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Study of Efficacy of CDZ173 in Patients With APDS/PASLI

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ClinicalTrials.gov Identifier: NCT02435173
Recruitment Status : Recruiting
First Posted : May 6, 2015
Last Update Posted : October 16, 2019
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
This study is designed to explore CDZ173, a selective PI3Kδ inhibitor, in patients with genetically activated PI3Kδ, i.e., patients with APDS/PASLI. The study consists of two parts. Part I is 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 is designed to assess efficacy and safety of CDZ173 in this population.

Condition or disease Intervention/treatment Phase
Common Variable Immunodeficiency (CVID) More Specifically Activated PI3Kdelta Syndrome (APDS) p110delta-activating Mutation Causing Senescent T Cells Lymphadenopathy and Immunodeficiency (PASLI) Drug: CDZ173 Phase 2 Phase 3

Detailed Description:

This study is designed to explore CDZ173, a selective PI3Kδ inhibitor, in patients with genetically activated PI3Kδ, i.e., patients with APDS/PASLI (Activated phosphoinositide 3-kinase delta syndrome/ p110δ-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency)I.

The study consists of two parts. Part I is 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 is designed to assess efficacy and safety of CDZ173 in this population.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Intervention Model Description:

Part I of the study was a non-randomized, open-label, within-patient up-titration study.

Part II is a randomized, subject, investigator and sponsor-blinded, placebo-controlled, fixed dose study

Masking: Triple (Participant, Care Provider, Investigator)
Masking Description: Part I was a non-randomized, open-label study Part II is a randomized subject, investigator and sponsor-blinded, placebo controlled study
Primary Purpose: Treatment
Official Title: 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 in Patients With APDS/PASLI
Actual Study Start Date : August 24, 2015
Estimated Primary Completion Date : July 9, 2020
Estimated Study Completion Date : July 9, 2020


Arm Intervention/treatment
CDZ173
Part I was with-in patient dose escalation with CDZ173 10, 30 and 70 mg bid. Part II is randomized placebo-controlled with CDZ173 70 mg bid and matching placebo
Drug: CDZ173
Part I 10, 30 and 70 mg bid Part II 70 mg bid and matching placebo
Other Name: Leniolisib

Placebo Comparator: Placebo
Part II is placebo controlled
Drug: CDZ173
Part I 10, 30 and 70 mg bid Part II 70 mg bid and matching placebo
Other Name: Leniolisib




Primary Outcome Measures :
  1. Part I: Safety and tolerability of CDZ173 in patients with APDS/PASLI as measured by safety assessments [ Time Frame: 12 weeks ]
    Part I: Safety assessments including AEs, physical exam, vital signs, ECG, and safety laboratory evaluations

  2. Part I: To assess the dose-PD and PK/PD relationship of CDZ173 in patients with APDS/PASLI for dose selection in Part II [ Time Frame: 12 weeks ]
    Part I:Single and multiple dose concentrations of CDZ173 and pAkt inhibition in unstimulated and stimulated whole blood

  3. Part II: To assess the clinical efficacy of CDZ173 in patients with APDS/PASLI [ Time Frame: 12 weeks ]

    Part II - Co-primary endpoint;

    1. Change from baseline in the log10 transformed sum of product of diameters (SPD) in the index lesions selected as per the Cheson methodology from MRI/CT imaging.
    2. Change from baseline in percentage of naïve B cells out of total B cells


Secondary Outcome Measures :
  1. Part I & II: To assess the pharmacokinetics of CDZ173 in patients with APDS/PASLI [ Time Frame: 12 weeks ]
    Part I & II: Single dose CDZ173 PK parameters (including but not limited to Cmax and AUC) and trough evaluations after multiple dose

  2. Part I & II: To assess the efficacy of CDZ173 to modify health-related quality of life in patients with APDS/PASLI [ Time Frame: 12 weeks ]
    Part I & II: SF-36 (Short Form 36) Survey and WPAI-CIQ (Work Productivity Activity Impairment plus Classroom Impairment Questionnaire)

  3. Part I & II: To assess the efficacy of CDZ173 by the Physician's Global Assessment (PGA) and the Patient's Global Assessment (PtGA) [ Time Frame: 12 weeks ]
    Part I & II: Visual analogue scales for PGA and PtGA

  4. Part I & II: To assess biomarkers reflecting the efficacy of CDZ173 to reduce systemic inflammatory components of the disease [ Time Frame: 12 weeks ]
    C reactive protein (CRP), Lactate dehydrogenase (LDH) For Part II additional: beta2 microglobulin, ferritin, fibrinogen and erythrocyte sedimentation rate (ESR)

  5. Part I & II: To assess the treatment benefit to individual patients [ Time Frame: 12 weeks ]
    Part I & II: Narratives

  6. Part II: To assess the safety and tolerability of CDZ173 in patients with APDS/PASLI [ Time Frame: 12 weeks ]
    All safety parameters, including AEs, physical exam, vital signs, ECG, safety laboratory (hematology, blood chemistry, urinalysis)

  7. Part II: To assess the effect of CDZ173 on lymphadenopathy(non-index lesions and spleen) [ Time Frame: 12 weeks ]
    MRI/CT imaging - e.g. 3D volume of index and measurable non-index lesions selected as per the Cheson methodology, and 3D volume and bi-dimensional size of the spleen



Information from the National Library of Medicine

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Ages Eligible for Study:   12 Years to 75 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion Criteria:

  • patients who have a documented APDS/PASLI-associated genetic PI3K delta mutation
  • In Part I and Part II, 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.

Key Exclusion Criteria:

  • Any medically significant disease or condition that is unrelated to APDS/PASLI

Other protocol-defined inclusion/exclusion criteria may apply.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02435173


Contacts
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Contact: Novartis Pharmaceuticals 1-888-669-6682 novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +41613241111

Locations
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United States, Maryland
National Institute of Health NIH Recruiting
Bethesda, Maryland, United States, 20814
Contact: Sharon Webster    301-496-2771    Sharon.webster@nih.gov   
Czechia
Novartis Investigative Site Recruiting
Prague 5, Czechia, 150 00
Ireland
Novartis Investigative Site Recruiting
Dublin, Ireland
Italy
Novartis Investigative Site Recruiting
Palermo, PA, Italy, 90127
Novartis Investigative Site Recruiting
Brescia, Italy, 25123
Netherlands
Novartis Investigative Site Recruiting
Rotterdam, Netherlands, 3000 CA
Russian Federation
Novartis Investigative Site Recruiting
Moscow, Russian Federation, 117198
United Kingdom
Novartis Investigative Site Recruiting
Belfast, United Kingdom, BT9 7AB
Novartis Investigative Site Recruiting
London, United Kingdom, NW3 2PF
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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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 automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02435173     History of Changes
Other Study ID Numbers: CCDZ173X2201
2014-003876-22 ( EudraCT Number )
First Posted: May 6, 2015    Key Record Dates
Last Update Posted: October 16, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
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


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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
APDS PASLI PI3Kdelta
Additional relevant MeSH terms:
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Lymphadenopathy
Immunologic Deficiency Syndromes
Common Variable Immunodeficiency
Immune System Diseases
Lymphatic Diseases