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NCT02435173

Study of Efficacy of CDZ173 in Patients With APDS/PASLI

Completed Phase 2, PHASE3 Results posted Last updated 10 August 2022
What this trial tests

Phase 2, PHASE3 trial testing CDZ173 in Common Variable Immunodeficiency (CVID), APDS / PASLI in 37 participants. Completed in 16 August 2021.

Timeline
24 August 2015
Primary endpoint
16 August 2021
16 August 2021

Quick facts

Lead sponsorNovartis Pharmaceuticals
PhasePhase 2, PHASE3
StatusCompleted
Study typeINTERVENTIONAL
Allocationrandomized
Designparallel
Maskingtriple
Primary purposetreatment
Enrollment37
Start date24 August 2015
Primary completion16 August 2021
Estimated completion16 August 2021
Sites10 locations across Italy, Netherlands, Russia, Ireland, United Kingdom, Germany, Belarus, United States

Drugs / interventions tested

Conditions studied

Sponsor

Novartis Pharmaceuticals — full company profile →

Who can join

Adults 12 to 75, any sex, with Common Variable Immunodeficiency (CVID), APDS / PASLI. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Part I: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) Primary · From the start of treatment to 30 days after end of treatment, assessed up to maximum duration of 114 days

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.

CDZ173 10 mg AEs
GroupValue95% CI
Part I: CDZ173 10 mg2
CDZ173 10 mg SAEs
GroupValue95% CI
Part I: CDZ173 10 mg0
CDZ173 30 mg AEs
GroupValue95% CI
Part I: CDZ173 10 mg2
CDZ173 30 mg SAEs
GroupValue95% CI
Part I: CDZ173 10 mg0
CDZ173 70 mg AEs
GroupValue95% CI
Part I: CDZ173 10 mg4
CDZ173 70 mg SAEs
GroupValue95% CI
Part I: CDZ173 10 mg0
Part I: CDZ173 Dose Concentration Primary · Days 1, 29 and 57 (0.25 and 3 h post morning dose) and Day 84

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.

Day 1: 0.25 h post-dose
GroupValue95% CI
Part I: CDZ17310.10± 1.10
Day 1: 3 h post-dose
GroupValue95% CI
Part I: CDZ173321.00± 115.00
Day 29: 0.25 h post-dose
GroupValue95% CI
Part I: CDZ173249.00± 540.00
Day 29: 3 h post-dose
GroupValue95% CI
Part I: CDZ173916.00± 185.00
Day 57: 0.25 h post-dose
GroupValue95% CI
Part I: CDZ173150.00± 143.00
Day 57: 3 h post-dose
GroupValue95% CI
Part I: CDZ1731710.00± 782.00
Day 84
GroupValue95% CI
Part I: CDZ173998.00± 455.00
Part I: Percentage of Inhibition of Unstimulated and Stimulated pAkt Levels in B Cells Primary · Baseline, days 29 and 57 (3 and 12 h post-dose) and day 84

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 availab

CD20B Unstimulated: Day 29 - 3 h post-dose
GroupValue95% CI
Part I: CDZ17382.07± 7.25
CD20B Stimulated: Day 29 - 3 h post-dose
GroupValue95% CI
Part I: CDZ17378.00± 7.25
CD20B Unstimulated: Day 29 - 12 h post-dose
GroupValue95% CI
Part I: CDZ17350.58± 18.73
CD20B Stimulated: Day 29 - 12 h post-dose
GroupValue95% CI
Part I: CDZ17347.14± 7.83
CD20B Unstimulated: Day 57 - 3 h post-dose
GroupValue95% CI
Part I: CDZ17386.61± 5.26
CD20B Stimulated: Day 57 - 3 h post-dose
GroupValue95% CI
Part I: CDZ17360.98± 54.05
CD20B Unstimulated: Day 57 - 12 h post-dose
GroupValue95% CI
Part I: CDZ17353.18± 16.59
CD20B Stimulated: Day 57 - 12 h post-dose
GroupValue95% CI
Part I: CDZ17363.65± 21.03
Part II: Change From Baseline in the log10 Transformed Sum of Product of Diameters (SPD) in the Index Lesions Primary · Baseline and Day 85

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 su

GroupValue95% CI
Part II: CDZ173-0.30± 0.04
Part II: Placebo-0.06± 0.06
Part II: Change From Baseline in Percentage of naïve B Cells Out of Total B Cells Primary · Baseline and Day 85

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.

GroupValue95% CI
Part II: CDZ17334.76± 3.08
Part II: Placebo-5.37± 3.95
Part I & II: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) for CDZ173 Secondary · Part I: Days 1, 29 and 57 / Part II: Day 1

Venous whole blood samples were collected for activity-based pharmacokinetics characterization. AUClast was calculated from plasma concentration-time data using non-compartmental methods. AUClast was calculated at the first day of every CDZ173 dose level (10, 30 and 70 mg) for Part I and (70 mg) for Part II. No methods for imputation of missing data were used.

Day 1
GroupValue95% CI
Part I: CDZ1731760.0± 441.0
Part II: CDZ17310400.0± 2800.0
Day 29
GroupValue95% CI
Part I: CDZ1734760.0± 816.0
Day 57
GroupValue95% CI
Part I: CDZ17310800.0± 3310.0
Part I & II: Maximum Observed Plasma Concentration (Cmax) for CDZ173 Secondary · Part I: Days 1, 29 and 57 / Part II: Day 1

Venous whole blood samples were collected for activity-based pharmacokinetics characterization. Cmax was calculated from plasma concentration-time data using non-compartmental methods. Cmax was calculated at the first day of every CDZ173 dose level (10, 30 and 70 mg) for Part I and (70 mg) for Part II. No methods for imputation of missing data were used.

Day 1
GroupValue95% CI
Part I: CDZ173393.0± 137.0
Part II: CDZ1732150.0± 576.0
Day 29
GroupValue95% CI
Part I: CDZ1731060.0± 222.0
Day 57
GroupValue95% CI
Part I: CDZ1732540.0± 747.0
Part I & II: Mental Component Summary (MCS) and Physical Component Summary (PCS) From Short Form 36 (SF-36) Survey Secondary · Part I: Baseline and Days 29, 57 and 84 / Part II: Baseline and Days 29, 57 and 85

The SF-36 is a widely used and extensively studied instrument to measure health-related quality of life (HRQoL) among healthy subjects and patients with acute and chronic conditions. It consists of eight subscales that can be scored individually: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional, and Mental Health. The subscales are aggregated to derive two overall summary scores: the Physical Component Summary (PCS) and the Mental Component Summary (MCS) scores. PCS and MCS scores range from 0 to 100 with a higher score indicating a

Day -1: Mental Component Summary
GroupValue95% CI
Part I: CDZ17347.94± 8.22
Part II: CDZ17347.36± 7.98
Part II: Placebo45.94± 8.14
Day -1: Physical Component Summary
GroupValue95% CI
Part I: CDZ17347.54± 9.24
Part II: CDZ17344.49± 7.08
Part II: Placebo44.06± 8.59
Day 29: Mental Component Summary
GroupValue95% CI
Part I: CDZ17347.94± 8.22
Part II: CDZ17349.98± 8.06
Part II: Placebo49.52± 6.70
Day 29: Physical Component Summary
GroupValue95% CI
Part I: CDZ17347.54± 9.24
Part II: CDZ17347.87± 7.66
Part II: Placebo44.62± 7.57
Day 57: Mental Component Summary
GroupValue95% CI
Part I: CDZ17347.94± 8.22
Part II: CDZ17349.12± 8.17
Part II: Placebo45.92± 7.31
Day 57: Physical Component Summary
GroupValue95% CI
Part I: CDZ17347.54± 9.24
Part II: CDZ17347.04± 7.30
Part II: Placebo47.20± 9.75
Day 84 (Part I) / Day 85 (Part II): Mental Component Summary
GroupValue95% CI
Part I: CDZ17347.94± 8.22
Part II: CDZ17349.22± 8.17
Part II: Placebo47.32± 8.73
Day 84 (Part I) / Day 85 (Part II): Physical Component Summary
GroupValue95% CI
Part I: CDZ17347.54± 9.24
Part II: CDZ17347.59± 6.22
Part II: Placebo47.48± 8.48
Part I & II: Overall Work Impairment Due to Health Score From Work Productivity Activity Impairment and Classroom Impairment Questionnaire (WPAI-CIQ) Secondary · Part I: Baseline and Days 29, 57 and 84 / Part II: Baseline and Days 29, 57 and 85

The Work Productivity Activity Impairment (WPAI) questionnaire measures the amount of absence or presence for work attendance and daily work activity impairment attributable to APDS/PASLI. As younger participants (age 12 and above) were enrolled in the study the WPAI-CIQ was used for all participants as it also measures the amount of absence or presence for school attendance and daily classroom activity impairment. Participants responded for classroom or work-related questions depending on their situation. WPAI-CIQ consists of 10 questions that yield 4 types of scores: absenteeism, presenteeis

Baseline
GroupValue95% CI
Part I: CDZ17325.00± 35.36
Part II: CDZ17351.25± 37.23
Part II: Placebo5.00± 7.07
Day 29
GroupValue95% CI
Part I: CDZ17344.00± 0
Part II: CDZ17335.31± 23.12
Part II: Placebo5.00± 7.07
Day 57
GroupValue95% CI
Part I: CDZ17362.31± 0
Part II: CDZ17335.49± 24.70
Part II: Placebo10.00± 14.14
Day 84 (Part I) / Day 85 (Part II)
GroupValue95% CI
Part I: CDZ17344.41± 7.90
Part II: CDZ17335.59± 31.85
Part II: Placebo25.00± 7.07
Part I & II: Overall Classroom Impairment Due to Health Score From the Work Productivity Activity Impairment and Classroom Impairment Questionnaire (WPAI-CIQ) Secondary · Part I: Baseline and Days 29, 57 and 84 / Part II: Baseline and Days 29, 57 and 85

The Work Productivity Activity Impairment (WPAI) questionnaire measures the amount of absence or presence for work attendance and daily work activity impairment attributable to APDS/PASLI. As younger participants (age 12 and above) were enrolled in the study the WPAI-CIQ was used for all participants as it also measures the amount of absence or presence for school attendance and daily classroom activity impairment. Participants responded for classroom or work-related questions depending on their situation. WPAI-CIQ consists of 10 questions that yield 4 types of scores: absenteeism, presenteeis

Baseline
GroupValue95% CI
Part I: CDZ17365.68± 33.49
Part II: CDZ17347.33± 44.75
Part II: Placebo23.75± 30.92
Day 29
GroupValue95% CI
Part I: CDZ17357.30± 18.09
Part II: CDZ1730.00± 0
Part II: Placebo22.65± 24.37
Day 57
GroupValue95% CI
Part I: CDZ17370.13± 18.68
Part II: CDZ17312.14± 3.03
Part II: Placebo22.40± 26.16
Day 84 (Part I) / Day 85 (Part II)
GroupValue95% CI
Part I: CDZ17368.52± 18.74
Part II: CDZ17351.00± 0.00
Part II: Placebo5.00± 7.07
Part I & II: Physician's Global Assessment (PGA) Secondary · Part I: Baseline and Days 29, 57 and 84 / Part II: Baseline and Days 29, 57 and 85

In the physician's global assessment questionnaire the Investigator rated the disease activity of their patient using 100 mm Visual analogue Scale (VAS) ranging from "no disease activity" (0) to "maximal disease activity" (100). To enhance objectivity, the physician was not aware of the specific patient's global assessment, when performing his own assessment on that patient. No methods for imputation of missing data were used.

Baseline
GroupValue95% CI
Part I: CDZ17334.7± 17.07
Part II: CDZ17347.10± 17.65
Part II: Placebo41.38± 17.78
Day 29
GroupValue95% CI
Part I: CDZ17321.8± 9.70
Part II: CDZ17338.81± 23.73
Part II: Placebo29.75± 9.99
Day 57
GroupValue95% CI
Part I: CDZ17322.5± 13.55
Part II: CDZ17334.02± 18.89
Part II: Placebo24.13± 18.34
Day 84 (Part I) / Day 85 (Part II)
GroupValue95% CI
Part I: CDZ1738.8± 4.12
Part II: CDZ17326.70± 22.82
Part II: Placebo25.88± 16.15
Part I & II: Patient's Global Assessment (PtGA) Secondary · Part I: Baseline and Days 29, 57 and 84 / Part II: Baseline and Days 29, 57 and 85

In the patient's global assessment questionnaire patients are asked about their APDS/PASLI related well-being using 100 mm visual analogue scale (VAS) ranging from "very poor" (0) to "very good" (100). No methods for imputation of missing data were used.

Baseline
GroupValue95% CI
Part I: CDZ17362.0± 21.90
Part II: CDZ17354.53± 21.47
Part II: Placebo62.50± 26.56
Day 29
GroupValue95% CI
Part I: CDZ17365.0± 22.21
Part II: CDZ17368.37± 19.31
Part II: Placebo57.75± 24.03
Day 57
GroupValue95% CI
Part I: CDZ17367.5± 21.83
Part II: CDZ17364.79± 19.61
Part II: Placebo69.50± 21.93
Day 84 (Part I) / Day 85 (Part II)
GroupValue95% CI
Part I: CDZ17372.5± 13.37
Part II: CDZ17367.58± 16.57
Part II: Placebo60.25± 23.66

Adverse events — posted to ClinicalTrials.gov

Time frame: Part I and Part II: Adverse events (AEs) were reported from the start of treatment to 30 days after end of treatment, assessed up to maximum duration of 114 days for Part I and 115 days for Part II. For the subset of participants in Part II that rolled over to the extension study (CCDZ173X2201E1) directly after the last treatment dose in Part II, AEs were reported from the start of treatment to end of treatment, assessed up to maximum duration of 85 days.. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Part I: CDZ173 10 mg
Serious: 0/6 (0%)
Deaths: 0/6
Part I: CDZ173 30 mg
Serious: 0/6 (0%)
Deaths: 0/6
Part I: CDZ173 70 mg
Serious: 0/6 (0%)
Deaths: 0/6
Part I: Total
Serious: 0/6 (0%)
Deaths: 0/6
Part II: CDZ173 70 mg
Serious: 3/21 (14%)
Deaths: 0/21
Part II: Placebo
Serious: 2/10 (20%)
Deaths: 0/10

Serious adverse events (11 terms)

ReactionSystemPart I: CDZ173 10 mgPart I: CDZ173 30 mgPart I: CDZ173 70 mgPart I: TotalPart II: CDZ173 70 mgPart II: Placebo
LymphadenopathyBlood and lymphatic system disorders
Infective exacerbation of bronchiectasisInfections and infestations
MastoiditisInfections and infestations
Urinary tract infectionInfections and infestations
Alcohol poisoningInjury, poisoning and procedural complications
Lipase increasedInvestigations
Failure to thriveMetabolism and nutrition disorders
ComaNervous system disorders
DyspnoeaRespiratory, thoracic and mediastinal disorders
Pulmonary hypertensionRespiratory, thoracic and mediastinal disorders
Dependence on oxygen therapySocial circumstances
Other adverse events (95 terms — click to expand)

ReactionSystemPart I: CDZ173 10 mgPart I: CDZ173 30 mgPart I: CDZ173 70 mgPart I: TotalPart II: CDZ173 70 mgPart II: Placebo
HeadacheNervous system disorders
SinusitisInfections and infestations
NauseaGastrointestinal disorders
DiarrhoeaGastrointestinal disorders
AstheniaGeneral disorders
FatigueGeneral disorders
PyrexiaGeneral disorders
Upper respiratory tract infectionInfections and infestations
Back painMusculoskeletal and connective tissue disorders
Neck painMusculoskeletal and connective tissue disorders
AlopeciaSkin and subcutaneous tissue disorders
EczemaSkin and subcutaneous tissue disorders
Sinus tachycardiaCardiac disorders
TachycardiaCardiac disorders
Methylenetetrahydrofolate reductase gene mutationCongenital, familial and genetic disorders
DeafnessEar and labyrinth disorders
External ear painEar and labyrinth disorders
HypoacusisEar and labyrinth disorders
VertigoEar and labyrinth disorders
Conjunctivitis allergicEye disorders
EpiscleritisEye disorders
Abdominal discomfortGastrointestinal disorders
Abdominal painGastrointestinal disorders
Abdominal pain upperGastrointestinal disorders
Aphthous ulcerGastrointestinal disorders
ConstipationGastrointestinal disorders
Dental cariesGastrointestinal disorders
DyspepsiaGastrointestinal disorders
Gastrooesophageal reflux diseaseGastrointestinal disorders
HaematocheziaGastrointestinal disorders
ToothacheGastrointestinal disorders
VomitingGastrointestinal disorders
Vascular device occlusionGeneral disorders
Acute sinusitisInfections and infestations
Clostridium difficile colitisInfections and infestations
ConjunctivitisInfections and infestations
Fungal skin infectionInfections and infestations
GastroenteritisInfections and infestations
Gastrointestinal infectionInfections and infestations
Groin infectionInfections and infestations

Most-reported serious reactions: Lymphadenopathy, Infective exacerbation of bronchiectasis, Mastoiditis, Urinary tract infection, Alcohol poisoning, Lipase increased, Failure to thrive, Coma.

Data from ClinicalTrials.gov NCT02435173 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. PI3K inhibitors are finally coming of age.
    Vanhaesebroeck B, Perry MWD, Brown JR, André F, et al · · 2021 · cited 353× · PMID 34127844 · DOI 10.1038/s41573-021-00209-1
  2. PI3Kδ and primary immunodeficiencies.
    Lucas CL, Chandra A, Nejentsev S, Condliffe AM, et al · · 2016 · cited 266× · PMID 27616589 · DOI 10.1038/nri.2016.93
  3. Targeting senescent cells in translational medicine.
    Paez-Ribes M, González-Gualda E, Doherty GJ, Muñoz-Espín D. · · 2019 · cited 230× · PMID 31746100 · DOI 10.15252/emmm.201810234
  4. Effective "activated PI3Kδ syndrome"-targeted therapy with the PI3Kδ inhibitor leniolisib.
    Rao VK, Webster S, Dalm VASH, Šedivá A, et al · · 2017 · cited 221× · PMID 28972011 · DOI 10.1182/blood-2017-08-801191
  5. Human inborn errors of immunity: An expanding universe.
    Notarangelo LD, Bacchetta R, Casanova JL, Su HC. · · 2020 · cited 195× · PMID 32651211 · DOI 10.1126/sciimmunol.abb1662
  6. Conformational disruption of PI3Kδ regulation by immunodeficiency mutations in <i>PIK3CD</i> and <i>PIK3R1</i>.
    Dornan GL, Siempelkamp BD, Jenkins ML, Vadas O, et al · · 2017 · cited 95× · PMID 28167755 · DOI 10.1073/pnas.1617244114
  7. Discovery of CDZ173 (Leniolisib), Representing a Structurally Novel Class of PI3K Delta-Selective Inhibitors.
    Hoegenauer K, Soldermann N, Zécri F, Strang RS, et al · · 2017 · cited 85× · PMID 28947947 · DOI 10.1021/acsmedchemlett.7b00293
  8. A randomized, placebo-controlled phase 3 trial of the PI3Kδ inhibitor leniolisib for activated PI3Kδ syndrome.
    Rao VK, Webster S, Šedivá A, Plebani A, et al · · 2023 · cited 81× · PMID 36399712 · DOI 10.1182/blood.2022018546

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