Clinical Trials Register

Summary
EudraCT Number:	2016-001359-36
Sponsor's Protocol Code Number:	CA223-001
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-08-17
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2016-001359-36

A.3

Full title of the trial

A Phase I /II Dose Escalation and Cohort Expansion Study of the Safety, Tolerability and Efficacy of Anti-KIR (Lirilumab) Administered in Combination with Anti-PD-1 (Nivolumab) in Advanced Refractory Solid Tumors

A.3.1

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

A Phase 1/2 Study of an Anti-KIR Antibody in Combination With an Anti-PD1 Antibody in Patients With Advanced Solid Tumors

A.4.1

Sponsor's protocol code number

CA223-001

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1181-4018

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	BMS-936558, MDX1106, ONO-4538
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.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.2.5	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	Lirilumab
D.3.2	Product code	BMS-986105
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	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Lirilumb
D.3.9.2	Current sponsor code	BMS-986105
D.3.9.3	Other descriptive name	BMS986015
D.3.9.4	EV Substance Code	SUB174133
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

Solid tumors

E.1.1.1

Medical condition in easily understood language

Solid tumors

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	19.0
E.1.2	Level	PT
E.1.2	Classification code	10060121
E.1.2	Term	Squamous cell carcinoma of head and neck
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

-) To assess the safety and tolerability of lirilumab (BMS-986015) given in combination with nivolumab (BMS-936558) and to identify dose limiting toxicities (DLTs) and the maximally tolerated dose (MTD) of the combination, in subjects with advanced (metastatic and/or unresectable) solid tumors.
-) To assess the preliminary anti-tumor activity of the combination of lirilumab (BMS 986015) and nivolumab (BMS-936558) in subjects with advanced solid tumors.

E.2.2

Secondary objectives of the trial

-) To characterize the pharmacokinetics (PK) of lirilumab (BMS-986015) and nivolumab (BMS-936558) when co-administered.
-) To monitor immunogenicity of lirilumab (BMS-986015) and nivolumab
(BMS-936558) administered as combination therapy.
-) To assess the pharmacodynamic effect in tumor tissue on tumor infiltrating lymphocyte (TIL) subsets from melanoma (MEL), and head and neck squamous cell carcinoma (SCCHN) subjects treated with lirilumab (BMS-986015) given in combination with nivolumab (BMS-936558).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Signed Written Informed Consent

2) Target Population
a) Subjects must have histologic or cytologic confirmation of a solid malignancy that is advanced (metastatic and/or unresectable):for Cohort Expansion part 2
Head and Neck Squamous Cell Carcinoma (SCCHN) (oral cavity, pharynx, larynx)
ii. Subjects must have ≤ 5 prior treatment regimens. The following are not considered separate lines of treatment: addition of a compound to an on-going regimen, re-starting the same regimen after a drug holiday, or switching from intravenous to oral therapy
b) Presence of at least one lesion with measurable disease as defined by RECIST v1.1
criteria for response assessment.
c) ECOG status of 0 or 1.
fd Life expectancy of ≥ 12 weeks.

3) Age, Sex, and Reproductive Status
a) Men and women, ages > 18.

E.4

Principal exclusion criteria

1) Target Disease Exceptions

2) Medical History and Concurrent Diseases
a. Subjects with a prior malignancy are excluded, except adequately treated basal cell or squamous cell skin cancer, superficial bladder cancer, localized prostate cancer, carcinoma in situ of the cervix, or in situ ductal or lobular carcinoma of the breast.
b. Subjects with any active autoimmune disease or history of known or suspected autoimmune disease, with the exception of subjects with isolated vitiligo, resolved childhood asthma/atopy, and controlled thyroid disorders.

3) Prohibited Prior Treatments and/or Therapies
a. Prior therapy with an anti-KIR, anti-PD-1, or anti-PD-L1, antibody.
b. Prior treatment regimens with any immune cell modulating antibody such as anti-CD137 and anti-OX40.
c. Exposure to any other investigational drug within 4 weeks prior to the first dose of study drug (within 101 days for anti-CTLA4 therapy).
d. Any anti-cancer therapy (e.g., chemotherapy, biologics, vaccines, radiotherapy with curative intent, or hormonal treatment) within 4 weeks prior to the first dose of study drug administration (within 101 days for anti-CTLA4 therapy), with the exception of GnRH agonist therapy for subjects with prostate cancer.

4) Physical and Laboratory Test Findings

5) Sex and Reproductive Status
a) Women who are pregnant or are breastfeeding.

E.5 End points

E.5.1

Primary end point(s)

Safety is the primary endpoint in this Phase I/II study.

The primary objective (to assess the safety and tolerability of lirilumab (BMS-986015) given in combination with nivolumab (BMS-936558) and to identify dose limiting toxicities (DLTs) and the maximally tolerated dose (MTD) of the combination) will be measured by the following
primary endpoints:
a) Incidence of adverse events.
b) Incidence of clinical laboratory test abnormalities including hematology and serum chemistry, and thyroid panel abnormalities.

E.5.1.1

Timepoint(s) of evaluation of this end point

Incidence of adverse events will be collected from Day 1 until 100 days after the subject’s last dose of study drug or until they discontinue the study as per protocol.

Incidence of clinical laboratory test abnormalities will be assessed at specified time points as designated in the Time and Events Section (5.1) of the protocol.

E.5.2

Secondary end point(s)

Efficacy endpoint:
The secondary objective of assessing preliminary anti-tumor activity will be based on endpoints
described below using RECIST v1.1:
1) Best overall response (BOR) is the best response designation recorded from the start of the
study treatment until the end of treatment taking into account any requirement for confirmation,
based on RECIST v1.1 criteria.
2) Objective response rate (ORR) is defined as the total number of subjects whose BOR is either
CR or PR divided by the total number of subjects in the population of interest.
3) Duration of Response (DOR)
4) Progression-Free Survival Rate (PFSR) is defined as the probability of a subject remaining
progression-free and surviving to 24 weeks

Pharmacokinetics (PK)

Immunogenicity

Biomarkers

E.5.2.1

Timepoint(s) of evaluation of this end point

BOR will be determined based on tumor measurements occurring every 8 weeks during the Treatment period (Cycle 1 Day 1 through Cycle 12 Day 56), and once during the Clinical Follow-up period.
DOR defined as the number of days between the date of first response and the subsequent date of objectively documented disease progression based on the criteria (RECIST v1.1) or death
PFSR is 24 weeks

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

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

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)

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

Yes

E.8.4

The trial involves multiple sites in the 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

Belgium

Canada

France

Germany

Italy

Netherlands

Spain

Switzerland

United Kingdom

United States

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

Last Patient Last Visit

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:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

F.4.2.2

In the whole clinical trial

171

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 treatment phase of the study, BMS will not continue to supply study drug to subjects/investigators unless BMS chooses to extend the 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

2016-07-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-06-21

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

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IMP with orphan designation in the indication
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