Clinical Trials Register

Summary
EudraCT Number:	2013-000043-78
Sponsor's Protocol Code Number:	CA184-205
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2014-01-07
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

Germany - PEI

A.2

EudraCT number

2013-000043-78

A.3

Full title of the trial

Prospective randomized trial of an adjuvant therapy of completely resected Merkel Cell Carcinoma (MCC) with immune checkpoint blocking antibodies (Nivolumab, Opdivo®; Ipilimumab, Yervoy®) versus observation

A.3.1

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

Comparison of therapy of Merkel Cell Carcinoma (MCC) with Ipilimumab (Yervoy®) or Nivolumab (Opdivo®) versus observation only

A.3.2

Name or abbreviated title of the trial where available

ADMEC-O

A.4.1

Sponsor's protocol code number

CA184-205

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	United States
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	D-45122
B.5.3.4	Country	Germany
B.5.4	Telephone number	+492017234342
B.5.5	Fax number	+492017235935
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	Yes
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
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

completely resected Merkel cell carcinoma

E.1.1.1

Medical condition in easily understood language

Merkel cell carcinoma after surgical removal of the tumor

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	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10064025
E.1.2	Term	Merkel cell carcinoma
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

To estimate the efficacy of adjuvant nivolumab monotherapy in completely resected MCC patients in terms of disease-free survival (DFS) rate at 12, 24 and 48 months after date of randomization.

E.2.2

Secondary objectives of the trial

To describe the safety profile and additional efficacy parameters of the nivolumab treatment in MCC in terms of
- Adverse events according to CTCAE, Version 4.0 criteria, that are related to the administration of nivolumab
- Disease-free survival (DFS)
- Overall survival (OS) and OS rate at 12, 24 and 48 months after randomization

Explorative Objectives:
- To assess distant-metastases-free survival (DMFS) and DMFS rate at 12, 24 and 48 months after randomization
- To identify and validate prognostic/predictive biomarkers such as immune status, kinetics of the absolute lymphocyte count (ALC), or tumor microenvironment characteristics
- To assess quality of life (EORTC QLQ-C30) until 24 months after randomization

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

Translational Research Program.
The biology and the immunology of MCC are only partially 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. This translational research program will focus on the immune monitoring of the MCC patients treated in the phase II trial, as well as aim at the discovery of predictive and/or surrogate biomarkers for a successful immune therapy of MCC. The randomized design of the study allows distinguishing predictive from prognostic biomarkers. To reach this goal, sampling for translational research studies (tumor tissue, peripheral blood mononuclear cells (PBMC), plasma, serum) will be done as described in the study protocol.
These studies include:
- Prognostic/predictive value of the presence of tumor infiltrating lymphocytes in MCC lesions prior to therapy
- Expression of immune modulatory molecules in the tumor
- Presence of immune modulatory cells in the tumor
- Association with MCPyV
- Detection of circulating free MCC-specific DNS/microRNA in plasma and serum

E.3

Principal inclusion criteria

1. The patient is willing and able to give written informed consent.
2. Central histological confirmation of diagnosis of Merkel cell carcinoma (MCC).
3. All MCC manifestations have been completely resected by surgery within 12 weeks before enrolment.
4. No currently present metastases (as confirmed by standard imaging studies (e.g. suggested by S2k guidelines).
5. No previous systemic therapy for MCC.
6. Required values for initial laboratory tests:
- WBC ≥ 2000/uL
- ANC ≥ 1000/uL
- Platelets ≥ 75 x 103/uL
- Hemoglobin ≥ 8 g/dL (≥ 80 g/L)
- Creatinine ≤ 2.0 x ULN
- AST/ALT ≤ 2.5 x ULN
- Total Bilirubin ≤ 2.0 x ULN (except patients with Gilbert’s Syndrome, who must have a total bilirubin less than 3.0 mg/dL)
7. ECOG performance status of 0 or 1.
8. No active or chronic infection with HIV, Hepatitis B or C.
9. Men and women, ≥ 18 years of age.
10. Women of childbearing potential (WOCBP) must be using an adequate method of contraception (Pearl-Index < 1) to avoid pregnancy during treatment phase and for additional 5 months after the last dose of nivolumab, in such a manner that the risk of pregnancy is minimized. WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not post-menopausal. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours before the start of nivolumab.
11. Men of fathering potential must be using an adequate method of contraception to avoid conception during treatment phase and for additional 7 months after the last dose of nivolumab) in such a manner that the risk of pregnancy is minimized.

E.4

Principal exclusion criteria

1. Autoimmune disease: Patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn’s Disease, are excluded from this study, as are patients with a history of symptomatic disease requiring systemic steroids (e.g., rheumatoid arthritis, systemic progressive sclerosis, systemic lupus erythematosus, autoimmune vasculitis); autoimmune motor neuropathy.
2. Other serious illnesses, e.g., serious infections requiring i.v. antibiotics.
3. 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 immune deficient condition.
4. 4. Any underlying medical or psychiatric condition, which in the opinion of the investigator will make the administration of nivolumab hazardous or obscure the interpretation of AEs, such as a condition associated with frequent diarrhea.
5. Any non-oncology vaccine therapy for up to 1 month before or after any dose of nivolumab.
6. A history of prior or current treatment with a T cell potentiating agent (e.g. IL-2, interferon, anti-CTLA-4, anti-CD137, anti-PD1, anti-PD-L1, or anti-OX40 antibody).
7. Chronic use of immunosuppressive agents or systemic corticosteroids.
8. Women of childbearing potential (WOCBP), defined above in Section 5.1, who:
• are unwilling or unable to use an acceptable method of contraception to avoid pregnancy during treatment phase and for additional 5 months after the last dose of investigational product
• have a positive pregnancy test at baseline
• are pregnant or breastfeeding.
9. The patient has psychiatric or addictive disorders that may compromise his/her ability to give informed consent or to comply with the trial procedures.
10. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious) illness.
11. Men of reproductive potential unwilling to use an adequate method to avoid pregnancy during treatment phase and for additional 7 months after the last dose of investigational product.
12. Use of any investigational or non-registered product (drug or vaccine) other than the study treatment.

E.5 End points

E.5.1

Primary end point(s)

the primary endpoint is disease-free survival (DFS) rate at 12, 24 and 48 months after date of randomization.

E.5.1.1

Timepoint(s) of evaluation of this end point

at 12,24 and 48 months after date of randomization

E.5.2

Secondary end point(s)

- Adverse events according to CTCAE, Version 4.0 criteria, that are related to the administration of nivolumab
- Disease-free survival (DFS)
- Overall survival (OS) and OS rate at 12, 24 and 48 months after randomization

Explorative Objectives:
- Distant-metastasis-free survival (DMFS) and DMFS rate at 12, 24 and 48 months after randomization.
- Identification and validation of prognostic/predictive biomarkers
- Quality of life (EORTC QLQ-C30) until 24 months after randomization

E.5.2.1

Timepoint(s) of evaluation of this end point

DFS and DFS rate: at 12, 24 and 48 months after randomization
OS and OS rate: at 12, 24 and 48 months after randomization
DMFS and DMFS rate: at 12, 24 and 48 months after randomization
Quality of Life until 24 months after randomization

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

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

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

E.8.6.2

Trial being conducted completely outside of the EEA

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

2 years post LPFV (last patient first visit). First visit of the patient is defined as date of first infusion (treatment arm) or date of randomization (observation arm)

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

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:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

155

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

160

F.4.2

For a multinational trial

F.4.2.1

In the EEA

190

F.4.2.2

In the whole clinical trial

190

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 german guidelines for treatment of MCC-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

2014-04-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-02-19

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

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