Study of Efficacy of CDZ173 in Patients With APDS/PASLI

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/ p110δ-activating Mutation Causing Senescent T Cells, Lymphadenopathy and Immunodeficiency)

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.

Study Overview

• Status: Completed
• Conditions: Common Variable Immunodeficiency (CVID), APDS / PASLI
• Intervention / Treatment: Other: Placebo; Drug: CDZ173

Detailed Description

This was a 2-part (Part I and Part II), Phase 2/3, multi-center study in subjects with APDS/PASLI.

Part I of the study was a non-randomized, open-label, within-patient up-titration dose-finding part in 6 participants with APDS/PASLI. The starting dose was 10 mg followed by 30 mg and 70 mg b.i.d. for 4 weeks at each dose level respectively. Part I consisted of three distinct study periods:

Screening / Baseline visit (Day -50 to Day-1): This period was used to confirm that the study inclusion and exclusion criteria were met. Participants who were deemed eligible for enrollment into the study attended the clinic on Day -1 for baseline assessments prior to randomization.

Treatment period (Day 1 to Day 84): Participants started treatment on Day 1 receiving 10 mg of CDZ173 twice daily (b.i.d.) until Day 28. After a continuous safety review and a review of PK and PD data, participants assessed as satisfactory proceeded to the next dose levels: from Day 29 to Day 56 participants received 30 mg CDZ173 b.i.d. and from Day 57 to Day 84, if assessed as satisfactory, participants received 70 mg CDZ173 b.i.d.

Follow-up (Day 85-114): After completion of the treatment period, participants were followed-up for safety for four weeks until Day 114.

Part II was a randomized, subject, investigator and sponsor-blinded, placebo-controlled, fixed dose part investigating 31 participants with APDS/PASLI. The CDZ173 dose used in this Part was selected based on safety, tolerability, PK and PD data from Part I. Part II consisted of three distinct study periods:

Screening / Baseline visit (Day -50 to Day-1): This period was used to confirm that the study inclusion and exclusion criteria were met. Participants who were deemed eligible for enrollment into the study attended the clinic on Day -1 for baseline assessments prior to randomization.

Treatment period (Day 1 to Day 85): On Day 1, Participants were randomized to one of the two treatment groups in a 2:1 ratio to receive either 70 mg CDZ173 b.i.d. or matching placebo until Day 85.

Follow-up (Day 86-115): On Day 86, a subset of participants rolled over to CCDZ173X2201E1 extension study and were not followed up for safety after end of treatment in CCDZ173X2201. Participants, who did not directly roll over to the extension study, after last treatment dose were followed-up for safety for four weeks until Day 115.

• Study Type: Interventional
• Enrollment (Actual): 37
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Belarus
  • Minsk, Belarus, 223053
    • Novartis Investigative Site
• Czechia
  • Prague 5, Czechia, 150 00
    • Novartis Investigative Site
• Germany
  • Dresden, Germany, 01307
    • Novartis Investigative Site
• Ireland
  • Dublin, Ireland
    • Novartis Investigative Site
• Italy
  • Brescia, Italy, 25123
    • Novartis Investigative Site
  • PA
    • Palermo, PA, Italy, 90127
      • Novartis Investigative Site
• Netherlands
  • Rotterdam, Netherlands, 3000 CA
    • Novartis Investigative Site
• Russian Federation
  • Moscow, Russian Federation, 117198
    • Novartis Investigative Site
• United Kingdom
  • Belfast, United Kingdom, BT9 7AB
    • Novartis Investigative Site
• United States
  • Maryland
    • Bethesda, Maryland, United States, 20814
      • National Institute of Health NIH

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 75 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

• 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.

Key Exclusion Criteria:

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part I: CDZ173; 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; CDZ173 10 and 70 mg capsules for oral administration.; Other Names: Leniolisib
Experimental: Part II: CDZ173; Participants received CDZ173 70 mg b.i.d. from Day 1 to Day 85.	Drug: CDZ173; CDZ173 10 and 70 mg capsules for oral administration.; Other Names: Leniolisib
Placebo Comparator: Part II: Placebo; Participants received Placebo b.i.d. from Day 1 to Day 85.	Other: Placebo; Placebo capsules for oral administration

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part I & II: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) for CDZ173	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.	Part I: Days 1, 29 and 57 / Part II: Day 1
Part I & II: Maximum Observed Plasma Concentration (Cmax) for CDZ173	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.	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	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 more favorable health state (range = 0 "worst" - 100 "best"). No methods for imputation of missing data were used.	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)	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, presenteeism, work/classroom productivity loss and activity impairment. The Overall work impairment due to health (%) score ranges from 0 to 100% with 100% indicating total work impairment and 0% no impairment at all. No methods for imputation of missing data were used.	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)	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, presenteeism, work/classroom productivity loss and activity impairment. The Overall classroom impairment due to health (%) score ranges from 0 to 100% with 100% indicating total classroom impairment and 0% no impairment at all. A higher percentage indicates a negative outcome. No methods for imputation of missing data were used.	Part I: Baseline and Days 29, 57 and 84 / Part II: Baseline and Days 29, 57 and 85
Part I & II: Physician's Global Assessment (PGA)	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.	Part I: Baseline and Days 29, 57 and 84 / Part II: Baseline and Days 29, 57 and 85
Part I & II: Patient's Global Assessment (PtGA)	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.	Part I: Baseline and Days 29, 57 and 84 / Part II: Baseline and Days 29, 57 and 85
Part I & II: High Sensivity C Reactive Protein (hsCRP) as Biomarker for Systemic Inflammation	High Sensitivity C reactive protein is a blood test biomarker for inflammation in the body. Sequential blood samples were collected in all participants. HsCRP was measured in serum using a latex immunochemilunminometric assay (ICMA). No methods for imputation of missing data were used.	Part I: Baseline and Days 1, 15, 29, 57, 84 / Part II: Baseline and Days 1, 15, 29, 57, 85
Part I & II: Lactate Dehydrogenase (LDH) as Biomarker for Systemic Inflammation	Lactate dehydrogenase is a blood test biomarker for inflammation in the body. Sequential blood samples were collected in all participants. LDH was measured in serum using a latex immunochemilunminometric assay (ICMA). No methods for imputation of missing data were used.	Part I: Baseline and Days 1, 15, 29, 57, 84 / Part II: Baseline and Days 1, 15, 29, 57, 85
Part II: Beta2 Microglobulin as Biomarker for Systemic Inflammation	Beta2 microglobulin is a blood test biomarker for inflammation in the body. Sequential blood samples were collected in all participants. Beta2 microglobulin was measured in serum using a latex immunochemilunminometric assay (ICMA). No methods for imputation of missing data were used.	Baseline and Days 1, 15, 29, 57, 85
Part II: Ferritin as Biomarker for Systemic Inflammation	Ferritin is a blood test biomarker for inflammation in the body. Sequential blood samples were collected in all participants. Ferritin was measured in serum using a Electrochemiluminescence immunoassay (ECLIA). No methods for imputation of missing data were used.	Baseline and Days 1, 15, 29, 57, 85
Part II: Fibrinogen as Biomarker for Systemic Inflammation	Fibrinogen is a blood test biomarker for inflammation in the body. Sequential blood samples were collected in all participants. Fibrinogen was measured in serum using an Electrochemiluminescence immunoassay (ECLIA). No methods for imputation of missing data were used.	Baseline and Days 1, 15, 29, 57, 85
Part II: Erythrocyte Sedimentation Rate (ESR) as Biomarker for Systemic Inflammation	Erythrocyte sedimentation rate (ESR) is a blood test biomarker for inflammation in the body. Sequential blood samples were collected in all participants. ESR was measured in whole blood using the Westergren method. No methods for imputation of missing data were used.	Baseline and Days 1, 15, 29, 57, 85
Part II: 3D Volume of Index Lesions	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. The 3D volume of index lesions was identified as per the Cheson criteria. A reduction of the 3D volume of the index lesions indicated a positive outcome.	Baseline and Day 85
Part II: 3D Volume of the Spleen	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 spleen was performed and its 3D volume was identified as per the Cheson criteria. A reduction of the spleen volume indicated a positive outcome.	Baseline and Day 85

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Principal Investigator: Koneti V Rao, MD, National Institutes of Health (NIH); Principal Investigator: Virgil Dalm, MD, Erasmus Medical Center; Principal Investigator: Anna Šedivá, MD, Motol University

Publications and helpful links

General Publications

• Rao VK, Webster S, Sediva A, Plebani A, Schuetz C, Shcherbina A, Conlon N, Coulter TI, Dalm VA, Trizzino A, Zharankova Y, Kulm EM, Korholz JC, Lougaris V, Rodina Y, Radford K, Bradt J, Kucher K, Relan A, Holland SM, Lenardo MJ, Uzel G. Randomized, Placebo-Controlled, Phase 3 Trial of PI3Kdelta Inhibitor Leniolisib for Activated PI3Kdelta Syndrome. Blood. 2022 Nov 18:blood.2022018546. doi: 10.1182/blood.2022018546. Online ahead of print.
• 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.

Helpful Links

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

Study record dates

Study Major Dates

• Study Start (Actual): August 24, 2015
• Primary Completion (Actual): August 16, 2021
• Study Completion (Actual): August 16, 2021

Study Registration Dates

• First Submitted: February 24, 2015
• First Submitted That Met QC Criteria: April 30, 2015
• First Posted (Estimate): May 6, 2015

Study Record Updates

• Last Update Posted (Actual): August 10, 2022
• Last Update Submitted That Met QC Criteria: August 8, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: APDS; PASLI; PI3Kdelta
• Additional Relevant MeSH Terms: Immune System Diseases; Immunologic Deficiency Syndromes; Common Variable Immunodeficiency
• Other Study ID Numbers: CCDZ173X2201; 2014-003876-22 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No