Clinical Trials Register

Summary
EudraCT Number:	2012-003291-38
Sponsor's Protocol Code Number:	CA184-243
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:	2013-01-11
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

2012-003291-38

A.3

Full title of the trial

A Randomized, Open-Label, Multicenter Phase II Study of Ipilimumab Retreatment versus Chemotherapy for Subjects with Advanced Melanoma who Progressed after Initially Achieving Disease Control with Ipilimumab Therapy

Studio multicentrico di fase 2, randomizzato, in aperto, del ritrattamento con ipilimumab verso chemioterapia, in soggetti con melanoma avanzato che hanno avuto progressione di malattia dopo aver raggiunto inizialmente il controllo di malattia con la terapia con ipilimumab.

A.3.1

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

Study to compare the effect of ipilimumab retreatment with chemotherapy in advanced melanoma

Studio di confronto dell’effetto del ritrattamento con Ipilimumab rispetto alla chemioterapia in soggetti con melanoma avanzato

A.4.1

Sponsor's protocol code number

CA184-243

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, 4
B.5.3.2	Town/ city	Braine-l'Alleud
B.5.3.3	Post code	1420
B.5.3.4	Country	Italy
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.3.1	Product name	IPILIMUMAB
D.3.2	Product code	BMS-734016 / MDX010
D.3.4	Pharmaceutical form	Concentrate 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.3.8	INN - Proposed INN	IPILIMUMAB
D.3.9.1	CAS number	477202-00-9
D.3.9.2	Current sponsor code	BMS-734016 / MDX010
D.3.9.4	EV Substance Code	SUB29397
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	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 Melanoma

melanoma avanzato

E.1.1.1

Medical condition in easily understood language

Advanced Melanoma

melanoma avanzato

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	10027481
E.1.2	Term	Metastatic melanoma
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

The purpose of the study is to compare the 18-month overall survival rate in subjects with advanced melanoma receiving ipilimumab monotherapy (3 mg/kg) as retreatment versus chemotherapy of investigator’s choice in subjects who are randomized at the time of ipilimumab retreatment eligibility. This comparison will be done after the last randomized subject had the chance to be followed for 18 months.

L’obiettivo principale dello studio è quello di confrontare il tasso di sopravvivenza complessiva a 18 mesi in soggetti con melanoma avanzato che stanno ricevendo ipilimumab in monoterapia (3 mg/Kg) come ritrattamento rispetto alla chemioterapia a scelta dell’investigatore in soggetti che vengono randomizzati nel momento in cui risultano eligibili per il ritrattamento con ipilimumab. Questo confronto verrà analizzato dopo che l’ultimo soggetto randomizzato ha avuto la possibilità di essere seguito per 18 mesi.

E.2.2

Secondary objectives of the trial

To compare overall survival between retreatment with ipilimumab versus chemotherapy of investigator’s choice.-To compare best overall response rate (BORR by mWHO criteria) between retreatment with ipilimumab versus chemotherapy of investigator’s choice. - To compare Progression free survival (PFS by mWHO criteria) between retreatment with ipilimumab versus chemotherapy of investigator’s choice. - To assess the EORTC-QLQ-C30 between retreatment with ipilimumab versus chemotherapy of investigator’s choice

- Confrontare la sopravvivenza complessiva tra il ritrattamento con Ipilimumab e la chemioterapia a discrezione dell’investigatore - Confrontare la percentuale della migiore risposta complessiva (BORR tramite i criteri mWHO) tra il ritrattamento con Ipilimumab rispetto alla chemioterapia a discrezione dell’investigatore - Confrontare la sopravvivenza libera da progressione (PFS tramite i criteri mWHO) tra il ritrattamento con Ipilimumab rispetto alla chemioterapia a discrezione dell’investigatore - Valutare lo stato di salute complessivo rispetto alla qualità di vita in base all’ European Organisation for Research and Treatment of Care (EORTC) QLQ-C30 tra il ritrattamento con Ipilimumab rispetto alla chemioterapia a discrezione dell’investigatore.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Histological diagnosis of unresectable stage III or IV metastatic melanoma - Prior ipilimumab induction treatment (3mg/kg) - Documented disease control (SD ≥ 3 months or PR/CR) after ipilimumab Induction - Documented progressive disease following disease control

-Diagnosi istologica di Melanoma Metastatico o non operabile di Stadio III o IV; -Precedente trattamento di induzione con Ipilimumab (3mg/kg) -Controllo della malattia documentato (Stabilità SD > 3 mesi o Risposta Parziale o Completa PR/CR) dopo induzione con Ipilimumab -Progressione di malattia documentata dopo iniziale controllo di malattia

E.4

Principal exclusion criteria

- Subjects with brain metastasis are excluded, unless they are free of neurologic symptoms related to metastatic brain lesions and do not receive systemic corticosteroid therapy for the purpose of reducing intracranial inflammation in the 10 days prior to beginning retreatment with ipilimumab. - Any intervening anticancer therapy between last dose of ipilimumab induction and ipilimumab retreatment on study -Subjects who experienced any grade 3 irAE (except for endocrinopathies where clinical symptoms were controlled with appropriate hormone replacement therapy) or any grade 4 toxicity during prior treatment with ipilimumab. -Subjects with a prior irAE that has not improved to grade 1 or better atrandomization.

-Soggetti con metastasi cerebrali sono esclusi, a meno che non siano privi di sintomi neurologici legati alle lesioni cerebrali metastatiche e che non ricevono terapia con corticosteroidi sistemici per ridurre l’infiammazione intracranica nei 10 giorni precedenti l’inizio del ritrattamento con Ipilimumab. - Qualsiasi terapia anticancro effettuata tra l’ultima dose di induzione con Ipilimumab e l’inizio del ritrattamento con Ipilimumab nell’ambito dello studio - Soggetti che hanno avuto Eventi Avversi Immuno-Correlati (irAE) di Grado 3 (eccetto le endocrinopatie in cui i sintomi clinici erano controllati con appropriate terapie di sostituzione ormonale) o tossicità di Grado 4 durante il precedente trattamento con ipilimumab -Soggetti con precedenti Eventi Avversi Immuno-Correlati (irAE) che non sono migliorati al Grado 1 o risolti al momento della randomizzazione

E.5 End points

E.5.1

Primary end point(s)

Overall survival rate at 18 months from LPFV

Tasso di sopravvivenza complessiva a 18 mesi dalla LPFV.

E.5.1.1

Timepoint(s) of evaluation of this end point

Vital status will be assessed at each study visit. Analysis of overall survival rate will be done at 18 months from LPFV.

Lo stato di sopravvivenza verrà valutato ad ogni visita dello studio. L’analisi del tasso di sopravvivenza complessiva verrà effettuata a 18 mesi dal LPFV.

E.5.2

Secondary end point(s)

1. Overall survival. 2. Progression Free Survival 3. Best Overall Response Rate. 4. Assessment of EORTC QLQ-C30

1. Sopravvivenza complessiva 2. Sopravvivenza libera da progressione 3. Percentuale della migliore risposta complessiva 4. Valutazione dello stato di salute complessivo rispetto alla qualità di vita (EORTC QLQ-C30)

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Every study visit (q3months until 18 months, then q6months) 2. Every study visit (q3months until 18 months, then q6months) 3. Every three months (as of Month 3) until Month 18, and every 6 months thereafter. 4. At Baseline (week 1 prior to first dose), during treatment (every 6 weeks, always prior to dosing), at end of treatment, and at all visits thereafter

1. Ad ogni visita dello studio (ogni 3 mesi fino al mese 18, successivamente ogni 6 mesi) 2. Ad ogni visita dello studio (ogni 3 mesi fino al mese 18, successivamente ogni 6 mesi) 3. Ogni 3 mesi (a partire dal Mese 3) fino al Mese 18, e successivamente ogni 6 mesi 4. Al baseline (Settimana 1 prima della prima dose), durante il periodo di trattamento (ogni 6 settimane, sempre prima della dose), alla fine del trattamento, e successivamente a tutte le visite.

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

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Biomarker Assessments-Outcomes Research Assessm.-Health Related Resource Utilization (HRRU) Assessm.

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

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)

Yes

E.8.2.2

Placebo

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

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 remain open until the last subject randomized has been followed for 5 years or the study is terminated by the sponsor. Subjects who discontinue study drug therapy early - due to disease progression or study drug intolerance or for any other reason - will continue to be followed up for survival for 5 years after randomization.

Studio aperto fino a che l'ultimo soggetto randomizzato sia stato seguito x 5 anni o fino a interruzione studio da parte sponsor. Sogget.che hanno interrotto prima la terapia in studio saranno seguiti x per sopravvivenza x 5 anni dopo randomizzaz

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:

158

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

155

F.4.2.2

In the whole clinical trial

225

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)

the end of the study drug dosing period, BMS will not continue to supply study drug to subjects/investigators unless BMS chooses to modify the study. The investigator should ensure that the subject receives appropriate standard of care to treat the condition under study

Alla fine del periodo di trattamento con il farmaco in studio, BMS non continuerà a fornire il farmaco in studio ai soggetti/investigatori a meno che BMS non scelga di modificare lo studio. L’investigatore dovrebbe assicurare che i soggetti ricevano un trattamento standard appropriato per la malattia in studio.

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

2013-02-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-01-30

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2014-07-04

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