Clinical Trials Register

Summary
EudraCT Number:	2010-020347-12
Sponsor's Protocol Code Number:	CA204004
National Competent Authority:	Ireland - HPRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2011-05-10
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

Ireland - HPRA

A.2

EudraCT number

2010-020347-12

A.3

Full title of the trial

A Phase 3, Randomized, Open Label Trial of Lenalidomide/dexamethasone With or Without Elotuzumab in Relapsed or Refractory Multiple Myeloma

A.3.1

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

A Phase 3 Relapsed or Refractory Multiple Myeloma - Open label with or without Elotuzumab.

A.4.1

Sponsor's protocol code number

CA204004

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01239797

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	EU Start Up Department
B.5.3	Address:
B.5.3.1	Street Address	Parc de l'Alliance, Avenue de Finlande, 8
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	Elotuzumab
D.3.2	Product code	HuLuc63
D.3.4	Pharmaceutical form	Powder for 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	Elotuzumab
D.3.9.1	CAS number	915296-00-3
D.3.9.2	Current sponsor code	BMS-901608
D.3.9.3	Other descriptive name	HuLuc63; Anti-CS1
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	400
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	No
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	Yes
D.3.11.13.1	Other medicinal product type	Humanized monoclonal IgG1 antibody

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

Relapsed or Refractory Multiple Myeloma

E.1.1.1

Medical condition in easily understood language

Multiple myeloma is a type of blood cancer that affects the white blood cells that produce antibodies

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	LLT
E.1.2	Classification code	10028228
E.1.2	Term	Multiple myeloma
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 compare the Progression-Free Survival of lenalidomide/low-dose dexamethasone + elotuzumab (LdE) versus lenalidomide/low-dose dexamethasone (Ld) in subjects with relapsed or refractory multiple myeloma (MM).

-To compare the ORR of LdE versus Ld.

E.2.2

Secondary objectives of the trial

- To compare overall survival of LdE versus Ld.
-To compare the changes from baseline of the mean score of pain severity and of the mean score of pain interference using the Brief Pain Inventory- Short Form (BPI-SF) of LdE versus Ld. Exploratory Objectives, to asses of:
- safety in each arm
- the time to tumor response and duration of response among subjects who had an objective response and to assess time in response among all randomized subjects
- the PFS rates at 1, 2 and 3 years
- the OS rates at 3, 4, 5 and 6 years.
- the Health-related Quality of Life outcomes (EORTC QLQ-C30 and
QLQMY20).
- the serum concentrations of elotuzumab, in the presence of lenalidomide and dexamethasone
- the immunogenicity of elotuzumab.
Pharmacogenetic research objective:
To study the association between genetic variation and drug response.
Bristol-Myers Squibb may also use the DNA to study the causes and further progression of multiple myeloma.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Signed Written Informed Consent
a) Subject is, in the investigator's opinion, willing and able to comply with the protocol requirements.
b) Subject has given voluntary written informed consent before
performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to their future medical care.
2) Target Population
a) Age >or= 18 years or legal age of consent per local regulations
b) ECOG performance status >or= 2
c) Life-expectancy > 3 months
d) Documented evidence of multiple myeloma and
i) Received between 1 to 3 prior lines of therapy with documented
progression by EBMT criteria after the most recent therapy AND
ii) Measurable disease (subject must meet one of the following 5
criteria):
(a) serum IgG M-protein >or= 0.5 g/dL
(b) serum IgA M-protein >or= 0.5 g/dL
(c) serum IgM M-protein >or= 0.5 g/dL
(d) serum IgD M-protein >or= 0.05 g/dL
(e) Urine M-protein >or= 200 mg/24-hour
e) Prior lenalidomide exposure is permitted only if they fulfill all of the following:
i) Best response achieved was >or= PR
ii) Were not refractory to prior lenalidomide defined as no progression while receiving lenalidomide or within 9 months of last dose of lenalidomide
iii) Subject did not discontinue lenalidomide due to a Grade >or= 3
related AE
iv) Subject did not receive more than 9 cycles of lenalidomide and had at least 9 months between the last dose of lenalidomide and progression
3) Age and Reproductive Status
a) Men and women of childbearing potential (WOCBP) must be using 2 acceptable methods of contraception to avoid pregnancy throughout the study for a period of at least 1 month (4 weeks) before and women for up to 8 weeks, men for up to 90 days after the last dose of investigational product in such a manner that the risk of pregnancy is minimized. See Section 3.3.3 for the definition of WOCBP and Revlimid risk management plan guidelines.
b) WOCBP must have a negative serum or urine pregnancy test
(minimum sensitivity 25 IU/L or equivalent units of HCG). The first
should be performed within 10 - 14 days and the second within 24 hours prior to the start of the investigational product. A prescription for lenalidomide for a female of childbearing potential must not be issued by the prescriber until negative pregnancy tests have been verified by the prescriber.
c) Women must not be breastfeeding.
d) Men must agree to use a latex condom and a second form of birth
control during sexual contact with WOCBP, even if they have had a
successful vasectomy, and must agree to not donate semen during study drug therapy and for 90 days after therapy.
e) Subjects must be willing to refrain from blood donations during study drug therapy and for 8 weeks after therapy.
4) Pharmacogenetic
To participate in the Pharmacogenetic Sample Amendment, subjects
must provide a signed Pharmacogenetic Blood DNA informed consent.

E.4

Principal exclusion criteria

1) Target Disease Exceptions
a) Subjects with non-secretory or oligo-secretory or serum free lightchain only myeloma (subjects with measurable M protein only in the urine as defined under Inclusion Criteria would be eligible)
b) Active plasma cell leukemia (defined as either 20% of peripheral WBC comprised of plasma/CD138+ cells or an absolute count of 2 x 109/L).
2) Medical History and Concurrent Diseases
a) All Adverse Events of any prior chemotherapy, surgery, or radiotherapy not resolved to NCI CTCAE (v. 3.0) Grade <or= 2
b) POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
c) Significant cardiac disease as determined by the investigator including:
i) Known or suspected cardiac amyloidosis
ii) Congestive heart failure of Class III or IV of the NYHA classification;
iii) Uncontrolled angina, hypertension or arrhythmia
iv) Myocardial infarction in past 6 months
v) Any uncontrolled or severe cardiovascular disease
d) Prior cerebrovascular event with persistent neurologic deficit
e) Known HIV infection or active hepatitis A, B, or C
f) Any medical conditions that, in the investigator's opinion, would impose excessive risk to the subject. Examples of such conditions
include:
i) Any uncontrolled disease, such as pulmonary disease, infection, seizure disorder
ii) Active infection that requires parenteral anti-infective treatment
iii) Any altered mental status or any psychiatric condition that would interfere with the understanding of the informed consent
g) Prior or concurrent malignancy, except for the following:
i) Adequately treated basal cell or squamous cell skin cancer
ii) Or any other cancer from which the subject has been disease-free for > 5 years
h) Uncontrolled diabetes (defined as Hgb A1C >or= 8.0%).
i) Unable to tolerate thromboembolic prophylaxis including, as clinically indicated, aspirin, Coumadin (warfarin) or low-molecular weight
heparin.
3) Physical and Laboratory Test Findings
a) Corrected serum calcium >or= 11.5 mg/dl within 2 weeks of randomization (despite appropriate measure such a short course of
steroids, bisphosphonates, hydration, calcitonin)
b) Absolute neutrophil count < 1000 cells/mm3. No granulocyte colony stimulating factors (G-CSF or GM-CSF) allowed within 1 week of randomization. No pegylated granulocyte colony stimulating factors allowed within 3 weeks of randomization.
c) Platelets < 75,000 cell/mm3 (75 x 109/L). Qualifying laboratory value must occur at most recent measurement prior to randomization
and must be no more than 14 days prior to randomization. No transfusions are allowed within 72 hours prior to qualifying laboratory
value.
d) Hemoglobin < 8 g/dL. Qualifying laboratory value must occur at most recent measurement prior to randomization and must be no more than
14 days prior to randomization. No transfusions are allowed within 72 hours prior to qualifying laboratory value.
e) Total bilirubin >or= 2 x ULN , or direct bilirubin >or= 2.0 mg/dL
f) AST or ALT >or= 3 x ULN
g) Creatinine clearance (CrCl) < 30 mL/min measured by 24-hour urine collection or estimated by the Cockcroft and Gault formula
4) Prior Therapy or Surgery
a) Major surgery within 4 weeks prior to randomization as described in Section 3.4.4.
b) Administration of chemotherapy, biological, immunotherapy, or any investigational agent (therapeutic or diagnostic) within 3 weeks prior to randomization (14 days for non-myelosuppressive therapy). Subjects should be 6 weeks from last dose of nitrosourea, nitrogen mustards, melphalan or monoclonal antibody, 12 weeks from autologous SCT, and 16 weeks from allogeneic SCT.
c) If prior allogeneic stem cell transplant, history of moderate to severe chronic graft versus host disease (GvHD)
d) Treatment with plasmapheresis within 4 weeks prior to randomization.
e) Prior therapy with elotuzumab or any IMiD (including pomalidomide), except for prior thalidomide or lenalidomide (as defined in inclusion criteria).
f) Refractory to prior lenalidomide
g) Steroids within 3 weeks of randomization, except:
i) <or= 10 mg prednisone or equivalent per day
ii) Steroid with little to no systemic absorption (ie, topical or inhaled steroids)
5) Allergies and Adverse Drug Reaction
a) Known hypersensitivity to lenalidomide, dexamethasone, any excipients in the
elotuzumab formulation or recombinant protein
b) History of Grade 4 rash associated with thalidomide treatment
6) Sex and Reproductive Status
a) Sexually active fertile men not using 2 forms of effective birth control if their partners are WOCBP.
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.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint of progression-free survival (PFS) is defined as the time from randomization to the date of the first documented tumor progression as determined by the IRC using the EBMT criteria or to death due to any cause, provided death does not occur more than 10 weeks (2 or more assessment visits) after the last tumor assessment.

Objective Response Rate - The percentage of patients who have a partial or complete response to study therapy.

E.5.1.1

Timepoint(s) of evaluation of this end point

Every 4 weeks (+/-1 week) relative to the first dose of study medication.

E.5.2

Secondary end point(s)

Objective Response Rate - The percentage of patients who have a partial or complete response to study therapy.

Overall Survival - The period of time from study entry until the date of death or last known date alive.

E.5.2.1

Timepoint(s) of evaluation of this end point

All response endpoints assessed every 4 weeks (+/- 1 week). Survival will be assessed every 12 weeks in the Follow Up Phase of the trial.

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

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)

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

No comparator but background treatment

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

120

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

Austria

Belgium

Canada

Czech Republic

Denmark

France

Germany

Greece

Hungary

Ireland

Israel

Italy

Japan

Poland

Romania

Russian Federation

Spain

Switzerland

Turkey

United Kingdom

United States

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

Last Visit of the Last Subject

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