year post-CTTI | 
| Immune Reconstitution Efficacy - Total CD8 T Cells | The development of total CD8 T cells at one year as measured using flow cytometry | 1 year post-CTTI | 
| Immune Reconstitution Efficacy - Naive CD4 T Cells | The development of total naive CD4 T cells at one year as measured using flow cytometry | 1 year post-CTTI | 
| Immune Reconstitution Efficacy - Naive CD8 T Cells | The development of total naive CD8 T cells at one year as measured using flow cytometry | 1 year post-CTTI | 
| Immune Reconstitution Efficacy - Response to Mitogens | Measurement of the T cell proliferative response to the mitogen phytohemagglutin (PHA). | 1 year post-CTTI | 
| Thymus Allograft Biopsy | Evidence, on biopsy of the thymus tissue implanted in muscle, that shows the development of new T cells. | 2 to 3 months post-CTTI | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Complete DiGeorge Anomaly, DiGeorge Anomaly, Thymus Transplantation, DiGeorge Syndrome, Athymia, Parathyroid Transplantation, Hypocalcemia, Hypoparathyroidism, Low T cell numbers, Immunoreconstitution, Immunodeficiency, Complete Atypical DiGeorge Anomaly, Complete DiGeorge Syndrome, Complete Atypical DiGeorge Syndrome, Cultured Thymus Tissue Implantation (CTTI)