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Protocol Details

An open-label, non-randomized, within-patient dose-finding study followed by a randomized, subject, investigator and sponsor-blinded placebo controlled study to assess the efficacy and safety of CDZ173 (leniolisib) in patients with APDS/PASLI (Activated phosphoinositide 3-kinase delta syndrome/p110 -activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency)

This study is NOT currently recruiting participants.

Summary | Eligibility | Citations | Contacts




Sponsoring Institute

National Institute of Allergy and Infectious Diseases (NIAID)

Recruitment Detail

Type: Completed Study; data analyses ongoing
Gender: Male & Female
Min Age: 12 Years
Max Age: 75 Years

Referral Letter Required


Population Exclusion(s)

Pregnant Women



Recruitment Keyword(s)




Investigational Drug(s)

CDZ173, Leniolisib

Investigational Device(s)



Drug: CDZ173, leniolisib
Drug: Placebo

Supporting Site

National Institute of Allergy and Infectious Diseases


- APDS/PASLI is a rare disease that impairs the immune system. The current treatment only improves the disease s symptoms. Researchers want to see if the new drug CDZ173 can treat the disease itself.


- To see if CDZ173 can be used to treat APDS/PASLI.


- People ages 16-75 with APDS/PASLI.


- Participants will be screened with medical history, physical exam, and blood and urine tests. They will be screened for certain diseases. They will have an electrocardiogram (EKG) and CT scan.

- For EKG, participants heart activity will be measured. Sticky pads will be put on their arms, legs, and chest.

- For CT, participants will lie on a table inside a machine that takes pictures. A dye will be injected through an IV in their arm.

- Participants will repeat some screening tests. They will also complete questionnaires about how APDS/PASLI affects them.

- Participants will take the study drug by mouth twice a day for 3 months. The dose will vary. They will keep a drug diary.

- Participants will visit the clinic weekly. Visits will last 2-4 hours. They will repeat some screening tests and complete questionnaires. Visits where doses are increased will take longer. Participants may be admitted and may get an IV for the collection of serial blood samples.

- About 28 days after the last drug dose, participants will have a final visit. They will repeat some screening tests.

- Participants will be contacted by phone 2 times within 30 days of the final visit to discuss their health.

- The study lasts 16 weeks.

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Patients eligible for inclusion in this study have to fulfill all of the following criteria:

1. Written informed consent must be obtained before any assessment is performed.

2. Male and female patients age 12 to 75 years of age (inclusive), who have a documented APDS/PASLI-associated genetic PI3K delta mutation. Patients with mutations in either PIK3CD or PIK3R1 can be included.

3. In Part I and II of the study patients must have nodal and/or extranodal lymphoproliferation and clinical findings and manifestations compatible with APDS/PASLI such as a history of repeated oto-sino-pulmonary infections and/or organ dysfunction (e.g., lung, liver). Additionally in Part II, patients must have at least one measurable nodal lesion on a CT or MRI scan. The baseline scan can be used for this assessment. In case the baseline scan result is not yet available and a patient has a historical scan performed within one year of screening, this can be used for eligibility purposes. If more than one scan is available, the latest one is the one that has to be used

for eligibility.

4. At screening, vital signs (systolic and diastolic blood pressure and pulse rate) will be assessed in the sitting position after the patient has rested for at least three minutes. Sitting vital signs should be within the following ranges:

-Systolic blood pressure, 90-139 mm Hg

-Diastolic blood pressure, 50-89 mm Hg

-Pulse rate, 50 - 100 bpm: up to 110 bpm in adolescents

5. Patients must have a minimum body weight of 45 kg.

6. Patients or their legal representatives (for patients under the age of 18 years) must be able to communicate well with the Investigator, to understand and comply with the requirements of the study.


Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No additional exclusions may be applied by the Investigator, in order to ensure that the study population will be representative of all eligible patients.

1. Use of other investigational drugs within 5 half-lives of enrollment, or within 30 days, whichever is longer.

2. History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes.

3. Previous or concurrent use of immunosuppressive medication such as:

-mTOR inhibitor (e.g., siroliMus, rapamycin, everolimus) or a PI3K delta inhibitor (selective or non-selective PI3K inhibitors) within 6 weeks prior to first dosing, however short-term use for up to a total of 5 days is allowed but only up to 1 month prior to enrollment in the study.

-B cell depleters (e.g., rituximab) within 6 months prior to first dosing of study medication; if patients have received prior treatment with a B cell depleter, absolute B lymphocyte counts in the blood must have regained normal values.

-Belimumab or cyclophosphamide within 6 months prior to first dosing of study medication.

-Cyclosporine A, mycophenolate, 6-mercaptopurine, azathioprine or methotrexate within 3 months prior to first dosing of study medication.

-Glucocorticoids above 25 mg prednisone or equivalent per day within 2 weeks prior to first dosing of study medication.

-Other immunosuppressive medication where effects are expected to persist at start of dosing of study medication.

4. History or current diagnosis of ECG abnormalities indicating significant risk of safety for patients participating in the study such as:

- History of familial long QT syndrome or known family history of Torsades de Pointes

- Concomitant clinically significant cardiac arrhythmias, e.g. sustained ventricular tachycardia, and clinically significant second or third degree Atrioventricular (AV) block without a pacemaker

- Resting QTcF (Fridericia preferred, but Bazett acceptable) > 450 msec in male patients of the age group 16 75 years, > 460 msec in female patients of the age group 16 75 years and > 440 msec in patients of the age group 12 15 years, if the measurement is confirmed with an additional ECG repeated as soon as possible. Concomitant use of agents known to prolong the QT interval unless it can be permanently discontinued for the duration of the study

5. Current use of medication known to be strong inhibitors or moderate or strong inducers of isoenzyme CYP3A, and the treatment cannot be discontinued or switched to a different medication prior to starting study treatment.

6. Current use of medication that are 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)).

7. Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of drugs, or which may jeopardize the patient in case of participation in the study. The Investigator should make this determination in consideration of the patient s medical history and/or clinical or laboratory evidence of any of the following (conditions due to APDS/PASLI are permitted):

- Uncontrolled hypertension (greater than or equal to 160/95 mmHg)

- Congestive heart failure (New York Heart Association status of class III or IV)

- Chronic obstructive pulmonary disease (GOLD stage 3-4)

- Inflammatory bowel disease, peptic ulcers, gastrointestinal including rectal bleeding

- Major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel resection

-Pancreatic injury or pancreatitis

- Liver disease or liver injury as indicated by clinically significant abnormal liver function tests. ALT and AST greater than 2.5 times upper limit of normal

- History of renal injury/renal disease (e.g. renal trauma, glomerulonephritis, or one kidney only) or presence of impaired renal function as indicated by a serum creatinine level exceeding 1.5 mg/dL (133 micromoles/L)

- Evidence of urinary obstruction or difficulty in voiding at screening

- Uncontrolled diabetes (insulin dependent or non-insulin dependent)

8. History of acquired immunodeficiency diseases, including a positive HIV (ELISA and Western blot) test result at screening.

9. A positive Hepatitis B surface antigen or Hepatitis C test (by PCR) result at screening.

10. 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 whether there is evidence of local recurrence or metastases.

11. Uncontrolled chronic or recurrent infectious disease (with the exception of those that are considered to be characteristic of APDS/PASLI) or evidence of tuberculosis infection as defined by a positive QuantiFERON TB-Gold test at Screening. If presence of latent tuberculosis is established then treatment according to local country guidelines must have been completed before patients can be considered for enrollment.

12. Donation or loss of 400 mL or more of blood within 8 weeks before randomization.

13. Administration of live vaccines (including any attenuated live vaccines) starting from 6 weeks before study entry, during the study and up to 7 days after the last dose of CDZ173 should be excluded.

14. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.

15. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing of study medication and for 2 days after stopping study treatment. Highly effective contraception methods include:

-Total abstinence (when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception

-Female sterilization (have had surgical bilateral oophorectomy and/or hysterectomy), total hysterectomy or tubal ligation at least 6 weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment

-Male sterilization (at least 6 months prior to screening). For female patients on the study, the vasectomized male partner should be the sole partner for that patient

- Use of oral, injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception.

In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment.

Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.

Note: In the case where a safety laboratory assessment at screening is outside of the range specified above, the assessment may be repeated once prior to randomization. If the repeat value remains outside of the specified ranges, the patient is excluded from the study.

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Lucas CL, Kuehn HS, Zhao F, Niemela JE, Deenick EK, Palendira U, Avery DT, Moens L, Cannons JL, Biancalana M, Stoddard J, Ouyang W, Frucht DM, Rao VK, Atkinson TP, Agharahimi A, Hussey AA, Folio LR, Olivier KN, Fleisher TA, Pittaluga S, Holland SM, Cohen JI, Oliveira JB, Tangye SG, Schwartzberg PL, Lenardo MJ, Uzel G. Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110 result in T cell senescence and human immunodeficiency. Nat Immunol. 2014 Jan;15(1):88-97. doi: 10.1038/ni.2771. Epub 2013 Oct 28.

Crank MC, Grossman JK, Moir S, Pittaluga S, Buckner CM, Kardava L, Agharahimi A, Meuwissen H, Stoddard J, Niemela J, Kuehn H, Rosenzweig SD. Mutations in PIK3CD can cause hyper IgM syndrome (HIGM) associated with increased cancer susceptibility. J Clin Immunol. 2014 Apr;34(3):272-6. doi: 10.1007/s10875-014-0012-9. Epub 2014 Mar 8.

Angulo I, Vadas O, Gar(SqrRoot)(Beta)on F, Banham-Hall E, Plagnol V, Leahy TR, Baxendale H, Coulter T, Curtis J, Wu C, Blake-Palmer K, Perisic O, Smyth D, Maes M, Fiddler C, Juss J, Cilliers D, Markelj G, Chandra A, Farmer G, Kielkowska A, Clark J, Kracker S, Debr(SqrRoot)(Copyright) M, Picard C, Pellier I, Jabado N, Morris JA, Barcenas-Morales G, Fischer A, Stephens L, Hawkins P, Barrett JC, Abinun M, Clatworthy M, Durandy A, Doffinger R, Chilvers ER, Cant AJ, Kumararatne D, Okkenhaug K, Williams RL, Condliffe A, Nejentsev S. Phosphoinositide 3-kinase gene mutation predisposes to respiratory infection and airway damage. Science. 2013 Nov 15;342(6160):866-71. doi: 10.1126/science.1243292. Epub 2013 Oct 17.

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Principal Investigator

Referral Contact

For more information:

V. Koneti Rao, M.D.
National Institute of Allergy and Infectious Diseases (NIAID)

Alanvin D. Orpia, R.N.
National Institute of Allergy and Infectious Diseases (NIAID)
National Institutes of Health
Building 10
Room 12C106
10 Center Drive
Bethesda, Maryland 20892
(240) 669-2935

Office of Patient Recruitment
National Institutes of Health Clinical Center (CC)
Building 61, 10 Cloister Court
Bethesda, Maryland 20892
Toll Free: 1-800-411-1222
Local Phone: 301-451-4383
TTY: TTY Users Dial 7-1-1

Clinical Trials Number:


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