Clinical Trials Register

Summary
EudraCT Number:	2014-001286-28
Sponsor's Protocol Code Number:	CA209172
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-08-01
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

Germany - PEI

A.2

EudraCT number

2014-001286-28

A.3

Full title of the trial

A Single-Arm, Open-Label, Multicenter Clinical Trial with Nivolumab (BMS936558) for Subjects with Histologically Confirmed Stage III
(unresectable) or Stage IV Melanoma Progressing After Prior Treatment
Containing an Anti-CTLA-4 Monoclonal Antibody

A.3.1

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

A multicenter clinical study with Nivolumab for subjects with confirmed stage III or stage IV melanoma after treament with an Anti-CTLA-4 antibody.

A.4.1

Sponsor's protocol code number

CA209172

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	GCT-SU
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	Belgium
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	Nivolumab
D.3.2	Product code	BMS-936558
D.3.4	Pharmaceutical form	Solution for injection/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	BMS936558
D.3.9.4	EV Substance Code	SUB32944
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

Histologically Confirmed Stage III (unresectable) or Stage IV Melanoma

E.1.1.1

Medical condition in easily understood language

Melanoma

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	10025671
E.1.2	Term	Malignant melanoma stage IV
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	20.0
E.1.2	Level	PT
E.1.2	Classification code	10025670
E.1.2	Term	Malignant melanoma stage III
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

The primary objective of this trial are:
- To determine the incidence of high-grade (CTCAE v4.0 Grade 3 or higher), treatment related, select adverse events in patients with histologically confirmed stage III (unresectable) or stage IV melanoma and progression after prior treatment containing an anti-CTLA-4 monoclonal antibody.

E.2.2

Secondary objectives of the trial

The secondary objectives:
- To determine the incidence and to characterize the outcome of all highgrade (CTCAE v4.0 Grade 3 or higher), select adverse events in patients
with histologically confirmed stage III (unresectable) or stage IV
melanoma and progression after prior treatment containing an antiCTLA-4
antibody, treated with nivolumab monotherapy.
- To estimate OS in all treated patients
- To estimate Investigator-assessed objective response rate (ORR)
Exploratory objectives: Refer to study protocol

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Signed Written Informed Consent
a) Patients must have signed and dated an IRB/IEC approved written
informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol-related procedures that are not part of normal patient care.
b) Patients must be willing and able to comply with scheduled visits,
treatment schedule, laboratory tests, and other requirements of the
study.
2. Target Population
a) Patients with progression after prior treatment containing an antiCTLA-4
monoclonal antibody (Cohorts 1 and 2):
i) Patients with histologically confirmed malignant melanoma
ii) Eastern Cooperative Oncology Group (ECOG) PS:
(1) PS 0 to 1 (Cohort 1)
(2) PS 2 (Cohort 2; a minimum of 50 patients and a maximum of 185;
clinical risk benefit ratio of Cohort 2 will be monitored by the Scientific
Steering Committee)
iii) Previously treated unresectable stage III or stage IV melanoma as
per the American Joint Committee on Cancer 2010 Guidelines36
regardless of BRAF mutation status
iv) Patients must have experienced disease progression or recurrence
after prior treatment containing an anti-CTLA-4 monoclonal antibody
v) Prior treatment with chemotherapy, interferon (adjuvant setting), IL2,
BRAF/MEK inhibitors for patients with known BRAF mutations, MEK
inhibitors for NRAS mutations, and cKIT inhibitor patients with known
cKIT mutations are allowed
vi) Patients with CNS metastases:
(1) Patients are eligible if CNS metastases are treated and patients are
neurologically returned to baseline (except for residual signs or
symptoms related to the CNS treatment) for at least 2 weeks prior to
enrollment. In addition, patients must be either off corticosteroids or on
a stable or decreasing dose 10 mg daily prednisone (or equivalent)
OR
(2) Patients are eligible if they have previously untreated CNS
metastases and are
neurologically asymptomatic. In addition, patients must be either off
corticosteroids or on a stable or decreasing dose of 10 mg daily
prednisone (or equivalent)
OR
(3) Patients with additional leptomeningeal metastases are eligible if
they are treated and neurologically returned to baseline (except for
residual signs or symptoms related to the CNS treatment) for at least 2
weeks prior to enrollment and have a life expectancy of at least 3
months. In addition, patients must be either off corticosteroids or on a
stable or decrease dose 10 mg daily prednisone (or equivalent)
vii)Prior chemotherapy or immunotherapy (tumor vaccine, cytokine, or
growth factor
given to control the cancer) must have been completed at least 4 weeks
before study drug administration, and all adverse events have either
returned to baseline or have been stabilized
viii) Prior palliative radiotherapy must have been completed at least 2
weeks prior to study drug administration
ix) Prior targeted therapy must have been completed at least 2 weeks
prior to study drug administration
x) Prior anti-CTLA-4 therapy must have been completed at least 4 weeks
before study drug administration
xi) Prior radiotherapy or radiosurgery must have be completed at least 2
weeks prior to the first dose of study drug
xii)Primary uveal (minimum of 30 patients) and mucosal melanoma are
allowed
xiii) Screening laboratory values must meet the following criteria prior
to commencement of treatment:
(1) WBCs ≥ 2000/μL
(2) Neutrophils ≥1500/μL
(3) Platelets ≥ 100 x 10³/μL
(4) Hemoglobin ≥ 9.0 g/dL
(5) Serum creatinine of ≤ 1.5 X ULN or creatinine clearance > 40
mL/minute (using Cockcroft/Gault formula)
(a) Female CrCl= [(140- age in years) x weight in kg x 0.85) ÷(72 x
serum creatinine in mg/ dL)]
(b) Male CrCl= [(140- age in years) x weight in kg x 1.00) ÷(72 x serum
creatinine in mg/ dL)]
(6) AST ≤ 3 X ULN
(7) ALT ≤ 3 X ULN
(8) Total bilirubin ≤ 1.5x ULN (except patients with Gilbert Syndrome
who must have total bilirubin < 3.0 mg/dL)
xiv) Patients with a known history of Grades 3-4 adverse reactions
during anti-CTLA-4 therapy will be allowed to participate if all toxicities
have resolved to Grade 1 (NCI CTCAE version 4) or baseline before
administration of nivolumab (minimum of 40 patients)
xv) Patients must have evaluable disease by CT or MRI per RECIST 1.1
criteria (radiographic tumor assessment performed within 6 weeks of
first dose of study drug)
or clinically apparent disease that the investigator can follow for
response.
xvi) Patient Re-enrollment: This study permits the re-enrollment of a
subject that has discontinued the study as a pre-treatment failure (ie, subject has not been treated). If re-enrolled, the subject must be re-consented.
For Other Inclusion Criteria please refer to Protocol

E.4

Principal exclusion criteria

1. Target Disease Exceptions
a) As of Amendment 02, this criterion is no longer applicable.
b) Patients with untreated, symptomatic CNS metastases are excluded
2. Medical History and Concurrent Diseases
a) As of Amendment 03, this criterion is not applicable.
b) Patients with a condition requiring systemic treatment with either
corticosteroids (>10 mg daily prednisone equivalent) or other
immunosuppressive medications within 14 days of study drug
administration. Inhaled or topical steroids and adrenal replacement
steroid doses > 10 mg daily prednisone equivalent are permitted in the
absence of active autoimmune disease.
c) Patients with previous malignancies (except non-melanoma skin
cancers, in situ bladder cancer, gastric or colon cancers, cervical
cancers/dysplasia or breast carcinoma in situ) are excluded unless a
complete remission was achieved at least 2 years prior to study entry
and no additional therapy is required or anticipated to be required
during the study period
d) Any serious or uncontrolled medical disorder or active infection that,
in the opinion of the investigator, may increase the risk associated with study participation, study drug administration, or would impair the ability of the patient to receive protocol therapy
e) Any treatment in a BMS-sponsored, interventional nivolumab trial or
ipilimumab trial
f) Known drug or alcohol abuse
3. Physical and Laboratory Test Findings
a) Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection
b) Positive test for HIV
4. Allergies and Adverse Drug Reaction
a) History of severe hypersensitivity reactions to other monoclonal
antibodies
b) History of allergy or intolerance (unacceptable adverse event) to
study drug components or Polysorbate-80-containing infusions.
c) As of Amendment 02, this criterion is no longer applicable.
5. Sex and Reproductive Status
a) WOCBP who are pregnant or breastfeeding
b) Women with a positive pregnancy test at enrollment or prior to
administration of study medication
c) Women treated with ORAL hormone replacement therapy (HRT) are to
be excluded unless the oral replacement therapy was stopped by investigator's discretion at least 4 weeks prior to screening and was changed to other contraception method.
6. As of Amendment 02, this criterion is no longer applicable
7. Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated
b) Subjects who are compulsorily detained for treatment of either a
psychiatric or physical (eg, infectious disease) illness
Eligibility criteria for this study have been carefully considered to ensure
the safety of the study subjects and that the results of the study can be
used. It is imperative that subjects fully meet all eligibility criteria.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is the incidence for high-grade (CTCAE v4.0 Grade
3 or higher), treatment-related, select adverse events.

E.5.1.1

Timepoint(s) of evaluation of this end point

The analysis of primary, secondary (excluding ORR), and exploratory
endpoints will be reported for the full safety analysis set and by cohorts
based on ECOG PS. ORR will be reported for the response evaluable
analysis set and by PS. OS and ORR will be further presented by initial
investigator-assessed objective response under treatment with an antiCTLA-4 monoclonal antibody.

Additional details regarding statistical analysis performed in the study are provided in the Statistical Analysis Plan (SAP), which will be finalized before data base lock.

E.5.2

Secondary end point(s)

The secondary endpoints include:
 - Incidence of all high-grade (Grades 3 and higher), select adverse
events
 - Median time to onset and median time to resolution (Grades 3-4) of
select adverse events
 - OS
 - Investigator-assessed ORR
The exploratory endpoints include:
 - Safety and tolerability will be measured by the incidence of all
adverse events, serious adverse events, deaths, and laboratory
abnormalities. Adverse event assessments and laboratory tests will be performed at baseline and continuously throughout the study at the
beginning of each subsequent cycle.
 - Investigator-assessed ORR
 - OS
 - Quality of Life as mean and change from baseline in domain scores
and health status index based on EORTC QLQ-C30 and EQ-5D-3L of the full
safety analysis set

E.5.2.1

Timepoint(s) of evaluation of this end point

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

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)

Information not present in EudraCT

E.8.2.2

Placebo

Information not present in EudraCT

E.8.2.3

Other

Information not present in EudraCT

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

210

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

Belgium

Czech Republic

Denmark

Finland

Germany

Greece

Hungary

Ireland

Italy

Netherlands

Norway

Poland

Portugal

Romania

Russian Federation

Spain

Sweden

Switzerland

United Kingdom

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

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:

520

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

400

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

400

F.4.2

For a multinational trial

F.4.2.1

In the EEA

800

F.4.2.2

In the whole clinical trial

920

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)

Normal standard of care.

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

2014-09-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-11-05

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

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