Clinical Trials Register

Summary
EudraCT Number:	2015-002509-13
Sponsor's Protocol Code Number:	3475-183
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-11-03
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

Spain - AEMPS

A.2

EudraCT number

2015-002509-13

A.3

Full title of the trial

A phase III study of Pomalidomide and low dose Dexamethasone with or without Pembrolizumab (MK3475) in refractory or relapsed and refractory Multiple Myeloma (rrMM) (KEYNOTE 183)

Estudio en fase III de pomalidomida y dexametasona en dosis baja con o sin pembrolizumab (MK3475) en el mieloma múltiple resistente o recidivante y resistente (MMrr). (KEYNOTE 183)

A.3.1

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

A phase III study of Pomalidomide and Dexamethasone with or without Pembrolizumab in refractory or relapsed and refractory Multiple Myeloma (rrMM).

Estudio en fase III de pomalidomida y dexametasona con o sin pembrolizumab en el mieloma múltiple resistente o recidivante y resistente (MMrr).

A.3.2

Name or abbreviated title of the trial where available

A phase III study of Pomalidomide and Dexamethasone with or without Pembrolizumab in rrMM

Estudio en fase III de pomalidomida y dexametasona con o sin pembrolizumab en el MMrr

A.4.1

Sponsor's protocol code number

3475-183

A.5.4

Other Identifiers

Name:

IND No:

Number:

118604

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	Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
B.1.3.4	Country	United States
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	Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Merck Sharp & Dohme de España S.A.
B.5.2	Functional name of contact point	Investigación Clínica
B.5.3	Address:
B.5.3.1	Street Address	C/ Josefa Valcárcel, 38
B.5.3.2	Town/ city	Madrid
B.5.3.3	Post code	28027
B.5.3.4	Country	United States
B.5.4	Telephone number	+34913210600
B.5.5	Fax number	+34913210590
B.5.6	E-mail	ensayos_clinicos@merck.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	Pembrolizumab
D.3.2	Product code	MK-3475
D.3.4	Pharmaceutical form	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	Pembrolizumab
D.3.9.1	CAS number	1374853-91-4
D.3.9.2	Current sponsor code	MK-3475
D.3.9.3	Other descriptive name	Anti-PD-1 monoclonal antibody
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	100
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)	Yes
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.2.1.2	Country which granted the Marketing Authorisation	Spain
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	Dexamethasone
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Dexamethasone
D.3.9.3	Other descriptive name	Dexamethasone
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	4
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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	No
D.IMP: 3
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.2.1.2	Country which granted the Marketing Authorisation	Spain
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	Dexamethasone
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Dexamethasone
D.3.9.3	Other descriptive name	Dexamethasone
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	8
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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	No
D.IMP: 4
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	Imnovid
D.2.1.1.2	Name of the Marketing Authorisation holder	Celgene Europe Ltd
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	Imnovid
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Pomalidomide
D.3.9.3	Other descriptive name	Pomalidomide
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	1
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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	No
D.IMP: 5
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	Imnovid
D.2.1.1.2	Name of the Marketing Authorisation holder	Celgene Europe Ltd
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	Imnovid
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Pomalidomide
D.3.9.3	Other descriptive name	Pomalidomide
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	4
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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	No
D.IMP: 6
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.2.1.2	Country which granted the Marketing Authorisation	Spain
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	Imnovid
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Pomalidomide
D.3.9.3	Other descriptive name	Pomalidomide
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	4
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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	No
D.IMP: 7
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.2.1.2	Country which granted the Marketing Authorisation	Spain
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	Imnovid
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Pomalidomide
D.3.9.3	Other descriptive name	Pomalidomide
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	3
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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	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

Patients with refractory or relapsed and refractory multiple myeloma (rrMM) who have failed at least 2 lines of prior treatment and have been previously exposed to an immunomodulatory drug (IMiDs) as lenalidomide or thalidomide and a proteasome inhibitor as bortezomib or carfilzomib.

Pacientes con mieloma múltiple resistente o recidivante y resistente (MMrr) que hayan recibido al menos 2 líneas de tratamiento previo, sean resistentes a la última línea de tratamiento y hayan estado expuestos anteriormente a un fármaco inmunomodulador (FIM), como lenalidomida o talidomida, y un inhibidor del proteasoma, como bortezomib o carfilzomib.

E.1.1.1

Medical condition in easily understood language

Patients with multiple myeloma that has progressed after receaving at least 2 lines of prior treatment. These treatments must have included lenalidomide or thalidomide and a proteasome inhibitor.

Pacientes con mieloma múltiple cuya enfermedad haya progresado y hayan recibido 2 líneas de tratamiento previo. Estos tratamientos deben incluir lenalidomida o talidomida y un inhibidor del proteasoma

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Compare the Progression Free Survival (PFS) as assessed by CAC blinded central review according to the International Myeloma Working Group response criteria, (IMWG criteria) between treatment arms.

Comparar la supervivencia sin progresión (SSP), evaluada mediante la revisión central enmascarada del CVC (Comité de Vigilancia de los datos), según los criterios de respuesta del International Myeloma Working Group (criterios del IMWG [1]) entre los grupos de tratamiento.

E.2.2

Secondary objectives of the trial

(1) Objective: Compare the Overall Survival (OS).
(2) Objective: Evaluate Overall Response Rate (ORR) and Disease Control Rate (DCR) as assessed by CAC blinded central review using IMWG criteria [1] or EBMT criteria for minor response only and Duration of Response (DOR) as assessed by CAC blinded central review using IMWG criteria
(3) Objective: To evaluate the safety and tolerability in both treatment arms.

(1)Objetivo: Comparar la supervivencia global (SG).
(2)Objetivo: Determinar la tasa de respuestas globales (TRG) y la tasa de control de la enfermedad (TCE) según la revisión central enmascarada del CVC aplicando los criterios del IMWG o solo los criterios del EBMT para la respuesta menor y la duración de la respuesta (DR) según la revisión central enmascarada del CVC aplicando los criterios del IMWG
(3)Objetivo: Evaluar la seguridad y tolerabilidad en ambos grupos de tratamiento.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Merck will conduct Future Biomedical Research on DNA (blood) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time.

Merck llevará a cabo investigaciones biomédicas futuras con las
muestras obtenidas específicamente con estos fines durante este ensayo
clínico. Estas investigaciones tendrán por objeto el análisis de
biomarcadores para abordar aspectos nuevos que no se describen en
otras partes del protocolo (como parte del ensayo principal) y solo se
llevarán a cabo en muestras de los sujetos que hayan otorgado el
consentimiento correspondiente. El objetivo de la obtención de muestras
para investigaciones biomédicas futuras consiste en estudiar e
identificar biomarcadores que proporcionen información a los científicos
sobre las enfermedades y sus tratamientos. El objetivo último es utilizar
tal información para desarrollar fármacos más seguros y eficaces y/o
para garantizar que los pacientes reciban la dosis correcta del fármaco
adecuado en el momento preciso.

E.3

Principal inclusion criteria

1.Must have undergone prior treatment with > or = to 2 treatment lines of anti-myeloma therapy and must have failed their last line of treatment defined as documented disease progression during or within 60 days of completing their last anti-myeloma therapy (refractory to last line of treatment).
2.Prior anti-myeloma treatments must have included an IMiD (lenalidomide or thalidomide) AND proteasome inhibitor (bortezomib or carfilzomib) alone or in combination and subject must have failed therapy with an IMiD OR proteasome inhibitor defined as one of the following:
a.Refractory: Documented progressive disease on or within 60 days of completing treatment with an IMiD and/or proteasome inhibitor OR
b. Relapsed and refractory: In case of prior response [> or = to partial response (PR)] to an IMiD or proteasome inhibitor, subjects must have relapsed within 6 months after stopping treatment with and IMiD and/or proteasome inhibitor containing regimens
3.Confirmed diagnosis of active MM and measurable disease defined as:
?Serum monoclonal protein (M-protein) levels > or = to 0.5 g/dL or
?Urine monoclonal protein (M-protein) levels > or = to 200 mg/24-hours or
?Subjects without measurable serum and urine M-protein levels, an abnormal serum free light chain ratio (FLC ?/?) with involved FLC level > or = to 100 mg/L. (Normal serum FLC ?/? value: 0.26 - 1.65)
?Presence of CRAB features
4.Provide, archival (< or = to 60 days) or newly obtained bone marrow biopsy or aspirate material for disease assessment and biomarker analysis.
5.Performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.

1.Deben haber recibido anteriormente > o = a 2 líneas de tratamiento antimieloma y no deben haber respondido a su última línea, definiendo la falta de respuesta como progresión documentada de la enfermedad durante su último tratamiento frente al mieloma o en los 60 días siguientes (resistente a la última línea de tratamiento).
2.Los tratamientos previos contra el mieloma deben haber consistido en un FIM (lenalidomida o talidomida) Y un inhibidor del proteasoma (bortezomib o carfilzomib) solos o en combinación , y el paciente no debe haber respondido al tratamiento con un FIM O un inhibidor del proteasoma, definiendo la falta de respuesta como una de las circunstancias siguientes:
a.Resistente: Progresión documentada de la enfermedad al finalizar el tratamiento con un FIM y/o un inhibidor del proteasoma o en los 60 días posteriores, O
b.Recidivante y resistente: En caso de respuesta previa [> o = a respuesta parcial (RP)] a un FIM o inhibidor del proteasoma, los pacientes deben presentar una recidiva en los 6 meses siguientes a la suspensión del tratamiento con pautas que contengan FIM y/o inhibidores del proteasoma
3.Deberán tener un diagnóstico confirmado de mieloma múltiple activo y enfermedad mensurable, definida de la manera siguiente:
a.Concentraciones séricas de proteína monoclonal (proteína M) > o = a 0,5 g/dl o
b.Concentraciones urinarias de proteína monoclonal (proteína M) > o = a 200 mg/ 24 horas o
c.en los pacientes sin concentraciones mensurables de proteína M en el suero y la orina, un índice anormal de cadenas ligeras libres en suero (CLL ?/?) con una concentración de CLL afectadas > o = a 100 mg/l. (Valor normal de CLL ?/? en suero: 0,26 - 1,65).
d.Presencia de características CRAB del mieloma
4.Deberán ser capaces de proporcionar muestras de archivo (< o = a 60 días) o recién obtenidas de biopsia o aspirado de médula ósea para evaluación de la enfermedad y análisis de biomarcadores en la selección.
5.Tienen que presentar un estado funcional del Eastern Cooperative Oncology Group (ECOG) de 0 o 1.

E.4

Principal exclusion criteria

1.Subjects with non-secretory or oligo-secretory myeloma, smoldering multiple myeloma (SMM), monoclonal gammopathy of undetermined significance (MGUS), plasma cell leukemia or Waldenström's macroglobulinemia.
2.History of repeated infections, primary amyloidosis, hyperviscosity or POEMS syndrome.
3.Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not recovered (i.e. < or = to Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
4.Has had prior anti-myeloma therapy including but not limited to dexamethasone, IMiDs, proteasome inhibitors, chemotherapy, or radiation therapy within 2 weeks prior to Study Day 1 who has not recovered (i.e. ? Grade 1 or at baseline) from adverse events due to a previously administered agent.
5.Has undergone prior allogeneic hematopoetic stem cell transplantation within the last 5 years. (Subjects who have had a transplant greater than 5 years ago are eligible as long as there are no symptoms of Graft versus Host Disease (GVHD).
6.Has received autologous stem cell transplant (auto-SCT) within 12 weeks before the first infusion or are planning for or are eligible for auto-SCT.
7.Has known hypersensitivity to thalidomide, lenalidomide or dexamethasone.
8.Has received previous therapy with pomalidomide.
9.Subjects unable or unwilling to undergo antithrombotic prophylactic treatment.
10.Subjects with peripheral neuropathy > or = to Grade 2.
11.Has evidence of active, non-infectious pneumonitis.
12.Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody.

1.Pacientes con mieloma no secretor u oligosecretor, mieloma múltiple asintomático (MMA), gammapatía monoclonal de importancia indeterminada (GMII), leucemia de de células plasmáticas o macroglobulinemia de Waldenström
2.Antecedentes de infecciones repetidas, amiloidosis primaria, hiperviscosidad o síndrome POEMS
3.Recepción de un anticuerpo monoclonal en las 4 semanas previas al día 1 del estudio o ausencia de recuperación (es decir, a un grado < o = a 1 o al nivel basal) de los acontecimientos adversos provocados por los fármacos administrados más de 4 semanas antes.
4.Tratamiento antimieloma previo, por ejemplo, dexametasona, FIM, inhibidores del proteasoma, quimioterapia o radioterapia en las 2 semanas previas al día 1 del estudio y ausencia de recuperación (es decir, a un grado < o = a 1 o al nivel basal) de los acontecimientos adversos provocados por un medicamento administrado anteriormente
5.Alotrasplante de células progenitoras hematopoyéticas en los 5 años precedentes. (Si el trasplante se realizó más de 5 años antes, el paciente podrá participar siempre que no presente síntomas de enfermedad de injerto contra huésped [EICH]).
6.Autotrasplante de células progenitoras (auto-TCP) en las 12 semanas previas a la primera infusión o previsión o idoneidad para un auto-TCP.
7.Hipersensibilidad conocida a talidomida, lenalidomida o dexametasona.
8.Tratamiento previo con pomalidomida.
9.Incapacidad para someterse a una profilaxis tromboembólica
10.Neuropatía periférica > o = a grado 2.
11.Indicios de neumonitis no infecciosa activa.
12.Tratamiento previo con un anticuerpo anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137 o anti-CTLA-4

E.5 End points

E.5.1

Primary end point(s)

The primary end point of the study is Progression-free survival (PFS) ? the International Myeloma Working Group response criteria (IMWG 2006) by blinded central review.
PFS is defined as the time from randomization to the first documented disease progression per IMWG 2006 based on blinded central review or death due to any cause, whichever occurs first.

El criterio de valoración principal de este estudio es la Supervivencia sin progresión (SSP) - los criterios de respuesta del International Myeloma Working Group (IMWG de 2006) según la revisión central enmascarada del CVC
La SSP se define como el tiempo transcurrido entre la aleatorización y la primera progresión documentada de la enfermedad conforme a los criterios del IMWG de 2006 según la revisión central enmascarada del CVC o la muerte por cualquier causa, lo que ocurra antes.

E.5.1.1

Timepoint(s) of evaluation of this end point

1.PFS Analysis/First OS Analysis: ~ 20 months after trial starts (when all subjects are enrolled, 230 PFS events and ~123 OS events are observed).

1. SSP Análisis/ Primer SG análisis: Aprox. 20 meses después del comienzo del ensayo (Cuando todos los sujetos hayan sido reclutados, 230 eventos de SSP y aprox. 123 eventos de SG se hayan observado)

E.5.2

Secondary end point(s)

1.Compare the Overall Survival (OS).
2.Evaluate Overall Response Rate (ORR) and Disease Control Rate (DCR) as assessed by CAC blinded central review and as per investigator assessment using IMWG criteria or EBMT criteria for minor response only and Duration of Response (DOR) as assessed by CAC blinded central review and as per investigator assessment using IMWG criteria
3.To evaluate the safety and tolerability in both treatment arms.

1.Comparar la supervivencia global (SG).
2. Determinar la tasa de respuestas globales (TRG) y la tasa de control de la enfermedad (TCE) según la revisión central enmascarada del CVC aplicando los criterios del IMWG o solo los criterios del EBMT para la respuesta menor y la duración de la respuesta (DR) según la revisión central enmascarada del CVC aplicando los criterios del IMWG
3. Evaluar la seguridad y tolerabilidad en ambos grupos de tratamiento.

E.5.2.1

Timepoint(s) of evaluation of this end point

1.An interim safety analysis will take place after 15 subjects in each treatment arm have completed 1 cycle of therapy.
2.Final OS Analysis: ~ 10 mos after main PFS analysis or ~ 185 OS events, whichever comes first.

1. Será realizado un análisis intermedio de seguridad después de que 15 pacientes hayan completado un ciclo de tratamiento en cada rama.
2. Análisis final de SG: aprox. 10 meses después del primer análisis de SSP o aprox. cuando hayan ocurrido 185 eventos de SG, lo que ocurra primero.

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

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

Yes

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)

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

France

Germany

Israel

Italy

Japan

Spain

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

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:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

225

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

300

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)

Standard of Care.

Practica clínica habitual

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

2015-11-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-11-10

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2020-07-16

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