This study is currently recruiting participants.
Number
000186-I
Sponsoring Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Recruitment Detail
Type: Enrolling by Invitation Gender: Male & Female Min Age: 3 Years Max Age: 12 Years
Referral Letter Required
No
Population Exclusion(s)
None
Keywords
Gene Therapy; UCLA; CGD
Recruitment Keyword(s)
Condition(s)
Chronic Granulomatous Disease (CGD)
Investigational Drug(s)
G1XCGD lentiviral vector containing the human CGD gene
Investigational Device(s)
Intervention(s)
Drug: Busulfan Drug: Ustekinumab Drug: Rituximab Drug: Sirolimus Drug: Corticortisone
Supporting Site
National Institute of Allergy and Infectious Diseases
X-Linked Chronic Granulomatous Disease (X-CGD) is caused by a gene mutation that makes the immune system to not work properly. Researchers want to see if a lentiviral gene transfer treatment will have the ability to make the patient s immune system more normal, in particular reduce the risk of CGD related infections. The gene transfer takes a person s own stem cells, cultures them to put the normal gene in, then gives the cells back to the person.
Objective:
To test a gene transfer treatment for X-CGD.
Eligibility:
Children ages 3-12 with X-CGD
Design:
Participants will be screened under protocol 05-I-0123. They will undergo:
Medical history
Physical exam
Heart tests
Imaging tests, as needed
Blood tests
Lung function tests, as needed
Dental and audiology exams, if needed
Quality of life questionnaire
Bone marrow aspiration. A needle will be inserted into the hip bone or breastbone to collect bone marrow.
Some screening tests will be repeated during the study.
Participants will have an apheresis procedure under protocol 94-I-0073. Stem cells will be collected.
Participants will get a series of drugs to prepare them for the gene transfer.
Participants will stay at the NIH Clinical Center for a little over a month. They will get a central line. It is a large intravenous (IV) catheter that is placed into a vein of the neck, chest, or arm. They will get chemotherapy and their corrected stem cells through their IV line.
Participants will have 12 follow-up outpatient visits in the 2 years after their gene transfer, as well as visits with their local doctor. Then they will enroll in another study for long-term follow-up visits that will last for 13 years.
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INCLUSION CRITERIA: In order to be eligible to participate in this study, an individual must meet all of the following criteria: -Must have confirmed molecular diagnosis of X-linked CGD confirmed by deoxyribonucleic acid (DNA) sequencing and supported by laboratory evidence for absent or reduction >70% of the biochemical activity of the NADPH-oxidase. -At least 1 prior ongoing or refractory severe infection and/or inflammatory complications requiring hospitalization despite conventional therapy. -No 10/10 HLA-matched donor available after initial search of National Marrow Donor Program (NMDP) registries within the last year. -Must weigh at least 15 kg and no more than 40 kg body weight. -Male or female, and must be at least 3 years of age, but no older than 60. -Parent/guardian must be willing to sign and date informed consent form for child and where appropriate, child may sign assent. -Stated willingness to comply with all study procedures and availability for the duration of the study. -Ability to take oral medication and be willing to adhere to the prophylactic regimen. -Apheresis of patients for the hematopoietic stem cells collected as a part of this protocol will be performed according to the Standard of Care apheresis practices established in the NIH CC Department of Transfusion Medicine for such procedures. -For apheresis pediatric patients: --Must weigh at least 15 kg body weight; --Preserved renal function (creatinine less than or equal to 2.5 mg/dL; less than or equal to 3+ proteinuria); preserved hepatic function (bilirubin less than or equal to 2.0 mg/dl); -Must be negative for co-infection with human immunodeficiency virus (HIV) or hepatitis B virus (HBsAg positive) or hepatitis C virus (HCV ribonucleic acid (RNA) positive), adenovirus, parvovirus B 19 or toxoplasmosis or mycobacterial infection (prior or current) -For females of reproductive potential, must agree to use of 2 highly effective contraception throughout study participation and for at least 3 months after the study. -For females: --Condoms, male or female, with or without a spermicide; --Diaphragm or cervical cap with spermicide; --Intrauterine device; --Contraceptive pills or patch, Norplant, Depo-Provera, or other FDA- approved contraceptive method; -For males of reproductive potential: use of condoms or other methods to ensure effective contraception with partner. -Agreement to adhere to Lifestyle Considerations throughout study duration. -Ability of subject (Legally Authorized Representative [LAR]) to understand and the willingness to sign a written informed consent document. -For the Natural History Protocol (05-I-0213): All patients must be willing to allow storage of blood samples for future studies. -Must provide a durable power of attorney (DPA) for health care decisions to an appropriate adult relative or guardian in accordance to NIH-200 "NIH Advance Directive for Health Care and Medical Research Participation." EXCLUSION CRITERIA: An individual who meets any of the following criteria will be excluded from participation in this study: -Patient/Parent/Guardian unable or unwilling to comply with the protocol requirements. -Contraindication for leukapheresis (anemia Hb <8g/dl, cardiovascular instability, severe coagulopathy). -Known allergic reactions to components of busulfan or DMSO -Patients who are unable to lie prone during the bone marrow harvesting procedure (in the case of bone marrow harvest, contraindication to general anesthesia). -Have a 10/10 HLA identical (A,B,C,DR,DQ) family or unrelated adult donor unless there is deemed to be an unacceptable risk associated with an allogeneic procedure. -Tested positive (definitive) for the presence of multiple types (2 or more) of anti-platelet antibodies. -Appropriate organ function as outlined below must be observed within 8 weeks of entering this trial. a. Hematologic i. Anemia (hemoglobin < 8 g/dl). ii. Neutropenia (absolute granulocyte count <1,000/mm3 ). iii. Thrombocytopenia (platelet count < 150,000/mm3). iv. Prothrombin Time (PT) INR or Partial thromboplastin time (PTT) > 2 X the upper limits of normal (ULN) (patients with a correctable deficiency controlled on medication will not be excluded). v. Cytogenetic abnormalities known to be associated with hematopoietic defect on peripheral blood or bone marrow. b. Infectious i. Evidence of infection with HIV-1 and -2, Hepatitis B, Hepatitis C, adenovirus, parvovirus B 19 or toxoplasmosis within 8 weeks prior to mobilization/apheresis or bone marrow harvest. CMV infection is allowable as long as the infection is under control. ii. History of infection with mycobacteria or Bacille Calmette-Guerin (BCG) vaccination. c. Pulmonary i. Resting O2 saturation by pulse oximetry < 90% on room air. d. Cardiac i. Abnormal electrocardiogram (ECG) indicating cardiac pathology. ii. Uncorrected congenital cardiac malformation with clinical symptomatology. iii. Active cardiac disease, including clinical evidence of congestive heart failure, cyanosis, hypotension. iv. Poor cardiac function as evidenced by LV ejection fraction <40% on echocardiogram. e. Neurological i. Significant neurologic abnormality by examination. ii. Uncontrolled seizure disorder. f. Renal i. Renal insufficiency: serum creatinine greater than or equal to 2.5 mg/dl, or greater than or equal to 3+ proteinuria. -Chemistry Lab abnormalities: Serum sodium greater than or equal to 156 mmol/L or less than or equal to 129 mmol/L, potassium greater than or equal to 6.1 mmol/L or less than or equal to 2.9 mmol/L, calcium greater than or equal to 3.2 mmol/L or < 1.74 mmol/L , magnesium greater than or equal to 1.24 mmol/L or < 0.39 mmol/L, phosphate greater than or equal to 5.1 mmol/L or < 1.9 mmol/L. -Serum transaminases > 5X the upper limit of normal (ULN). Serum bilirubin > 2X the upper limit of normal (ULN). Serum glucose > 1.5x the upper limit of normal (ULN). -General --Expected survival < 6 months. --Major congenital anomaly. --Known allergic reactions to components of busulfan or DMSO or contraindication for administration of conditioning medication. --Evidence of active malignant disease. -Treatment with another investigational drug or other intervention within 6 months. -Unable to undergo apheresis as per the NIH CC Department of Transfusion Medicine Standard of Care apheresis procedures. a. Patients who are hemodynamically unstable (systolic or diastolic blood pressure fall of 20 mm Hg from the stable patient s baseline measurement) or requiring mechanical respiratory assistance are excluded. History of vasculitis. -Administration of gamma-interferon within 30 days before the infusion of transduced, autologous CD34+ cells. -Any other condition that, in the opinion of the Investigator, may compromise the safety or compliance of the patient or would preclude the patient from successful study completion.
In order to be eligible to participate in this study, an individual must meet all of the following criteria:
-Must have confirmed molecular diagnosis of X-linked CGD confirmed by deoxyribonucleic acid (DNA) sequencing and supported by laboratory evidence for absent or reduction >70% of the biochemical activity of the NADPH-oxidase.
-At least 1 prior ongoing or refractory severe infection and/or inflammatory complications requiring hospitalization despite conventional therapy.
-No 10/10 HLA-matched donor available after initial search of National Marrow Donor Program (NMDP) registries within the last year.
-Must weigh at least 15 kg and no more than 40 kg body weight.
-Male or female, and must be at least 3 years of age, but no older than 60.
-Parent/guardian must be willing to sign and date informed consent form for child and where appropriate, child may sign assent.
-Stated willingness to comply with all study procedures and availability for the duration of the study.
-Ability to take oral medication and be willing to adhere to the prophylactic regimen.
-Apheresis of patients for the hematopoietic stem cells collected as a part of this protocol will be performed according to the Standard of Care apheresis practices established in the NIH CC Department of Transfusion Medicine for such procedures.
-For apheresis pediatric patients:
--Must weigh at least 15 kg body weight;
--Preserved renal function (creatinine less than or equal to 2.5 mg/dL; less than or equal to 3+ proteinuria); preserved hepatic function (bilirubin less than or equal to 2.0 mg/dl);
-Must be negative for co-infection with human immunodeficiency virus (HIV) or hepatitis B virus (HBsAg positive) or hepatitis C virus (HCV ribonucleic acid (RNA) positive), adenovirus, parvovirus B 19 or toxoplasmosis or mycobacterial infection (prior or current)
-For females of reproductive potential, must agree to use of 2 highly effective contraception throughout study participation and for at least 3 months after the study.
-For females:
--Condoms, male or female, with or without a spermicide;
--Diaphragm or cervical cap with spermicide;
--Intrauterine device;
--Contraceptive pills or patch, Norplant, Depo-Provera, or other FDA- approved contraceptive method;
-For males of reproductive potential: use of condoms or other methods to ensure effective contraception with partner.
-Agreement to adhere to Lifestyle Considerations throughout study duration.
-Ability of subject (Legally Authorized Representative [LAR]) to understand and the willingness to sign a written informed consent document.
-For the Natural History Protocol (05-I-0213): All patients must be willing to allow storage of blood samples for future studies.
-Must provide a durable power of attorney (DPA) for health care decisions to an appropriate adult relative or guardian in accordance to NIH-200 "NIH Advance Directive for Health Care and Medical Research Participation."
EXCLUSION CRITERIA:
An individual who meets any of the following criteria will be excluded from participation in this study:
-Patient/Parent/Guardian unable or unwilling to comply with the protocol requirements.
-Contraindication for leukapheresis (anemia Hb <8g/dl, cardiovascular instability, severe coagulopathy).
-Known allergic reactions to components of busulfan or DMSO
-Patients who are unable to lie prone during the bone marrow harvesting procedure (in the case of bone marrow harvest, contraindication to general anesthesia).
-Have a 10/10 HLA identical (A,B,C,DR,DQ) family or unrelated adult donor unless there is deemed to be an unacceptable risk associated with an allogeneic procedure.
-Tested positive (definitive) for the presence of multiple types (2 or more) of anti-platelet antibodies.
-Appropriate organ function as outlined below must be observed within 8 weeks of entering this trial.
a. Hematologic
i. Anemia (hemoglobin < 8 g/dl).
ii. Neutropenia (absolute granulocyte count <1,000/mm3 ).
iii. Thrombocytopenia (platelet count < 150,000/mm3).
iv. Prothrombin Time (PT) INR or Partial thromboplastin time (PTT) > 2 X the upper limits of normal (ULN) (patients with a correctable deficiency controlled on medication will not be excluded).
v. Cytogenetic abnormalities known to be associated with hematopoietic defect on peripheral blood or bone marrow.
b. Infectious
i. Evidence of infection with HIV-1 and -2, Hepatitis B, Hepatitis C, adenovirus, parvovirus B 19 or toxoplasmosis within 8 weeks prior to mobilization/apheresis or bone marrow harvest. CMV infection is allowable as long as the infection is under control.
ii. History of infection with mycobacteria or Bacille Calmette-Guerin (BCG) vaccination.
c. Pulmonary
i. Resting O2 saturation by pulse oximetry < 90% on room air.
d. Cardiac
i. Abnormal electrocardiogram (ECG) indicating cardiac pathology.
ii. Uncorrected congenital cardiac malformation with clinical symptomatology.
iii. Active cardiac disease, including clinical evidence of congestive heart failure, cyanosis, hypotension.
iv. Poor cardiac function as evidenced by LV ejection fraction <40% on echocardiogram.
e. Neurological
i. Significant neurologic abnormality by examination.
ii. Uncontrolled seizure disorder.
f. Renal
i. Renal insufficiency: serum creatinine greater than or equal to 2.5 mg/dl, or greater than or equal to 3+ proteinuria.
-Chemistry Lab abnormalities: Serum sodium greater than or equal to 156 mmol/L or less than or equal to 129 mmol/L, potassium greater than or equal to 6.1 mmol/L or less than or equal to 2.9 mmol/L, calcium greater than or equal to 3.2 mmol/L or < 1.74 mmol/L , magnesium greater than or equal to 1.24 mmol/L or < 0.39 mmol/L, phosphate greater than or equal to 5.1 mmol/L or < 1.9 mmol/L.
-Serum transaminases > 5X the upper limit of normal (ULN).
Serum bilirubin > 2X the upper limit of normal (ULN).
Serum glucose > 1.5x the upper limit of normal (ULN).
-General
--Expected survival < 6 months.
--Major congenital anomaly.
--Known allergic reactions to components of busulfan or DMSO or contraindication for administration of conditioning medication.
--Evidence of active malignant disease.
-Treatment with another investigational drug or other intervention within 6 months.
-Unable to undergo apheresis as per the NIH CC Department of Transfusion Medicine Standard of Care apheresis procedures.
a. Patients who are hemodynamically unstable (systolic or diastolic blood pressure fall of 20 mm Hg from the stable patient s baseline measurement) or requiring mechanical respiratory assistance are excluded.
History of vasculitis.
-Administration of gamma-interferon within 30 days before the infusion of transduced, autologous CD34+ cells.
-Any other condition that, in the opinion of the Investigator, may compromise the safety or compliance of the patient or would preclude the patient from successful study completion.
Principal Investigator
Referral Contact
For more information: