Clinical Trials Register

Summary
EudraCT Number:	2014-001167-12
Sponsor's Protocol Code Number:	IMMUNED
National Competent Authority:	Austria - BASG
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2017-11-13
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

Austria - BASG

A.2

EudraCT number

2014-001167-12

A.3

Full title of the trial

A Phase II Randomized, Double-Blind Trial of Immunotherapy with Nivolumab or Nivolumab plus Ipilimumab versus Double-Placebo Control as a Post-Surgical/Post-Radiation Treatment for Stage IV Melanoma with No Evidence of Disease

Randomisierte, doppelt-verblindete Placebo-kontrollierte Immuntherapie mit Nivolumab oder Nivolumab plus Ipilimumab oder Placebo-Kontrolle zur Behandlung von Patienten mit Melanom im Stadium IV ohne Krankheitsanzeichen (No Evidence of Disease) nach kompletter chirurgischer Entfernung oder Strahlentherapie

A.3.1

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

Investigation of immunotherapy with nivolumab compared to nivolumab plus ipilimumab compared to placebo for patients with Stage IV melanoma with no evidence of disease after surgery or radiotherapy

A.3.2

Name or abbreviated title of the trial where available

Immuned

A.4.1

Sponsor's protocol code number

IMMUNED

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	University of Essen
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Non-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
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	University Hospital Essen
B.5.2	Functional name of contact point	Departement of Dermatology
B.5.3	Address:
B.5.3.1	Street Address	Hufelandstr. 55
B.5.3.2	Town/ city	Essen
B.5.3.3	Post code	45147
B.5.3.4	Country	Germany
B.5.4	Telephone number	00492017234342
B.5.5	Fax number	00492017235935
B.5.6	E-mail	dirk.schadendorf@uk-essen.de

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.2.1.1.1	Trade name	Yervoy
D.2.1.1.2	Name of the Marketing Authorisation holder	Bristol-Myers Squibb Pharma EEIG
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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.3.4	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.3.9.4	EV Substance Code	SUB29397
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	5
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.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.2.1.1.1	Trade name	OPDIVO
D.2.1.1.2	Name of the Marketing Authorisation holder	Bristol-Myers Squibb Pharma EEIG
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Nivolumab
D.3.2	Product code	BMS-936558
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	NIVOLUMAB
D.3.9.1	CAS number	946414-94-4
D.3.9.2	Current sponsor code	BMS-936558-01
D.3.9.3	Other descriptive name	NIVOLUMAB
D.3.9.4	EV Substance Code	SUB122750
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection/infusion
D.8.4	Route of administration of the placebo	Intravenous use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection/infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Stage IV melanoma with no evidence of disease after surgery or radiotherapy

Melanom im Stadium IV ohne Krankheitsanzeichen (No Evidence of Disease) nach kompletter chirurgischer Entfernung oder Strahlentherapie

E.1.1.1

Medical condition in easily understood language

Advanced melanoma with no evidence of disease after surgery or radiotherapy

Fortgeschrittenes Melanom ohne Krankheitsanzeichen (No Evidence of Disease) nach Operation oder Bestrahlung

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	20.0
E.1.2	Level	PT
E.1.2	Classification code	10025650
E.1.2	Term	Malignant melanoma
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

Ti assess the efficacy of adjuvant immunotherapy with Nivolumab alone or in combination with Ipilimumab in stage IV melanoma patients with no evidence of disease

E.2.2

Secondary objectives of the trial

Overall survival (OS) and safety / toxicity

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

Despite major recent advances in melanoma biology and the immunology, these are still not completely understood, thus it appears mandatory to implement a comprehensive translational research program in order to establish the means to identify the group of patients most likely to benefit from therapy. The randomized design of the study will allow distinguishing predictive from prognostic biomarkers. This translational research program will focus on the discovery of predictive and/or surrogate biomarkers for a successful immune therapy of melanoma. Thus, sampling for biomarker studies (tumor tissue, plasma, serum) will be done as described in the study protocol.

E.3

Principal inclusion criteria

1.Stage IV melanoma arising from a primary cutaneous site or metastatic from an unknown primary site with no evidence of disease (NED) after surgery or radiation therapy (conducted within 8 weeks before enrolment)
2.Signed written informed consent
3.Men and women, aged 18 to 80 years
4.Known BRAF status
5.Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study
6.Minimum life expectancy of five years excluding their melanoma diagnosis
7.ECOG performance status of or 1
8.Tumor tissue from the resected site of disease must be provided for biomarker analyses. In order to be randomized a subject must have a PD-L 1 expression classification (positive (≥ 5% tumor cells expressing PD-L1) or negative (< 5% tumor cells expressing PD-L1)). If an insufficient amount of tumor tissue from the resected site is provided for analysis, acquisition of additional archived tumor tissue (block and/or slides) for the biomarker analyses is required.
9.Prior radiotherapy must have been completed at least 2 weeks prior to study drug administration
10.Screening laboratory values must meet the following criteria and should be obtained within 14 days prior to randomization:
oWBC ≥ 2000/μL
oNeutrophils ≥ 1500/μL
oPlatelets ≥ 100 x103/μL
oHemoglobin ≥ 9.0 g/dL
oSerum creatinine ≤ 1.5xUL
oCreatinine clearance (CrCl) ≥ 40mL/min if using the Cockcroft-Gault formula
11.Negative pregnancy test for female subjects and effective contraception (Pearl-Index <1) for both male and female subjects if the risk of conception exists

E.4

Principal exclusion criteria

1.History of primary uveal or mucosal melanoma
2.Prior therapy with CTLA4 or PD1 antibodies
3.The patient has psychiatric or addictive disorders that may compromise his/her ability to give informed consent or to comply with the trial procedures.
4.Lack of availability for clinical follow-up assessments.
5.Any immunosuppressive therapy given within the past 30 days prior to study drug administration (excluding physiologic steroid hormone replacement)
6.Other malignancies within the past five years requiring treatment except basal or squamous skin carcinomas or carcinoma in situ of the cervix
7.Serious cardiac, gastrointestinal, hepatic or pulmonary disease reducing life expectancy to less than five years
8.Patients with serious intercurrent illness, requiring hospitalization.
9.Other serious illnesses, e.g., serious infections requiring antibiotics or bleeding disorders.
10.The patient is known to be positive for Human Immunodeficiency Virus (HIV) or other chronic infections (HBV, HCV).or has another confirmed or suspected immunosuppressive or immunodeficient condition.
11.Known hypersensitivity reaction to any of the components of study treatment
12.Pregnancy (absence to be confirmed by ß-HCG serum test, minimum sensitivity 25IU/L or equivalent units of HCG)) or lactation period
13.Women of childbearing potential (WOCBP): Refusal or inability to use effective means of contraception (Pearl-Index <1). WOCBP receiving Nivolumab will be instructed to adhere to contraception until 31 weeks after the last dose of investigational product
14.Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year (Pearl-Index <1). Men receiving Nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception until 31 weeks after the last dose of investigational product
15.Known alcohol or drug abuse
16.Participation in another clinical study and use of any investigational or non-registered product (drug or vaccine) other than the study treatment within the 30 days before registration
17.Significant disease or condition which, in the investigator’s opinion, would exclude the patient from the study
18.Legal incapacity or limited legal capacity

E.5 End points

E.5.1

Primary end point(s)

Progression-free survival

E.5.1.1

Timepoint(s) of evaluation of this end point

Study enrolment until day of progression/death

E.5.2

Secondary end point(s)

1. Overall survival (OS)
2. Safety/Toxicity

E.5.2.1

Timepoint(s) of evaluation of this end point

Study enrolment until death/end of study

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

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

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)

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

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

Austria

Germany

Switzerland

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:

156

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

156

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

312

F.4.2.2

In the whole clinical trial

312

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 finishing or discontinuing the participation in the trial patients will be treated according to the current local guidelines for treatment of melanoma patients.

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

2017-12-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-03-28

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-06-27

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