Clinical Trials Register

Summary
EudraCT Number:	2016-003202-14
Sponsor's Protocol Code Number:	PCYC-1141-CA
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-02-01
Trial 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

Italy - Italian Medicines Agency

A.2

EudraCT number

2016-003202-14

A.3

Full title of the trial

A Multicenter, Randomized, Double-blind, Placebo-controlled Phase 3 Study of the Bruton's Tyrosine Kinase (BTK) Inhibitor, Ibrutinib, in Combination with Rituximab versus Placebo in Combination with Rituximab in Treatment Naïve Subjects with Follicular Lymphoma

Studio di Fase 3, Multicentrico, Randomizzato, in Doppio Cieco, Controllato con Placebo, sull’inibitore della Tirosin Chinasi di Bruton (BTK), Ibrutinib, in combinazione con Rituximab rispetto a placebo in combinazione con Rituximab in pazienti con linfoma follicolare naive al trattamento

A.3.1

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

A Clinical Study of Rituximab with Ibrutinib Compared to Rituxumab Alone, and Subsequently of Ibrutinib Alone Compared to Placebo in Treatment Naïve Subjects with Follicular Lymphoma

Studio clinico di Rituximab con Ibrutinib rispetto a Rituxumab in monoterapia e successivamente di Ibrutinib in monoterapia rispetto al placebo in soggetti naïve al trattamento con linfoma follicolare

A.3.2

Name or abbreviated title of the trial where available

PERSPECTIVE

A.4.1

Sponsor's protocol code number

PCYC-1141-CA

A.5.1

ISRCTN (International Standard Randomised Controlled Trial) Number

ISRCTN00000000

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02947347

A.5.3

WHO Universal Trial Reference Number (UTRN)

U0000-0000-0000

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	PHARMACYCLICS, LLC
B.1.3.4	Country	United States
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	Pharmacyclics LLC
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Pharmacyclics Switzerland GmbH, An AbbVie Company
B.5.2	Functional name of contact point	Medical Monitor
B.5.3	Address:
B.5.3.1	Street Address	Muhlentalstrasse 36
B.5.3.2	Town/ city	Shaffhausen
B.5.3.3	Post code	CH-8200
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	+410525560831
B.5.5	Fax number	000000
B.5.6	E-mail	bhauns@pcyc.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.3.1	Product name	Ibrutinib
D.3.2	Product code	[PCI-32765]
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	Ibrutinib
D.3.9.1	CAS number	936563-96-1
D.3.9.2	Current sponsor code	PCI-32765
D.3.9.3	Other descriptive name	IBRUTINIB
D.3.9.4	EV Substance Code	SUB120863
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	140
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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

Follicular lymphoma

linfoma follicolare

E.1.1.1

Medical condition in easily understood language

Lymphoma

linfoma

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10029473
E.1.2	Term	Nodular (follicular) lymphoma
E.1.2	System Organ Class	100000004864

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

Analysis Study 1
To evaluate whether the addition of ibrutinib to rituximab will result in prolongation of progression-free survival (PFS) when compared with rituximab alone in treatment naïve subjects with follicular lymphoma
Discontinuation Analysis Study
For subjects who are re-randomized for Part 2, to evaluate whether continuous treatment with ibrutinib will result in prolongation of PFS when compared with finite treatment with ibrutinib

Studio di analisi 1
Valutare se l'aggiunta di ibrutinib a rituximab determinerà il prolungamento della sopravvivenza libera da progressione (PFS) rispetto a rituximab in monoterapia in soggetti naïve al trattamento con linfoma follicolare
Studio di analisi dell'interruzione
Per i soggetti che sono ri-randomizzati nella Parte 2, valutare se il trattamento continuo con ibrutinib determinerà il prolungamento della PFS rispetto al trattamento limitato con ibrutinib

E.2.2

Secondary objectives of the trial

Analysis Study 1
* During Part 1, to evaluate whether the addition of ibrutinib to rituximab will result in improvement in investigator-assessed CR rate and ORR when compared with rituximab alone in treatment naïve subjects with follicular lymphoma
* To evaluate whether the addition of ibrutinib to rituximab will result in prolongation of OS (Arm A vs. Arm B) through Part 2
* To evaluate the safety and tolerability of ibrutinib combined with rituximab compared to rituximab alone in treatment naïve subjects with follicular lymphoma
Discontinuation Analysis Study
* To evaluate the long-term safety and tolerability of ibrutinib after completing the rituximab maintenance in treatment naïve subjects with follicular lymphoma

Studio di analisi 1
* Durante la Parte 1, valutare se l'aggiunta di ibrutinib a rituximab determinerà il miglioramento del tasso di CR e ORR valutato dallo sperimentatore rispetto a rituximab in monoterapia in soggetti naïve al trattamento con linfoma follicolare
* Valutare se l'aggiunta di ibrutinib a rituximab determinerà una riduzione nelle reazioni correlate all’infusione
* Valutare se l'aggiunta di ibrutinib a rituximab determinerà il prolungamento dell'OS (Braccio A vs Braccio B) fino alla Parte 2
* Valutare la sicurezza e la tollerabilità di ibrutinib in associazione con rituximab rispetto a rituximab in monoterapia in soggetti naïve al trattamento con linfoma follicolare
Studio di analisi dell'interruzione
* Valutare la sicurezza e la tollerabilità a lungo termine di ibrutinib dopo il completamento della terapia di mantenimento con rituximab in soggetti naïve al trattamento con linfoma follicolare

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

* Histologically confirmed diagnosis of follicular lymphoma CD20+ (Grade 1, 2 or 3a) Ann Arbor Stage II, III or IV disease.
* Measurable disease.
* Subjects 70 years of age or older with any comorbidity per investigator medical judgment; OR subjects 60-69 years of age who have one or more comorbidities that make them a candidate to receive single-agent rituximab therapy.
* Meets one or more Groupe d'Etude des Lymphomes Folliculaire (GELF) criteria.
* Adequate hematologic function within protocol-defined parameters.
* Adequate hepatic and renal function within protocol-defined parameters.
* ECOG performance status score of 0-2.

* Diagnosi di linfoma follicolare CD20+ (Grado 1, 2 o 3a) confermato istologicamente; malattia in stadio II, III o IV secondo la classificazione di Ann Arbor.
* Malattia misurabile.
* Soggetti di età pari o superiore a 70 anni con qualsiasi comorbidità in base al giudizio clinico dello sperimentatore; OPPURE soggetti di 60-69 anni di età che presentano una o più comorbilità che li rendono candidati idonei a ricevere terapia con rituximab come agente singolo.
* Soddisfa uno o più dei seguenti criteri del Groupe d'Etude des Lymphomes Folliculaire (GELF).
* Funzioni ematologiche adeguate entro i parametri definiti dal protocollo.
* Funzioni epatiche e renali adeguate entro i parametri definiti dal protocollo.
* ECOG (Eastern Cooperative Oncology Group) di 0-2.

E.4

Principal exclusion criteria

* Transformed lymphoma.
* Prior treatment for follicular lymphoma.
* Central nervous system lymphoma or leptomeningeal disease.
* Currently active, clinically significant cardiovascular disease

* Linfoma trasformato
* Trattamento precedente per il linfoma follicolare
* Linfoma clinicamente evidente a livello del sistema nervoso centrale o malattia leptomeningea.
* Attuale malattia cardiovascolare clinicamente significativa in atto.

E.5 End points

E.5.1

Primary end point(s)

Analysis Study 1:
Progression-free survival (PFS) in Part 1
Discontinuation Analysis Study:
Progression-free survival (PFS) in Part 2 (Arm A1 vs. Arm A2)

Studio di analisi 1:
Sopravvivenza libera da progressione (PFS) nella Parte 1
Studio di analisi dell'interruzione:
Sopravvivenza libera da progressione (PFS) nella Parte 2 (Braccio A1 vs Braccio A2)

E.5.1.1

Timepoint(s) of evaluation of this end point

Analysis Study 1:
Approx. 5 years after the start of the study
Discontinuation Analysis Study:
Approx. 3 years when all the re-randomized subjects have been followed for approximately 36 months

Studio di analisi 1:
Circa 5 anni dopo l'inizio dello studio
Studio di analisi dell'interruzione:
Circa 3 anni da quando tutti i soggetti ri-randomizzati sono stati seguiti per circa 36 mesi

E.5.2

Secondary end point(s)

Analysis Study 1:
* Complete response (CR) rate in Part 1 as defined by the International Working Group (IWG) Revised Response Criteria for Malignant Lymphoma (Cheson 2014)
* Overall response rate (ORR) (Cheson 2014) in Part 1
* Overall survival (OS) (Arm A vs. Arm B) through Part 2
* Frequency, severity, seriousness, and relatedness of adverse events (AEs) in Part 1
Discontinuation Analysis Study:
Frequency, severity, seriousness, and relatedness of adverse events (AEs) in Part 2

Studio di analisi 1:
* Tasso di risposta completa (CR) nella Parte 1 come definito dai criteri di risposta modificati per il linfoma maligno dell'International Working Group (IWG) (Cheson 2014)
* Tasso di risposta globale (ORR) (Cheson 2014) nella Parte 1
* Tasso di reazione correlato all’infusione (Braccio A vs Braccio B)
* Sopravvivenza globale (OS) (Braccio A vs Braccio B) fino alla Parte 2
* Frequenza, gravità, serietà e correlazione degli eventi avversi (AE) nella Parte 1
Studio di analisi dell'interruzione:
Frequenza, gravità, serietà e correlazione degli eventi avversi (AE) nella Parte 2

E.5.2.1

Timepoint(s) of evaluation of this end point

CR and ORR:
Approx. 5 years after the start of the study
OS:
Approx. 8 years [(5 years (Part 1) + 3 years (Part 2)]
Analysis Study 1:
Frequency, severity, seriousness and relatedness of AE in Part 1 will take approx. 5 years
Discontinuation Analysis Study:
Frequency, severity, seriousness, and relatedness of adverse events in Part 2 will take approx. 3 years after Part 1 is complete

CR e ORR:
Circa 5 anni dopo l'inizio dello studio
OS:
Circa 8 anni [(5 anni (Parte 1) + 3 anni (Parte 2)]
Studio di analisi 1:
Frequenza, gravità, serietà e correlazione degli AE nella Parte 1 richiederanno circa 5 anni
Studio di analisi dell'interruzione:
Frequenza, gravità, serietà e correlazione degli eventi avversi nella Parte 2 richiederanno circa 3 anni dopo il completamento della Parte 1

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

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

Yes

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)

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

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

115

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

Information not present in EudraCT

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

Australia

Canada

Israel

New Zealand

Russian Federation

Taiwan

Turkey

United States

Austria

Belgium

Czechia

France

Greece

Hungary

Italy

Netherlands

Poland

Portugal

Spain

United Kingdom

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

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

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)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

240

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

200

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

128

F.4.2

For a multinational trial

F.4.2.1

In the EEA

285

F.4.2.2

In the whole clinical trial

440

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)

Further treatment will be made available in a separate long-term follow-up study

L'ulteriore trattamento sarà reso disponibile in uno studio di follow-up a lungo termine separato

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

2017-11-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-09-14

P. End of Trial
P.	End of Trial Status	Ongoing

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