Study of Efficacy of CDZ173 in Patients With APDS/PASLI

NCT02435173 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: CCDZ173X22012014-003876-22
• Study Type: interventional
• Target: 37
• Locations: 9 countries
• Sites: 10

Brief Summary

This study was designed to explore CDZ173, a selective PI3Kδ inhibitor, in patients with genetically activated PI3Kδ, i.e., patients with Activated phosphoinositide 3-kinase delta syndrome/ p110δ-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency (APDS/PASLI). The study consisted of two parts: Part I was the open label part designed to establish the safety and pharmacokinetics of CDZ173 in the target population, as well as to select the optimal dose to be tested in Part II. Part II was designed to assess efficacy and safety of CDZ173 in the target population.

Conditions

Common Variable Immunodeficiency (CVID), APDS / PASLI

Keywords

APDS; PASLI; PI3Kdelta

Outcome Measures

Primary Outcomes (5)

• Part I: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

  Number of participants with AEs and SAEs, including significant changes from baseline in physical findings, vital signs, electrocardiograms and laboratory values qualifying and reported as AEs. The number of participants in each category (AEs and SAEs) is reported per dose level: CDZ173 10 mg from Day 1 to Day 28, CDZ173 30 mg from day 29 to day 56 and CDZ173 70 mg from day 57 to day 84.

  From the start of treatment to 30 days after end of treatment, assessed up to maximum duration of 114 days

• Part I: CDZ173 Dose Concentration

  Venous whole blood samples were collected for the assessment of the dose-PD and the PK/PD relationship of CDZ173 in participants with APDS/PASLI for dose selection in Part II. CDZ173 was determined by a validated Liquid chromatography - Mass spectometry (LC-MS) method; anticipated Lower Limit of Quantification (LLOQ) was 3 ng/mL. Concentrations below the LLOQ were reported as "zero" and no methods for imputation of missing data were used.

  Days 1, 29 and 57 (0.25 and 3 h post morning dose) and Day 84

• Part I: Percentage of Inhibition of Unstimulated and Stimulated pAkt Levels in B Cells

  Phosphorylation of Akt in ex vivo stimulated and unstimulated B cells was quantified at baseline and at the end of the 4-week treatment period for each of the three dose levels. Determination of the percentage (%) of CD20B+ phospho-Akt positive cells after ex vivo stimulation of whole blood was performed by flow cytometry analysis. The percentage of inhibition of pAkt was defined as (-1) \* percent change from baseline pAkt value. Unstimulated cells served as controls at each time point. Baseline was defined as the mean of the day -1 value and the pre-dose value on Day 1 when both were available (if one was missing, then baseline was defined as the existing value). A higher percentage of inhibition of stimulated B cells indicates improvement. No methods for imputation of missing data were used.

  Baseline, days 29 and 57 (3 and 12 h post-dose) and day 84

• Part II: Change From Baseline in the log10 Transformed Sum of Product of Diameters (SPD) in the Index Lesions

  For the assessment of the impact of CDZ173 on lymphadenopathy, participants were scanned in a magnetic resonance imaging (MRI) or a computed tomography (CT) scanner as based on clinical practice and local regulation. MRI or CT imaging of the neck, chest, abdomen and pelvis was performed. Index lesions were selected from measurable nodal and extranodal lesions as per the Cheson methodology. A maximum of six of the largest dominant lesions were selected and documented at baseline and assessed again at the end of treatment. The change in lymph node size was measured using the log10 transformed sum of product of diameters (SPD), the sum of the longest lesion diameter (mm)" and "longest perpendicular diameter (mm)". A lower score indicates index lesions SPD reduction. A negative change from baseline indicates improvement.

  Baseline and Day 85

• Part II: Change From Baseline in Percentage of naïve B Cells Out of Total B Cells

  APDS/PASLI patients suffer from dysregulation in B cell function and differentiation with low numbers of naive B cells. Change from baseline in percentage of naïve B cells out of total B cells at the end of treatment was assessed by flow cytometry to evaluate the pharmacodynamic effect of CDZ173 on B cell immunophenotyping. A higher percentage in naïve B out of total B cells is a positive outcome. A positive change from baseline indicates improvement.

  Baseline and Day 85

Secondary Outcomes (15)

• Part I & II: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) for CDZ173

  Part I: Days 1, 29 and 57 / Part II: Day 1

• Part I & II: Maximum Observed Plasma Concentration (Cmax) for CDZ173

  Part I: Days 1, 29 and 57 / Part II: Day 1

• Part I & II: Mental Component Summary (MCS) and Physical Component Summary (PCS) From Short Form 36 (SF-36) Survey

  Part I: Baseline and Days 29, 57 and 84 / Part II: Baseline and Days 29, 57 and 85

• Part I & II: Overall Work Impairment Due to Health Score From Work Productivity Activity Impairment and Classroom Impairment Questionnaire (WPAI-CIQ)

  Part I: Baseline and Days 29, 57 and 84 / Part II: Baseline and Days 29, 57 and 85

• Part I & II: Overall Classroom Impairment Due to Health Score From the Work Productivity Activity Impairment and Classroom Impairment Questionnaire (WPAI-CIQ)

  Part I: Baseline and Days 29, 57 and 84 / Part II: Baseline and Days 29, 57 and 85

Study Arms (3)

Part I: CDZ173

EXPERIMENTAL

Participants consecutively received CDZ173 10 mg twice a day (b.i.d.) from Day 1 to Day 28, CDZ173 30 mg b.i.d. from Day 29 to Day 56 and CDZ173 70 mg b.i.d. from Day 57 to Day 84.

Drug: CDZ173

Part II: CDZ173

EXPERIMENTAL

Participants received CDZ173 70 mg b.i.d. from Day 1 to Day 85.

Drug: CDZ173

Part II: Placebo

PLACEBO COMPARATOR

Participants received Placebo b.i.d. from Day 1 to Day 85.

Other: Placebo

Interventions

CDZ173 DRUG

CDZ173 10 and 70 mg capsules for oral administration.

Also known as: Leniolisib

Part I: CDZ173; Part II: CDZ173

Placebo OTHER

Placebo capsules for oral administration

Part II: Placebo

Eligibility Criteria

• Age: 12 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Male and female patients 12 to 75 years of age (inclusive), who had a documented APDS/PASLI-associated genetic PI3K delta mutation.
• In Part I and Part II, patients must had 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 had at least one measurable nodal lesion on a CT or MRI scan.
• At screening, vital signs (systolic and diastolic blood pressure and pulse rate) were assessed in the sitting position after the patient rested for at least three minutes.

You may not qualify if:

• Previous or concurrent use of immunosuppressive medication.
• Current use of medication known to be strong inhibitor or moderate or strong inducers of isoenzyme CYP3A, if treatment cannot be discontinued or switched to a different medication prior to starting study treatment.
• Current use of medications that are metabolized by isoenzyme CYP1A2 and have a narrow therapeutic index (drugs whose exposureresponse 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)).
• Administration of live vaccines (this includes 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.
• 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.
• 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.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (10)

National Institute of Health NIH

Bethesda, Maryland, 20814, United States

Location

Novartis Investigative Site

Minsk, 223053, Belarus

Location

Novartis Investigative Site

Prague, 150 00, Czechia

Location

Novartis Investigative Site

Dresden, 01307, Germany

Location

Novartis Investigative Site

Dublin, Ireland

Location

Novartis Investigative Site

Palermo, PA, 90127, Italy

Location

Novartis Investigative Site

Brescia, 25123, Italy

Location

Novartis Investigative Site

Rotterdam, 3000 CA, Netherlands

Location

Novartis Investigative Site

Moscow, 117198, Russia

Location

Novartis Investigative Site

Belfast, BT9 7AB, United Kingdom

Location

Related Publications (3)

• Upton JEM, Williams KW, Cant A, Santos A, Bana E Costa J, Bradt J, Harrington A, Gwaltney C. Key outcomes in treatment of activated phosphoinositide 3-kinase delta syndrome: An e-Delphi panel study and responder threshold application. PLoS One. 2025 Oct 15;20(10):e0333341. doi: 10.1371/journal.pone.0333341. eCollection 2025.

  PMID: 41091701 DERIVED

• Rao VK, Webster S, Sediva A, Plebani A, Schuetz C, Shcherbina A, Conlon N, Coulter T, Dalm VA, Trizzino A, Zharankova Y, Kulm E, Korholz J, Lougaris V, Rodina Y, Radford K, Bradt J, Kucher K, Relan A, Holland SM, Lenardo MJ, Uzel G. A randomized, placebo-controlled phase 3 trial of the PI3Kdelta inhibitor leniolisib for activated PI3Kdelta syndrome. Blood. 2023 Mar 2;141(9):971-983. doi: 10.1182/blood.2022018546.

  PMID: 36399712 DERIVED

• Rao VK, Webster S, Dalm VASH, Sediva A, van Hagen PM, Holland S, Rosenzweig SD, Christ AD, Sloth B, Cabanski M, Joshi AD, de Buck S, Doucet J, Guerini D, Kalis C, Pylvaenaeinen I, Soldermann N, Kashyap A, Uzel G, Lenardo MJ, Patel DD, Lucas CL, Burkhart C. Effective "activated PI3Kdelta syndrome"-targeted therapy with the PI3Kdelta inhibitor leniolisib. Blood. 2017 Nov 23;130(21):2307-2316. doi: 10.1182/blood-2017-08-801191. Epub 2017 Sep 29.

  PMID: 28972011 DERIVED

Related Links

• A Plain Language Trial Summary is available on novctrd.com
• A pediatric Plain Language Trial Summary is available on novctrd.com

MeSH Terms

Conditions

Common Variable Immunodeficiency; Activated PI3K-delta Syndrome

Interventions

leniolisib

Condition Hierarchy (Ancestors)

Immunologic Deficiency Syndromes; Immune System Diseases

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

Novartis.email@Novartis.com

+ 1 862 778 8300

Study Officials

• Koneti V Rao, MD

  National Institutes of Health (NIH)

  PRINCIPAL INVESTIGATOR

• Virgil Dalm, MD

  Erasmus Medical Center

  PRINCIPAL INVESTIGATOR

• Anna Šedivá, MD

  Motol University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Part I of the study was a non-randomized, open-label, within-patient up-titration dose-finding part in 6 participants with APDS/PASLI. Part II was a randomized, subject, investigator and sponsor-blinded, placebo-controlled, fixed dose part investigating 31 participants with APDS/PASLI.

Study Record Dates

• First Submitted: February 24, 2015
• First Posted: May 6, 2015
• Study Start: August 24, 2015
• Primary Completion: August 16, 2021
• Study Completion: August 16, 2021
• Last Updated: August 10, 2022
• Results First Posted: March 11, 2022

Record last verified: 2022-08

Data Sharing

• IPD Sharing: Will share

Locations

US (1); NL (1); RU (1); IT (2); GB (1); CZ (1); IE (1); DE (1); BE (1)