Clinical Trials Register

Summary
EudraCT Number:	2011-002957-67
Sponsor's Protocol Code Number:	CA209-010
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:	2011-12-16
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

2011-002957-67

A.3

Full title of the trial

A Randomized, Blinded, Phase 2 Dose-Ranging Study of BMS-936558 (MDX-1106) in Subjects With Progressive Advanced/Metastatic Clear-Cell Renal Cell Carcinoma Who Have Received Prior Anti-Angiogenic Therapy Revised Protocol 01 incorporating Administrative Letter 01 and Amendment 02

Studio di fase 2 dose-ranging randomizzato, in cieco, di BMS-936558 (MDX-1106) nei soggetti con carcinoma a cellule renali a cellule chiare avanzato/metastatico in progressione che hanno ricevuto una precedente terapia anti-angiogenica. Protocollo revised 01 che incorpora l`™administrative Letter 01 e l`™emendamento 02

A.3.1

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

A Phase 2 Dose-Ranging Study of BMS-936558 (MDX-1106) In Subjects With Advanced/Metastatic Clear-Cell Renal Cell Carcinoma

Studio di fase 2 dose-ranging di BMS-936558 (MDX-1106) nei soggetti con carcinoma a cellule renali a cellule chiare avanzato/metastatico.

A.4.1

Sponsor's protocol code number

CA209-010

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01354431

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	BRISTOL-MYERS SQUIBB INTERNATIONAL CORPORATION
B.1.3.4	Country	Belgium
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	Bristol-Myers Squibb International Corporation
B.4.2	Country	Belgium
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Bristol-Myers Squibb International Corporation
B.5.2	Functional name of contact point	EU Study Start-Up Unit
B.5.3	Address:
B.5.3.1	Street Address	Parc de l'Alliance - Avenue de Finlande, 8
B.5.3.2	Town/ city	Braine-l'Alleud
B.5.3.3	Post code	1420
B.5.3.4	Country	Italy
B.5.4	Telephone number	+32 2 352 7893
B.5.5	Fax number	+32 2 352 7164
B.5.6	E-mail	clinical.trials@bms.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	BMS-936558
D.3.4	Pharmaceutical form	Powder for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	BMS-936558-01
D.3.9.3	Other descriptive name	Anti-PD-1 Human Monoclonal Antibody; MDX-1106
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Advanced/Metastatic renal cell carcinoma with a clear cell

carcinoma a cellule renali a cellule chiare avanzato/metastatico

E.1.1.1

Medical condition in easily understood language

Advanced/Metastatic renal cell carcinoma with a clear cell

carcinoma a cellule renali a cellule chiare avanzato/metastatico

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	PT
E.1.2	Classification code	10038410
E.1.2	Term	Renal cell carcinoma recurrent
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	PT
E.1.2	Classification code	10050513
E.1.2	Term	Metastatic renal cell carcinoma
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 evaluate the dose response relationship in the 0.3, 2, and 10 mg/kg BMS-936558 arms as measured by Progression-free survival (PFS).

Valutare la correlazione tra la dose e la risposta nei tre bracci 0.3, 2 e 10 mg/kg di BMS-936558, misurata dalla sopravvivenza libera da progressione (PFS).

E.2.2

Secondary objectives of the trial

To estimate PFS in the BMS-936558 arms • To estimate the response rate in the BMS-936558 arms • To estimate the Overall Survival (OS) in the BMS-936558 arms • To estimate the rate of adverse events in the BMS-936558 arms + Exploratory Objectives: • To evaluate changes in QTc in each treatment arm • To estimate the immune-related response rate (irRR) and irPFS in the 2 and 10 mg/kg BMS-936558 arms relative to the 0.3 mg/kg arm • To explore associations between PD-L1 expression in tumors and other immune response biomarkers on clinical outcome • To characterize the pharmacokinetics of BMS-936558 and to explore exposure-safety and exposure-efficacy relationships.

o Definire la PFS nei bracci di trattamento con BMS-936558 o Determinare il tasso di risposta nei bracci di trattamento con BMS-936558 o Determinare la sopravvivenza totale (OS) nei bracci di trattamento con BMS-936558 o Determinare il tasso di eventi avversi nei bracci di trattamento con BMS-936558 Obiettivi esplorativi: o Valutare i cambiamenti del QTc in ogni braccio di trattamento o Determinare il tasso di risposta immuno-corretalo (irRR) e irPFS nei bracci 2.0 e 10mg/kg di BMS-936558 rispetto al braccio 0.3 mg/kg. o Determinare l’associazione tra l’espressione di PD-L1 nei tumori e di altri biomarcatori correlati alla risposta immunitaria con il risultato clinico o Caratterizzare la farmacocinetica di BMS-936558 ed definire la correlazione tra esposizione-sicurezza ed esposizione-efficacia.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Histologic confirmation of RCC with a clear cell component. • Previous treatment with at least one anti-angiogenic agent • Progressed within 6 months of study enrollment • Subjects should not have had more than 3 prior treatments for locally advanced or metastatic disease. • Must have available tumor tissue for submission • Subjects must also meet various laboratory parameters for inclusion (see Protocol section 3.3.1 item 4)

• conferma istologica di carcinoma a cellule renali (RCC) con la componente a cellule chiare • precedente trattamento con almeno una terapia anti-angiogenica • progressione entro 6 mesi dall’arruolamento nello studio . • I soggetti non devono aver ricevuto più di 3 regimi chemioterapici precedenti nella fase avanzata/metastatica • Tessuto tumorale deve essere disponibile per la sottomissione. • I soggetti devono rispettare dei paramenti di laboratorio per l’inclusione nello studio (si veda Protoclo sezione 3.3.1 punto 4).

E.4

Principal exclusion criteria

• Active CNS metastases within 30 days of study enrollment • Subjects with any active autoimmune disease or a history of known autoimmune disease • Subjects with uncontrolled adrenal insufficiency • Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured

• Metastasi cerebrali attive entro 30 giorni dall’arruolamento nello studio • Soggetti affetti da una malattia autoimmune attiva o con una storia di una nota malattia autoimmune • Soggetti con un’insuffficienza surrenalica non controllata • Precedente tumore attivo nei precedenti 3 anni ad eccezione dei tumori curabili localmente che sono stati appatentemente trattati

E.5 End points

E.5.1

Primary end point(s)

Progression free survival as measured by tumor assessments (radiographic scans) and the collection of death data. It will be compared to the doses given across the 3 treatment arms to see if a dose response exists.

La sopravvivenza libera da progressione viene determinata dalle valutazioni del tumore (valutazione radiologica) e dalla raccolta dei dati sulla morte. Questa sarà confrontata alle dosi date nei 3 bracci di trattamento per vedere se esiste una correlazione dose-risposta.

E.5.1.1

Timepoint(s) of evaluation of this end point

Tumor assessments (radiographic scans) will be done every 6 weeks from randomization for the first 12 months, then every 12 weeks until progression is documented. Subjects will be assessed for survival every 3 months.

La valutazione del tumore (valutazione radiologica) viene condotta ogni 6 settimane per i primi 12 mesi dalla randomizzazione, e poi ogni 12 settimane fino ad una documentata progressione della malattia. I soggetti saranno valutati per la sopravvivenza ogni 3 mesi.

E.5.2

Secondary end point(s)

• Progression free survival in the BMS-936558 arms • The tumor response rate in the BMS-936558 arms as assessed by the Investigator assessment of best overall response • The overall survival in the BMS-936558 arms as collected by death data.

o La sopravvivenza libera da progressione nei bracci di trattamento con BMS-936558 o Il tasso di risposta nei bracci di trattamento con BMS-936558 valutato dallo sperimentatore come “best overall response” o La sopravvivenza nei bracci di trattamento con BMS-936558 valutata dalla raccolta dei dati sulla morte.

E.5.2.1

Timepoint(s) of evaluation of this end point

• Progression free survival will be assessed in each individual treatment arm by tumor assessments every 6 weeks • The tumor response rate will be assessed on all subjects at the time they discontinue study treatment by the Investigators assessment of best overall response for a subject • The survival in each treatment arm will be assessed by the collection of death data every 3 months following the discontinuation of study therapy until a subjects death

La sopravvivenza libera da progressione sarà determinata dalla valutazione del tumore ogni 6 settimane in ogni singolo braccio di trattamento Il tasso di risposta sarà valutata su tutti i pazienti una sola vota al momento della discontinuazione dal trattamento in studio a seguito della valutazione dello sperimentatore della “best overall response” per ogni soggetto

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

Yes

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

exploratory assessments

Valutazioni di tipo esplorativo

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

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

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

dose-ranging

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

Canada

United States

E.8.7

Trial has a data monitoring committee

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 study will end when analysis of survival is complete. This analysis will be conducted after 75% of the subjects have died or 2 years of follow-up time from the analysis of PFS, whichever comes first.

Lo studio si concluderà quando l’analisi della sopravvivenza sarà completa. Quest’analisi sarà condotta o dopo che il 75% dei soggetti sono morti o dopo 2 anni di follow up iniziato dall’analisi della PFS, a seconda di quale evento si verifica prima

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:

136

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

181

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)

At the conclusion of the study, subjects who continue to demonstrate clinical benefit will be eligible to receive study drug. See Protocol section 3.2 Post Study Access to Therapy for further details.

details Alla conclusione dello studio, i soggetti che continuano a ricevere un beneficio clinico saranno eleggibii a ricevere il farmaco in studio. Si faccia riferimento alla sezione 3.2 del protocollo (Post Study Access to therapy) per ulteriori dettagli.

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

2011-11-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-11-02

P. End of Trial
P.	End of Trial Status	Completed

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