Clinical Trials Register

Summary
EudraCT Number:	2021-003208-42
Sponsor's Protocol Code Number:	CA209-6GE
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2022-03-17
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

Belgium - FPS Health-DGM

A.2

EudraCT number

2021-003208-42

A.3

Full title of the trial

A Phase 3, Open Label, Randomized, Non-Inferiority Pharmacokinetic Study of Nivolumab Administered Subcutaneously (Nivo SC) Versus Intravenous Administration of Nivolumab in Participants with Stage IIIA/B/C/D or Stage IV Adjuvant Melanoma Following Complete Resection

A.3.1

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

A Pharmacokinetic Study of Nivolumab Administered Subcutaneously vs Intravenous Nivolumab in Participants with Stage III A/B/C/D or Stage IV Melanoma Following Complete Resection

A.3.2

Name or abbreviated title of the trial where available

CheckMate-6GE: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 6GE

A.4.1

Sponsor's protocol code number

CA209-6GE

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1266-6116

A.5.4

Other Identifiers

Name:

IND

Number:

150,904

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	GSM-CT
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 Subcutaneous coformulated with excipient rHuPH20
D.3.2	Product code	BMS-986298-01
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous 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-986298
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	150
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	Yes
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	Comparator
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 (100 mg/10 ml)
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-10 ml vial-COMMERCIAL
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	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

Resected Stage IIIA/B/C/D or Stage IV melanoma in an adjuvant setting

E.1.1.1

Medical condition in easily understood language

Melanoma Stage III or Stage IV

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	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	21.1
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

Part 1:
- To demonstrate PK (pharmacokinetics) non-inferiority of nivolumab SC coformulated with rHuPH20 (recombinant human hyaluronidase PH20 enzyme) versus nivolumab IV (intravenous administration).

Part 2:
- To characterize the PK of nivolumab SC coformulated with rHuPH20.

E.2.2

Secondary objectives of the trial

Part 1, Key secondary:
- To assess the safety and tolerability of nivolumab SC coformulated with rHuPH20 and nivolumab IV.
- To assess the efficacy of nivolumab SC coformulated with rHuPH20 and nivolumab IV.

Part 1, Other Secondary:
- To characterize additional PK parameters following nivolumab SC coformulated with rHuPH20 and nivolumab IV.
- To evaluate the immunogenicity of nivolumab SC coformulated with rHuPH20 and nivolumab IV and the impact of anti-nivolumab antibodies on safety.
- To assess satisfaction with route of treatment administration.

Part 2:
- To characterize additional PK parameters following nivolumab SC coformulated with rHuPH20.
- To assess the safety and tolerability profile of nivolumab SC injection with rHuPH20.
- To assess the immunogenicity of nivolumab SC and the impact of anti-nivolumab antibodies on safety.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• All participants must have been diagnosed with either Stage IIIA (> 1mm tumor in lymph node)/B/C/D or Stage IV melanoma by AJCC 8th edition and have histologically confirmed melanoma (as documented in the pathology report) that is completely surgically resected (free of disease) with negative margins in order to be eligible. All melanomas, except uveal and mucosal melanoma, regardless of primary site of disease, will be allowed.
• Complete resection must be performed within 12 weeks prior to
randomization (Part 1) or treatment assignment (Part 2). Management of residual lymph nodes after positive sentinel lymph node biopsy (ie, completion lymph node dissection) will be as per local standards and recommendations for the individual participant.
• Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1.

E.4

Principal exclusion criteria

• History of uveal or mucosal melanoma.
• Untreated/unresected CNS metastases or leptomeningeal metastases.
• Participants with an active, known or suspected autoimmune disease. Participants with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
• Participants with serious or uncontrolled medical disorders within 4 weeks prior to screening.
- Additionally, in the case of prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, acute symptoms must have resolved and based on investigator assessment in consultation with the Medical Monitor, there are no sequelae that would place the participant at a higher risk of receiving investigational treatment.
• Concurrent malignancy (present during screening) requiring treatment or history of prior malignancy active within 2 years prior to randomization (Part 1) or treatment assignment (Part 2) (ie, participants with a history of prior malignancy are eligible if treatment was completed at least 2 years before randomization/treatment assignment and the patient has no evidence of disease). Participants with history of prior early stage basal/squamous cell skin cancer or noninvasive or in situ cancers that have undergone definitive treatment at any time are also eligible.
• Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) within 14 days or other immunosuppressive medications within 30 days of start of study treatment. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
• Any condition that according to investigator criteria makes a participant ineligible from participation in the study, including but not limited to medical conditions (including psychological, psychiatric), or social conditions; or conditions that can impact ability to comply with protocol requirements (eg, conditions that preclude the use of IV or subcutaneous [SC] route of study drug administration) or that can put the participant at risk. Participants with history of self-harm including suicidal attempts will be excluded from the study.
• Prior immunotherapy treatments for any prior malignancies are not permitted (such as, but not limited to anti-programmed death-1, anti-programmed death-ligand 1, anti-programmed death-ligand 2, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways).
• Participants treated with anti-cancer therapy directed against the resected melanoma (for example, but not limited to, systemic, local, radiation, and radiopharmaceuticals) except:
- Surgery for the melanoma lesion(s)
- Adjuvant radiation therapy after neurosurgical resection for CNS lesions
- Prior adjuvant interferon completed ≥ 6 months prior to randomization (Part 1) or treatment assignment (Part 2).
• Treatment with any live attenuated vaccine within 30 days of first study treatment (Vaccines that are not live attenuated are allowed, including COVID-19 vaccines).
• History of allergy or hypersensitivity to study drug components or device components.
• Known human immunodeficiency virus (HIV) positive with an AIDS defining opportunistic infection within the last year, or a current CD4 count < 350 cells/uL.
Participants with HIV are eligible if:
i) they have received antiretroviral therapy (ART) for at least 4 weeks prior to randomization (Part 1) or treatment assignment (Part 2) as clinically indicated while enrolled on study.
ii) they continue on ART as clinically indicated while enrolled on study.
iii) CD4 counts and viral load are monitored per standard of care by a local healthcare provider.
NOTE: Testing for HIV must be performed at sites where mandated locally. HIV positive participants must be excluded where mandated locally.

E.5 End points

E.5.1

Primary end point(s)

Part 1
-Cavgd28 (Time averaged nivolumab serum concentration over the first 28 days)
- Cminss (Minimum nivolumab serum concentration at steady-state)

Part 2
-Cavgd28

E.5.1.1

Timepoint(s) of evaluation of this end point

Part 1
-Cavgd28 : First 28 days of treatment
-Cminss : 17 weeks after the start of treatment

Part 2
-Cavgd28 : First 28 days of treatment

E.5.2

Secondary end point(s)

Part 1, Key secondary:
a) Incidence of all AEs/SAEs, treatment-related AEs, including IMAEs, SAEs, AEs (including device-related adverse reactions, injection/infusion-related AEs) leading to discontinuation or death, and laboratory abnormalities for each treatment group.
b) RFS (recurrence-free survival) per investigator - rates at 12, 18, 24, and 36 months follow-up.
c) OS (overall survival) rates at 12, 18, 24, and 36 months follow-up.

Part 1, other secondary:
d) Cmind28 (minimum nivolumab serum concentration on Day 28), Cmax1 (maximum nivolumab serum concentration after the first dose), Tmax (time to maximum nivolumab serum concentration after the first dose.)
e) Cmaxss (maximum nivolumab serum concentration at steady-state), and Cavgss (time-averaged nivolumab serum concentration at steady-state).
f) Percentage of participants who develop anti-nivolumab antibodies and neutralizing antibodies, if applicable, and the impact of anti-nivolumab antibodies on AEs, administration-related reactions, and events within MedDRA SMQ Anaphylactic reactions
g) Mean CTSQ (Cancer Treatment Satisfaction Questionnaire) Satisfaction domain scores and score change from baseline at each assessment time point.

Part 2
h) Cmind28, Cmax1, Tmax
i) Cmaxss, Cavgss, and Cminss.
j) Incidence of AEs/SAEs, treatment-related AEs, including IMAEs, SAEs, AEs (including device-related adverse reactions, injection/infusion-related AEs) leading to discontinuation or death, and laboratory abnormalities.
k) Percentage of participants who develop anti-nivolumab antibodies and neutralizing antibodies, if applicable, and the impact of anti-nivolumab antibodies on AEs, administration-related reactions, and events within MedDRA SMQ Anaphylactic reactions.

E.5.2.1

Timepoint(s) of evaluation of this end point

a) Up to 100 days after the last treatment of study intervention or up to discontinuation of study treatment
b) Until recurrence event, up to minimum follow-up of 12 months from last participant randomized in the study or death whichever is earlier
c) Until death, up to 36 months
d) First 28 days of treatment
e) 17 weeks after the start of treatment
f) Up to 100 days after the last study treatment or up to discontinuation of study treatment
g) At each assessment time Point
h) First 28 days of treatment
i) 17 weeks after the start of treatment
j) Up to 100 days after the last treatment of study intervention or up to discontinuation of study treatment
k) Up to 100 days after the last study treatment or up to discontinuation of study treatment

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

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Tolerability, Immunogenicity

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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

Australia

Canada

United States

Belgium

France

Germany

Italy

Poland

United Kingdom

Spain

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

End of trial is defined as the last participant last visit or completion of Follow-up Visit 2.

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:

276

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

103

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

In situations where consent cannot be given by participants, consent can be given by their legally acceptable representatives (as per country regulation) in accordance with ICH GCP Guidelines.

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

235

F.4.2.2

In the whole clinical trial

379

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)

At the end of the study, BMS will not continue to provide BMS-supplied study intervention to participants/investigators unless BMS chooses to extend the study. The investigator should ensure that the participant receives appropriate standard of care to treat the condition under study.

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

2022-05-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-07-26

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

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IMP with orphan designation in the indication
Orphan Designation Number:
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