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

• Register: EUCTR
• Last refreshed on: 28 February 2019
• Main ID: EUCTR2014-001286-28-HU
• Date of registration: 29/12/2014
• Prospective Registration: Yes
• Primary sponsor: Bristol-Myers Squibb International Corporation
• Public title: A multicenter clinical study with Nivolumab for subjects with confirmed stage III or stage IV melanoma post treament with an Anti-CTLA-4 antibody.
• Scientific title: A Single-Arm, Open-Label, Multicenter Clinical Trial with Nivolumab (BMS-936558) for Subjects with Histologically Confirmed Stage III (unresectable) or Stage IV Melanoma Progressing After Prior Treatment Containing an Anti-CTLA-4 Monoclonal Antibody
• Date of first enrolment: 16/03/2015
• Target sample size: 920
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-001286-28
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: Placebo: Other: Number of treatment arms in the trial: 1
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Austria, Belgium, Bulgaria, Croatia, Czech Republic, Denmark, Estonia, Finland, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Malta, Netherlands, Norway, Poland, Portugal, Romania, Russian Federation, Slovakia, Slovenia, Spain, Sweden, Switzerland, United Kingdom

Contacts

• Name: GCT-SU
• Affiliation: Bristol-Myers Squibb International Corporation

• Name: GCT-SU
• Affiliation: Bristol-Myers Squibb International Corporation

Key inclusion & exclusion criteria

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 anti-
CTLA-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), IL-
2, 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
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
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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, i

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Histologically Confirmed Stage III (unresectable) or Stage IV Melanoma
MedDRA version: 20.0 Level: PT Classification code 10025671 Term: Malignant melanoma stage IV System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 20.0 Level: PT Classification code 10025670 Term: Malignant melanoma stage III System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Therapeutic area: Diseases [C] - Cancer [C04]

Intervention(s)

Product Name: Nivolumab
Product Code: BMS-936558
Pharmaceutical Form: Solution for injection/infusion
INN or Proposed INN: NIVOLUMAB
CAS Number: 946414-94-4
Current Sponsor code: BMS-936558-01
Other descriptive name: BMS936558
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 10-

Primary Outcome(s)

Secondary Objective: 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 anti-
CTLA-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

Main Objective: 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.

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 anti-
CTLA-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 before data base lock.

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.

Secondary Outcome(s)

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

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 anti-
CTLA-4 monoclonal antibody.

Secondary ID(s)

CA209-172

2014-001286-28-BE

Source(s) of Monetary Support

Bristol-Myers Squibb International Corporation

Ethics review

Status: Approved
Approval date:
Contact: