This study is currently recruiting participants.
Number
001976-I
Sponsoring Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Recruitment Detail
Type: Participants currently recruited/enrolled Gender: Male & Female Min Age: 12 Years Max Age: 75 Years
Referral Letter Required
Yes
Population Exclusion(s)
Neonates;Pregnant Women;Adults who are or may become unable to consent
Keywords
Primary Immune Deficiency; Immune Dysregulation; Phosphoinositol Kinase Pathway; Leniolisib; Inborn Errors of Immunity; Activated Pi3K-delta Syndrome (APDS); Autoimmune Cytopenia; Lymphadenopathy; Lymphoproliferation; CTLA-4
Recruitment Keyword(s)
None
Condition(s)
CTLA-4 Deficiency; SOCS1 Deficiency; ALPS (Autoimmune Lymphoproliferative Syndrome); PTEN Deficiency
Investigational Drug(s)
Leniolisib
Investigational Device(s)
Intervention(s)
Drug: leniolisib
Supporting Site
National Institute of Allergy and Infectious Diseases
Primary immunodeficiencies (PID) are rare disorders that develop when the immune system does not develop or function properly. Issues with immune function can affect many organs and lead to serious health problems. Leniolisib is a drug approved by the FDA to treat 1 specific PID disorder. Researchers want to know if this drug can help people with related PID disorders.
Objective:
To test an approved drug (leniolisib) in people with certain PID disorders.
Eligibility:
People aged 12 to 75 years with a PID disorder.
Design:
Participants will be screened. They will have a physical exam with blood tests. They will have tests of their heart and lung functions. They will provide a stool sample. They will fill out surveys about their health and how PID affects their life. They will have imaging scans, including an ultrasound of their liver. An ultrasound is a test that uses sound waves to look inside the body.
Leniolisib is a tablet taken by mouth twice a day. Participants will take the drug for about 20 weeks. They will use an electronic form to track their doses and any symptoms they have.
Participants will have clinic visits about every 4 weeks for 6 months. Visits 2 and 3 will require 2 days each. Participants will have blood tests and fill out surveys during each visit. Imaging scans and the lung function test will be repeated on visit 6.
Participants may opt to participate in a phone interview at the end of the study. The interview will take about 1 hour.
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INCLUSION CRITERIA: -Subjects 12 to 75 years of age (inclusive). -Diagnosed with a PID due to disease-causing pathogenic or likely pathogenic variant(s) in the following genes: SOCS1, PTEN, CTLA4, NFKB1 (only those variants leading to NFKB pathway activation), or FAS (germline or somatic), or diagnosed with RAS-associated leukoproliferative disorder (and not juvenile myelomonocytic leukemia [JMML]) due to somatic variants in NRAS or KRAS. -Subjects must have 1 or more of the following: --One or more blood cytopenias related to the underlying PID (and not due to other medical conditions such as iron-deficiency or lead exposure) defined as hemoglobin <10 g/dL, platelet count <100,000/microL, or neutrophil count <1000/microL --Splenomegaly evident by CT imaging with craniocaudal spleen measurement >10 cm --Lymphadenopathy evident by CT imaging with at least 1 measurable index lymph node (long axis >1.5 cm) as per Cheson methodology --GLILD or other PID-related ILD with quantifiable CT chest imaging findings evident on baseline CT scan and previous pathologic confirmation of GLILD or other PID-related ILD -At screening, vital signs (systolic and diastolic blood pressure, pulse rate, and oxygen saturation in the absence of any supplemental oxygen) will be assessed in the sitting position after the subject has rested for at least three minutes. If the initial assessment yields vital sign parameters outside the defined ranges, a subsequent 2 assessments may be completed. If the average of all 3 repeated vital sign assessments are found within range, the subject is considered to have met this inclusion criterion. Ranges: --Systolic blood pressure 80-139 mm Hg --Diastolic blood pressure 50-89 mm Hg --Pulse rate 50-110 bpm --Oxygen saturation 93-100% -Subjects or their legal representatives (for subjects under the age of 18 years) must be able to communicate with the Investigator and understand and comply with the requirements of the study, including an ability to provide written informed consent before any assessment is performed (through an interpreter if non-English speaking). EXCLUSION CRITERIA: -Subject has had a successful hematopoietic stem cell transplant (HSCT). -Previous or concurrent use of immunosuppressive medication, such as: --Use of an mTOR inhibitor (e.g., sirolimus, everolimus) or a PI3K(delta) inhibitor (selective or non-selective PI3K inhibitors) within 3 weeks prior to first dosing of study medication. --Rituximab or other B-cell depleting antibodies, belimumab, cyclophosphamide, or alemtuzumab within 6 months prior to first dosing of study medication. --Cyclosporine A, mycophenolate mofetil, 6-mercaptopurine, azathioprine, methotrexate, tacrolimus, ruxolitinib, or other JAK inhibitors within 3 weeks prior to first dosing of study medication. --Corticosteroids above 25 mg prednisone or equivalent per day within 2 weeks prior to first dosing of study medication. Other immunosuppressive agents expected to have a significant impact on immune cell number or function. ---Abatacept is allowed during study if the subject has been receiving a stable dosing regimen for more than 3 months prior to first dosing of study medication. -Subject is receiving concurrent treatment with another investigational therapy or use of another investigational therapy less than 4 weeks or 5 half-lives (whichever is longer) prior to first dosing of study medication. -History of hypersensitivity to the study drug or to drugs of similar chemical classes. -Current use of medication known to be a strong inhibitor, or moderate or strong inducer, of isoenzyme cytochrome P450 CYP3A. Treatment can be discontinued or switched to a different medication prior to starting study treatment. -Current use of medications metabolized by isoenzyme CYP1A2 and have a narrow therapeutic index (drugs whose exposure response indicates that increases in their exposure levels by the concomitant use of potent inhibitors may lead to serious safety concerns [e.g., Torsades de Pointes]). -Current use of medications that act as breast cancer resistant protein (BCRP), organic anion transporting polypeptide (OATP)1B1, and OATP1B3 substrates. -Subject has a history or current electrocardiogram (ECG) abnormalities indicating a significant risk of safety for subjects participating in the study, such as the following: --History of familial long QT syndrome or known family history of Torsades de Pointes. --Clinically significant cardiac arrhythmias (e.g., sustained ventricular tachycardia and clinically significant second or third-degree atrioventricular block without a pacemaker). --Resting corrected QT interval (Fridericia preferred but Bazett acceptable) >450 msec in male subjects 16-75 years of age, >460 msec in female subjects 16-75 years of age, and >440 msec in all subjects 12-15 years of age. --Use of agents known to prolong the QT interval unless it can be permanently discontinued for the duration of the study. Azithromycin or levofloxacin (not both) may be continued if the subject has been receiving it for more than 1 month and the resting corrected QT interval is not greater than the limits above. -History of acquired immunodeficiency diseases, including a positive human immunodeficiency virus (HIV) test result at screening. -Uncontrolled chronic or recurrent infectious disease (except those considered to be characteristic of PID) or evidence of tuberculosis infection as defined by a positive QuantiFERON(R) TB-Gold test at Screening. If the presence of latent tuberculosis is established, treatment should be completed following CDC guidelines, and based on best clinical care practice. Exception can be made for patients with a positive test due to a history of having TB that was adequately treated or due to previously treated infection with cross-reactive non-tuberculous mycobacteria. -Any surgical or medical condition which may jeopardize the subject in case of participation in the study, or might significantly alter the absorption, distribution, metabolism, or excretion of drugs. The Investigator should make this determination in consideration of the subject s medical history and/or clinical or laboratory evidence of any of the following (conditions due to underlying clinical PID phenotype may be permitted): --Uncontrolled hypertension --Congestive heart failure (New York Heart Association status of class III or IV) --Chronic obstructive pulmonary disease (GOLD stage 3-4) --Chronic need for supplemental oxygen or invasive or noninvasive respiratory support --Major gastrointestinal tract surgery that may affect drug absorption (such as gastric bypass surgery, gastroenterostomy) --Acute pancreatitis --Liver failure or clinically significant liver disease or dysfunction as indicated by ALT or AST greater than 2.5 times the upper limit of normal, bilirubin greater than 2 times the upper limit of normal, international normalized ratio (INR) greater than 1.5 in the absence of anticoagulation, or presence of diuretic refractory ascites --History of significant renal injury/renal disease severely affecting renal function or presence of impaired renal function as indicated by glomerular filtration rate of less than 30 mL/min/1.73 m^2 estimated using cystatin C measurement. -A positive hepatitis B surface antigen, positive hepatitis B PCR, positive hepatitis C PCR, or positive hepatitis C antibody result at screening. --Subjects with a positive hepatitis B core antibody but negative hepatitis B surface antigen and negative hepatitis B PCR should receive tenofovir or other appropriate therapy while on study and have monthly hepatitis B surface antigen and hepatitis B PCR monitoring. -Administration of live vaccines (this includes any attenuated live vaccines) starting from 6 weeks before first dose of study medication, during the study, and up to 7 days after the last dose of leniolisib. -Subject has a previous diagnosis of lymphoma that has been treated with chemotherapy, radiotherapy, or transplant within 1 year of the first dose of study medication or is anticipated to require lymphoma treatment within 6 months of the first dose of study medication. -Subject has a history of malignancy (except lymphoma) within 3 years before the first dose of study medication or has evidence of residual disease from a previously diagnosed malignancy, except for adequately treated cancers of the skin (basal or squamous cell) or carcinoma in situ of the uterine cervix. -Subject has uncontrolled post-transplant lymphoproliferative disease (PTLD)-like EBV related lymphoproliferative disease. -Donation or loss of 400 mL or more of blood within 8 weeks before the first dose of study medication. -Subject has had major surgery requiring hospitalization or radiotherapy within 4 weeks prior to the first dose of study medication or has a planned or expected major surgical procedure during the study period. -Pregnant or nursing (lactating) individuals, where pregnancy is defined as the state of conception and until the termination of gestation, confirmed by a positive hCG serum laboratory test. -Individuals of child-bearing potential who are physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing of study medication and for 7 days after stopping study treatment. -Diagnosis of JMML.
-Subjects 12 to 75 years of age (inclusive).
-Diagnosed with a PID due to disease-causing pathogenic or likely pathogenic variant(s) in the following genes: SOCS1, PTEN, CTLA4, NFKB1 (only those variants leading to NFKB pathway activation), or FAS (germline or somatic), or diagnosed with RAS-associated leukoproliferative disorder (and not juvenile myelomonocytic leukemia [JMML]) due to somatic variants in NRAS or KRAS.
-Subjects must have 1 or more of the following:
--One or more blood cytopenias related to the underlying PID (and not due to other medical conditions such as iron-deficiency or lead exposure) defined as hemoglobin <10 g/dL, platelet count <100,000/microL, or neutrophil count <1000/microL
--Splenomegaly evident by CT imaging with craniocaudal spleen measurement >10 cm
--Lymphadenopathy evident by CT imaging with at least 1 measurable index lymph node (long axis >1.5 cm) as per Cheson methodology
--GLILD or other PID-related ILD with quantifiable CT chest imaging findings evident on baseline CT scan and previous pathologic confirmation of GLILD or other PID-related ILD
-At screening, vital signs (systolic and diastolic blood pressure, pulse rate, and oxygen saturation in the absence of any supplemental oxygen) will be assessed in the sitting position after the subject has rested for at least three minutes. If the initial assessment yields vital sign parameters outside the defined ranges, a subsequent 2 assessments may be completed. If the average of all 3 repeated vital sign assessments are found within range, the subject is considered to have met this inclusion criterion. Ranges:
--Systolic blood pressure 80-139 mm Hg
--Diastolic blood pressure 50-89 mm Hg
--Pulse rate 50-110 bpm
--Oxygen saturation 93-100%
-Subjects or their legal representatives (for subjects under the age of 18 years) must be able to communicate with the Investigator and understand and comply with the requirements of the study, including an ability to provide written informed consent before any assessment is performed (through an interpreter if non-English speaking).
EXCLUSION CRITERIA:
-Subject has had a successful hematopoietic stem cell transplant (HSCT).
-Previous or concurrent use of immunosuppressive medication, such as:
--Use of an mTOR inhibitor (e.g., sirolimus, everolimus) or a PI3K(delta) inhibitor (selective or non-selective PI3K inhibitors) within 3 weeks prior to first dosing of study medication.
--Rituximab or other B-cell depleting antibodies, belimumab, cyclophosphamide, or alemtuzumab within 6 months prior to first dosing of study medication.
--Cyclosporine A, mycophenolate mofetil, 6-mercaptopurine, azathioprine, methotrexate, tacrolimus, ruxolitinib, or other JAK inhibitors
within 3 weeks prior to first dosing of study medication.
--Corticosteroids above 25 mg prednisone or equivalent per day within 2 weeks prior to first dosing of study medication.
Other immunosuppressive agents expected to have a significant impact on immune cell number or function.
---Abatacept is allowed during study if the subject has been receiving a stable dosing regimen for more than 3 months prior to first dosing of study medication.
-Subject is receiving concurrent treatment with another investigational therapy or use of another investigational therapy less than 4 weeks or 5 half-lives (whichever is longer) prior to first dosing of study medication.
-History of hypersensitivity to the study drug or to drugs of similar chemical classes.
-Current use of medication known to be a strong inhibitor, or moderate or strong inducer, of isoenzyme cytochrome P450 CYP3A. Treatment can be discontinued or switched to a different medication prior to starting study treatment.
-Current use of medications metabolized by isoenzyme CYP1A2 and have a narrow therapeutic index (drugs whose exposure response indicates that increases in their exposure levels by the concomitant use of potent inhibitors may lead to serious safety concerns [e.g., Torsades de Pointes]).
-Current use of medications that act as breast cancer resistant protein (BCRP), organic anion transporting polypeptide (OATP)1B1, and OATP1B3 substrates.
-Subject has a history or current electrocardiogram (ECG) abnormalities indicating a significant risk of safety for subjects participating in the study, such as the following:
--History of familial long QT syndrome or known family history of Torsades de Pointes.
--Clinically significant cardiac arrhythmias (e.g., sustained ventricular tachycardia and clinically significant second or third-degree atrioventricular block without a pacemaker).
--Resting corrected QT interval (Fridericia preferred but Bazett acceptable) >450 msec in male subjects 16-75 years of age, >460 msec in female subjects 16-75 years of age, and >440 msec in all subjects 12-15 years of age.
--Use of agents known to prolong the QT interval unless it can be permanently discontinued for the duration of the study. Azithromycin or levofloxacin (not both) may be continued if the subject has been receiving it for more than 1 month and the resting corrected QT interval is not greater than the limits above.
-History of acquired immunodeficiency diseases, including a positive human immunodeficiency virus (HIV) test result at screening.
-Uncontrolled chronic or recurrent infectious disease (except those considered to be characteristic of PID) or evidence of tuberculosis infection as defined by a positive QuantiFERON(R) TB-Gold test at Screening. If the presence of latent tuberculosis is established, treatment should be completed following CDC guidelines, and based on best clinical care practice. Exception can be made for patients with a positive test due to a history of having TB that was adequately treated or due to previously treated infection with cross-reactive non-tuberculous mycobacteria.
-Any surgical or medical condition which may jeopardize the subject in case of participation in the study, or might significantly alter the absorption, distribution, metabolism, or excretion of drugs. The Investigator should make this determination in consideration of the subject s medical history and/or clinical or laboratory evidence of any of the following (conditions due to underlying clinical PID phenotype may be permitted):
--Uncontrolled hypertension
--Congestive heart failure (New York Heart Association status of class III or IV)
--Chronic obstructive pulmonary disease (GOLD stage 3-4)
--Chronic need for supplemental oxygen or invasive or noninvasive respiratory support
--Major gastrointestinal tract surgery that may affect drug absorption (such as gastric bypass surgery, gastroenterostomy)
--Acute pancreatitis
--Liver failure or clinically significant liver disease or dysfunction as indicated by ALT or AST greater than 2.5 times the upper limit of normal, bilirubin greater than 2 times the upper limit of normal, international normalized ratio (INR) greater than 1.5 in the absence of anticoagulation, or presence of diuretic refractory ascites
--History of significant renal injury/renal disease severely affecting renal function or presence of impaired renal function as indicated by glomerular filtration rate of less than 30 mL/min/1.73 m^2 estimated using cystatin C measurement.
-A positive hepatitis B surface antigen, positive hepatitis B PCR, positive hepatitis C PCR, or positive hepatitis C antibody result at screening.
--Subjects with a positive hepatitis B core antibody but negative hepatitis B surface antigen and negative hepatitis B PCR should receive tenofovir or other appropriate therapy while on study and have monthly hepatitis B surface antigen and hepatitis B PCR monitoring.
-Administration of live vaccines (this includes any attenuated live vaccines) starting from 6 weeks before first dose of study medication, during the study, and up to 7 days after the last dose of leniolisib.
-Subject has a previous diagnosis of lymphoma that has been treated with chemotherapy, radiotherapy, or transplant within 1 year of the first dose of study medication or is anticipated to require lymphoma treatment within 6 months of the first dose of study medication.
-Subject has a history of malignancy (except lymphoma) within 3 years before the first dose of study medication or has evidence of residual disease from a previously diagnosed malignancy, except for adequately treated cancers of the skin (basal or squamous cell) or carcinoma in situ of the uterine cervix.
-Subject has uncontrolled post-transplant lymphoproliferative disease (PTLD)-like EBV related lymphoproliferative disease.
-Donation or loss of 400 mL or more of blood within 8 weeks before the first dose of study medication.
-Subject has had major surgery requiring hospitalization or radiotherapy within 4 weeks prior to the first dose of study medication or has a planned or expected major surgical procedure during the study period.
-Pregnant or nursing (lactating) individuals, where pregnancy is defined as the state of conception and until the termination of gestation, confirmed by a positive hCG serum laboratory test.
-Individuals of child-bearing potential who are physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing of study medication and for 7 days after stopping study treatment.
-Diagnosis of JMML.
Principal Investigator
Referral Contact
For more information: