Clinical Trials Register

Summary
EudraCT Number:	2014-003876-22
Sponsor's Protocol Code Number:	CCDZ173X2201
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2020-09-04
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

France - ANSM

A.2

EudraCT number

2014-003876-22

A.3

Full title of the trial

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)

Etude en ouvert, non randomisée, de détermination de la dose intra patient, suivie par une étude randomisée, en aveugle pour les patients, les médecins-investigateurs et Novartis, contrôlée par placebo, évaluant l’efficacité et la sécurité d’emploi de CDZ173 (leniolisib) chez des patients atteints d’APDS/PASLI (Syndrome de PI3K-delta activée/Déficit immunitaire, lymphadénopathie et cellules T sénescentes dus à des mutations activatrices de p110-delta)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Study to assess the safety and efficacy of CDZ173 in patients with APDS/PASLI

A.3.2

Name or abbreviated title of the trial where available

Study of efficacy of CDZ173 in patients with APDS/PASLI

A.4.1

Sponsor's protocol code number

CCDZ173X2201

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Novartis Pharma Services AG
B.1.3.4	Country	Switzerland
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Novartis Pharma Services AG
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Novartis Pharma S.A.S
B.5.2	Functional name of contact point	Information&Communication Médicales
B.5.3	Address:
B.5.3.1	Street Address	8/10 rue Henry Sainte Claire Deville, CS 40150
B.5.3.2	Town/ city	Rueil-Malmaison
B.5.3.3	Post code	92563
B.5.3.4	Country	France
B.5.4	Telephone number	+33 1 5547 6600
B.5.5	Fax number	+33 1 5547 6100
B.5.6	E-mail	icm.phfr@novartis.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.2	Product code	CDZ173
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	leniolisib
D.3.9.2	Current sponsor code	CDZ173
D.3.9.4	EV Substance Code	SUB168935
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	70
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule, hard
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

APDS/PASLI (Activated phosphoinositide 3-kinase delta syndrome/ p110δ-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency)

APDS/PASLI (Syndrome de PI3K-delta activée/Déficit immunitaire, lymphadénopathie et cellules T sénescentes dus à des mutations activatrices de p110-delta)

E.1.1.1

Medical condition in easily understood language

Gain of function genetic mutation in the PI3Kdelta gene causing immunodeficiency

Gain fonctionnel du gène PI3K-delta muté entrainant un déficit immunitaire,

E.1.1.2

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

• Part I: To assess the safety and tolerability as well as the dose-PD and PK/PD relationship of CDZ173 in patients with APDS/PASLI enabling dose selection for Part II
• Part II: To assess the clinical efficacy of CDZ173 in patients with APDS/PASLI

• Partie I : évaluer la relation entre la dose et la pharmacodynamie (PD) et entre PK et PD de CDZ173 chez des patients atteints d’APDS/PASLI pour permettre la sélection de la dose dans la Partie II
• Partie II : évaluer l’efficacité de CDZ173 chez des patients atteints d’APDS/PASLI (sur la lymphadénopathie et la normalisation du phénotype immunitaire)

E.2.2

Secondary objectives of the trial

• Part II: To assess the effect of CDZ173 on lymphadenopathy (non-index lesions and spleen).
• Part I and II: To assess the pharmacokinetics of CDZ173 in patients with APDS/PASLI
• Part I and II: To assess the efficacy of CDZ173 to modify health-related quality of life in patients with APDS/PASLI
• Part I and II: To assess the efficacy of CDZ173 by the Physician’s Global Assessment and the Patient’s Global Assessment
• Part I and II: To assess biomarkers reflecting the efficacy of CDZ173 to reduce systemic inflammatory components of the disease
• Part I and II: To assess the treatment benefit to individual patients
• Part II: To assess the safety and tolerability of CDZ173 in patients with APDS/PASLI

• Partie II : évaluer l’effet de CDZ173 sur la lymphadénopathie (lésions non cibles et rate)
• Partie I et Partie II : évaluer la PK de CDZ173 chez des patients atteints d’APDS/PASLI
• Partie I et Partie II : évaluer l’efficacité de CDZ173 sur la qualité de vie liée à la santé des patients atteints d’APDS/PASLI
• Partie I et Partie II : évaluer l’efficacité de CDZ173 selon l’évaluation globale du médecin-investigateur (PGA, pour Physician’s Global Assessment) et l’évaluation globale du patient (PtGA, pour Patient’s Global Assessment)
• Partie I et Partie II : évaluer les biomarqueurs de l’efficacité de CDZ173 à réduire les composants inflammatoires systémiques de la maladie
• Partie I et Partie II : évaluer le bénéfice du traitement pour chaque patient
• Partie II : évaluer l’innocuité et la tolérance de CDZ173 chez des patients atteints d’APDS/PASLI

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Male and female patients 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.
• 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.
• 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, 90-160 mm Hg
• Diastolic blood pressure, 50-95 mm Hg
• Pulse rate, 40 - 100 bpm; up to 110 bpm in adolescents

• Patients masculins et féminins âgés de 12 à 75 ans (inclus) ayant une mutation génétique de PI3K-delta associée à l’APDS/PASLI documentée. Les patients ayant des mutations dans PIK3CD ou PIK3R1 peuvent être inclus
• Dans la Partie I et la Partie II, les patients doivent présenter une prolifération lymphocytaire nodale et/ou extranodale et des signes et manifestations cliniques compatibles avec l’APDS/PASLI, tels que : antécédents d’infections de la sphère ORL, sinusales et pulmonaires récurrentes et/ou une insuffisance d’organe (par exemple poumon ou foie). De plus, pour la Partie II, les patients doivent avoir au moins une lésion nodale mesurable par scanner ou IRM.
• Lors de la sélection, les signes vitaux doivent être mesurés en position assise après au moins 3 minutes de repos. Les signes vitaux en position assise doivent être compris entre :
- Tension artérielle systolique : 90-160 mmHg
- Tension artérielle diastolique : 50-95 mmHg
- Rythme cardiaque : 40-100 battements par minute (bpm) ; jusqu’à 110 bpm chez les adolescents.

E.4

Principal exclusion criteria

• Previous or concurrent use of immunosuppressive medication such as:
• use of an mTOR inhibitor (e.g., sirolimus, rapamycin, everolimus) or a PI3Kδ 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.
• 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 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)).
• 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.

E.5 End points

E.5.1

Primary end point(s)

• Part I: All safety parameters (including AEs, physical exam, vital signs, ECG, safety laboratory (hematology, blood chemistry, urinalysis))
• Part I: Single and multiple dose concentrations of CDZ173 and pAkt inhibition in unstimulated and stimulated whole blood
• Part II: Co-primary endpoint;
o 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.
o Change from baseline in percentage of naïve B cells out of total B cells

• Partie I : tous les paramètres de sécurité (incluant les évènements indésirables, examen clinique, signes vitaux, électrocardiogrammes (ECG), paramètres biologiques [hématologie, biochimie du sang, analyse d’urines])
• Partie I : Concentrations en CDZ173 après une dose unique ou des doses multiples et inhibition d’Akt phosphorylé (pAkt) dans des échantillons de sang total après stimulation ou non
• Partie II : Co-critères d’évaluation principaux :
o Variation par rapport à la baseline de la transformation log10 de la somme du produit des diamètres (SPD) des lésions cibles sélectionnées selon les critères de Cheson à partir des IRM/scanners
o Variation par rapport à la baseline du pourcentage de lymphocytes B naïfs parmi l’ensemble des lymphocytes B

E.5.1.1

Timepoint(s) of evaluation of this end point

From beginning to end of study

Du début à la fin de l'étude

E.5.2

Secondary end point(s)

• Part II: 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
• Part I and II: Single dose CDZ173 PK parameters (including but not limited to Cmax and AUC) and trough evaluations after multiple dose
• Part I and II: SF-36 (Short Form 36) Survey and WPAI-CIQ (Work Productivity Activity Impairment plus Classroom Impairment Questionnaire)
• Part I and II: Visual analogue scales for PGA and PtGA (for Part II the PGA is a key secondary endpoint)
• Part I and II:
o C reactive protein (CRP), Lactate dehydrogenase (LDH)
o For Part II additional: beta2 microglobulin, ferritin, fibrinogen and erythrocyte sedimentation rate (ESR)
• Part I and II: Narratives
• Part II: All safety parameters, including AEs, physical exam, vital signs, ECG, safety laboratory (hematology, blood chemistry, urinalysis)

• Partie II : IRM/scanners, par exemple volume en 3 dimensions des lésions cibles et non cibles mesurables selon les critères de Cheson, et volume en 3 dimensions et taille bidimensionnelle de la rate
• Parties I et II : Paramètres PK de CDZ173 après une dose unique (incluant notamment Cmax et aire sous la courbe [AUC]) et évaluations de Cmin après des doses multiples
• Parties I et II : Questionnaire SF-36 (pour Short Form 36) et questionnaire sur la baisse de la productivité au travail et des performances scolaires (WPAI-CIQ, pour Work Productivity Activity Impairment plus Classroom Impairment Questionnaire)
• Parties I et II : Echelles analogiques visuelles pour PGA et PtGA (PGA est un critère d’évaluation secondaire clé pour la Partie II)
• Parties I et II :
o Protéine C-réactive (CRP), lactate déshydrogénase (LDH)
o Additionnel pour la Partie II : bêta-2 microglobuline, ferritine, fibrinogène et vitesse de sédimentation (ESR pour erythrocyte sedimentation rate)
• Parties I et II : description de chaque cas
• Partie II : tous les paramètres de sécurité incluant les évènements indésirables, examen clinique, signes vitaux, électrocardiogrammes, paramètres biologiques [hématologie, biochimie du sang, analyse d’urines]

E.5.2.1

Timepoint(s) of evaluation of this end point

From beginning to end of study

Du début à la fin de l'étude

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Belarus

Czech Republic

France

Germany

Ireland

Italy

Netherlands

Russian Federation

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

Dernière visite du dernier patient

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

All patients completing the study will be offered continuous treatment in the extension study CCDZ173X2201E1. At a minimum, patients will be contacted for safety evaluations during the 30 days following the Study Completion visit, including a final post-study safety contact at the 30-day point. If the patients directly continue treatment in the extension study (CCDZ173X2201E1), the safety follow up is not needed as they will be followed up during the Visits in the extension study.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2020-10-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-10-13

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-06-02

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