Clinical Trials Register

Summary
EudraCT Number:	2012-000675-16
Sponsor's Protocol Code Number:	CBEZ235F2201
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-09-19
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2012-000675-16

A.3

Full title of the trial

A multicenter, two stage, phase II study, evaluating the efficacy of oral BEZ235 plus best supportive care (BSC) versus placebo plus BSC in the treatment of patients with advanced pancreatic neuroendocrine tumors (pNET) after failure of mTOR inhibitor therapy

Studio di Fase II, multicentrico, a due stadi, per valutare l'efficacia di BEZ235 somministrato per via orale in associazione alla miglior terapia di supporto (Best Supportive Care - BSC) rispetto a placebo in associazione alla BSC per il trattamento di pazienti con tumore neuroendocrino pancreatico (pNET) in stadio avanzato dopo il fallimento della terapia con inibitore di mTOR

A.3.1

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

Safety and efficacy of BEZ235 in patients with pancreatic neuroendocrine tumors (pNET)

Sicurezza ed efficacia di BEZ235 in pazienti con tumore neuroendocrino pancreatico (pNET)

A.4.1

Sponsor's protocol code number

CBEZ235F2201

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 FARMA
B.1.3.4	Country	Italy
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 FARMA
B.5.2	Functional name of contact point	Drug Regulatory Affairs
B.5.3	Address:
B.5.3.1	Street Address	Largo Umberto Boccioni, 1
B.5.3.2	Town/ city	ORIGGIO
B.5.3.3	Post code	21040
B.5.3.4	Country	Italy
B.5.4	Telephone number	02-96541
B.5.5	Fax number	02-9659066
B.5.6	E-mail	info.studiclinici@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.3.1	Product name	BEZ235
D.3.2	Product code	BEZ235
D.3.4	Pharmaceutical form	Powder for oral suspension
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.3.9.1	CAS number	1028385-32-1
D.3.9.2	Current sponsor code	BEZ235
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	200
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.IMP: 2
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	BEZ235
D.3.2	Product code	BEZ235
D.3.4	Pharmaceutical form	Powder for oral suspension
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.3.9.1	CAS number	1028385-32-1
D.3.9.2	Current sponsor code	BEZ235
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	300
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.IMP: 3
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	BEZ235
D.3.2	Product code	BEZ235
D.3.4	Pharmaceutical form	Powder for oral suspension
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.3.9.1	CAS number	1028385-32-1
D.3.9.2	Current sponsor code	BEZ235
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	400
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	Powder for oral suspension
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

Adult patient in advanced pancreatic neuroendocrine tumors

Pazienti adulti con con tumore neuroendocrino pancreatico in stadio avanzato

E.1.1.1

Medical condition in easily understood language

Adult patient with pancreatic neuroendocrine tumors

Pazienti adulti con con tumore neuroendocrino pancreatico

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	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10062476
E.1.2	Term	Neuroendocrine tumor
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To estimate the efficacy of BEZ235 in adult patients with advanced (unresectable or metastatic) pNET

Stimare l'efficacia di BEZ235 in pazienti adulti con pNET in stadio avanzato (non resecabile o metastatico)

E.2.2

Secondary objectives of the trial

To assess the safety and tolerability of BEZ235 therapy To evaluate the efficacy of BEZ235 per modified RECIST v.1.1.

Valutare la sicurezza e la tollerabilità della terapia con BEZ235. Valutare l'efficacia di BEZ235 in base ai criteri RECIST v.1.1 modificati.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

PHARMACOGENETIC:
Vers:00
Date:2012/06/14
Title:Biomarker Research Studies
Objectives:Biomarker studies are done to evaluate changes in genes and proteins and are important to learn about the effect of the drug on the body and cancer.

PHARMACOKINETIC/PHARMACODYNAMIC:
Vers:00
Date:2012/06/14
Title:Pharmacokinetic Research Study
Objectives:Pharmacokinetic study is done to evaluate the amount of BEZ235 compound in blood. 30 people who are taking part in the CBEZ235F2201 study will take part to pharmacokinetic evaluations.

FARMACOGENETICA:
Vers:00
Data:2012/06/14
Titolo:Studio complementare sugli indicatori biologici
Obiettivi:Gli studi sugli indicatori biologici sono effettuati per valutare le modifiche nei geni e nelle proteine e sono importanti per comprendere l'effetto del farmaco sull'organismo e sul tumore.

FARMACOCINETICA/FARMACODINAMICA:
Vers:00
Data:2012/06/14
Titolo:Studio complementare di farmacocinetica
Obiettivi:La valutazione farmacocinetica viene condotta per valutare il quantitativo di BEZ235 nel sangue. Prenderanno parte alla valutazione farmacocinetica 30 pazienti che partecipano allo studio CBEZ235F2201.

E.3

Principal inclusion criteria

1. Patient must have advanced (unresectable or metastatic), histologically confirmed low or intermediate grade pancreatic pNET according to the WHO 2010 classification (grade 1 or 2) and show radiological evidence of disease progression since last treatment. 2. Patients’ disease is refractory to treatment with mTOR inhibitor. Patients must not have taken another treatment between mTOR inhibitor and BEZ235. NOTE: Refractory is defined as progression while on treatment or within 3 months of treatment discontinuation. 3. Measurable disease per RECIST Version 1.1 using Computed Tomography (CT) or Magnetic Resonance Imaging (MRI). 4. Prior or concurrent therapy with SSA is permitted; however, for concurrent therapy with SSA while on study, patients must be on a stable dose at least 2 months prior to study start and must continue on the stable dose while receiving study treatment. 5. Adequate bone marrow function or organ function. 6. WHO PS ≤ 1. 7. Adult male or female patients ≥ 18 years of age.

1.Pazienti con pNET in stadio avanzato (non resecabile o metastatico), istologicamente confermato, di grado basso o intermedio in base alla classificazione WHO 2010 (grado 1 o 2) e che mostrano evidenza radiologica di progressione di malattia dall'ultimo trattamento. 2.Pazienti con malattia refrattaria al trattamento con inibitore di mTOR (progressione durante il trattamento o entro 3 mesi dall'interruzione del trattamento). I pazienti non devono aver assunto un altro trattamento tra l'inibitore di mTOR e BEZ235. 3.Malattia misurabile in base ai criteri RECIST versione 1.1. 4.É consentita la terapia pregressa o concomitante con SSA; i pazienti devono essere in trattamento con la stessa dose da almeno due mesi prima dell'inizio dello studio e devono mantenerere la stessa dose di trattamento durante la somministrazione del trattamento in studio. 5.Funzionalità del midollo osseo o funzionalità d'organo adeguata. 6.WHO PS ≤ 1. 7.Pazienti adulti di sesso maschile o femminile di età ≥ 18 anni.

E.4

Principal exclusion criteria

1. Patient has received previous treatment with any PI3K inhibitor or AKT inhibitor for the treatment of pNET. 2. Patient has discontinued prior mTOR inhibitor therapy due to toxicity. 3. Patient has poorly differentiated neuroendocrine carcinoma, high-grade neuroendocrine carcinoma, adenocarcinoid, goblet cell carcinoid and small cell carcinoma. 4. Patient has been treated with hepatic artery embolization within the last 6 months (1 month if there are other sites of measurable disease), or cryoablation/ radiofrequency ablation of hepatic metastasis within 2 months of enrollment. 5. Patients with more than 3 prior systemic treatment regimens. 6. Patient who has any severe and/or uncontrolled medical conditions. 7. Patient has any cardiac abnormalities. 8. Patient has impairment of GI function or GI disease that may significantly alter the absorption of study drug.

1.Pazienti che hanno ricevuto in precedenza un trattamento con qualsiasi inibitore di PI3K o AKT per il trattamento del pNET. 2.Pazienti che hanno discontinuato la terapia precedente con inibitore di mTOR per tossicità. 3.Pazienti con carcinoma neuroendocrino scarsamente differenziato, carcinoma neuroendocrino ad alto grado, adenocarcinoide, 'goblet cell carcinoid' e carcinoma a piccole cellule. 4.Pazienti trattati con embolizzazione dell'arteria epatica nei 6 mesi precedenti (1 mese se ci sono altri siti di malattia misurabile), o crioablazione/ablazione con radiofrequenza delle metastasi epatiche nei 2 mesi precedenti l'arruolamento. 5.Pazienti trattati in precedenza con più di 3 regimi sistemici. 6.Pazienti con qualsiasi condizione medica severa e/o non controllata. 7.Pazienti con anomalie cardiache. 8.Pazienti con deterioramento della funzionalità gastrointestinale o patologia gastrointestinale che potrebbe alterare in modo significativo l'assorbimento del farmaco in studio.

E.5 End points

E.5.1

Primary end point(s)

PFS rate at 16 weeks according to local radiological assessment per modified RECIST v1.1

Tasso di PFS a 16 settimane in base alla valutazione radiologica locale secondo i criteri RECIST v.1.1 modificati.

E.5.1.1

Timepoint(s) of evaluation of this end point

up to approx 18 months

fino a circa 18 mesi

E.5.2

Secondary end point(s)

Frequency and severity of adverse events;other safety data as considered appropriate. Overall Response Rate, Disease Control Rate, Duration of Response.

Frequenza e severità degli eventi avversi. Altri dati di sicurezza per quanto considerati appropriati. ORR, DCR, DoR (Overall Response Rate, Disease Control Rate, Duration of Response).

E.5.2.1

Timepoint(s) of evaluation of this end point

up to approx. 18 months for all secondary endpoint

fino a circa 18 mesi per tutti gli endpoint secondari

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

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

Yes

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)

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

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

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

Korea, Republic of

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

The end of study (last patient last visit) will occur after all patients have completed their last assessment as per protocol. The final analysis will be conducted after all enrolled patients have completed the study.

La fine dello studio (LPLV) avverrà dopo che tutti i pazienti hanno completato l'ultima valutazione per protocollo. L'analisi finale verrà effettuata dopo che tutti i pazienti arruolati hanno completato lo studio.

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

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)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

100

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

104

F.4.2.2

In the whole clinical trial

150

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)

After discontinuing study treatment further treatment is left to the physician's discretion, cross-over in some specific condition defined in the protocol.

Dopo l'interruzione del trattamento dello studio, sarà il medico a decidere l'ulteriore trattamento, il cross-over in specifiche condizioni è definito nel protocollo.

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

2012-09-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-09-10

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2015-07-03

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