Clinical Trials Register

Summary
EudraCT Number:	2014-001620-29
Sponsor's Protocol Code Number:	R2-GDP-GOTEL
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2014-07-22
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

Spain - AEMPS

A.2

EudraCT number

2014-001620-29

A.3

Full title of the trial

Phase II clinical trial to evaluate the combination of lenalidomide with R-GDP (rituximab, gemcitabine, dexamethasone and cisplatin) in patients diagnosed with refractory diffuse large B-cell lymphoma not candidates for high-dose chemotherapy and hematopoietic progenitor cell transplantation

Ensayo fase II para valorar la combinación de Lenalidomida con R-GDP (R2-GDP) en pacientes con linfoma difuso de células grandes B refractarios o en recaída (R/R LDCGB) no candidatos a quimioterapia a altas dosis y transplante de células progenitoras hematopoyéticas

A.3.1

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

Clinical trial to evaluate the treatment with a drug (lenalidomide) with the usually prescribed chemotherapy in patients diagnosed with diffuse large B-cell lymphoma (sort of blood cancer) which did not respond to previous treatments and who can not receive high-dose chemotherapy.

Ensayo clínico para evaluar el tratamiento con un medicamento (lenalidomida) añadido a la quimioterapia utilizada habitualmente en pacientes con linfoma difuso de células grandes B (cáncer de la sangre) que no han respondido bien a tratamientos previos y que no pueden recibir quimioterapia a altas dosis

A.4.1

Sponsor's protocol code number

R2-GDP-GOTEL

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	Grupo Español para el Tratamiento y Estudio de los Linfomas (GOTEL)
B.1.3.4	Country	Spain
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Grupo Español para el Tratamiento y Estudio de los Linfomas (GOTEL)
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Clinical Research Unit & Clinical Trials
B.5.2	Functional name of contact point	Clara M. Rosso Fernández
B.5.3	Address:
B.5.3.1	Street Address	Avda. Manuel Siurot S/N
B.5.3.2	Town/ city	Sevilla
B.5.3.3	Post code	41013
B.5.3.4	Country	Spain
B.5.4	Telephone number	0034955 01 34 14
B.5.5	Fax number	0034954 23 29 92
B.5.6	E-mail	claram.rosso.sspa@juntadeandalucia.es

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	Yes
D.2.1.1.1	Trade name	Revlimid 5 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Celgene Europe Limited
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	Lenalidomide
D.3.2	Product code	NA
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	LENALIDOMIDE
D.3.9.1	CAS number	191732-72-6
D.3.9.4	EV Substance Code	SUB25389
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	5 to 15
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: 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	Yes
D.2.1.1.1	Trade name	MabThera
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche
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	Rituximab
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	RITUXIMAB
D.3.9.1	CAS number	174722-31-7
D.3.9.4	EV Substance Code	SUB12570MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	375
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	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	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	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	Gemcitabine
D.3.4	Pharmaceutical form	Powder for 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	GEMCITABINE
D.3.9.3	Other descriptive name	GEMCITABINE HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB02324MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1000
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	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	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	Cisplatin
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	CISPLATIN
D.3.9.3	Other descriptive name	CISPLATIN
D.3.9.4	EV Substance Code	SUB07483MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	80
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	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	Yes
D.2.1.1.1	Trade name	Revlimid 10 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Celgene Europe Limited
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	Lenalidomide
D.3.2	Product code	NA
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	LENALIDOMIDE
D.3.9.1	CAS number	191732-72-6
D.3.9.4	EV Substance Code	SUB25389
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	10
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	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	Yes
D.2.1.1.1	Trade name	Revlimid 15 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Celgene Europe Limited
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	Lenalidomide
D.3.2	Product code	NA
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	LENALIDOMIDE
D.3.9.1	CAS number	191732-72-6
D.3.9.4	EV Substance Code	SUB25389
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	15
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

Refractory Diffuse large B-cell lymphoma.

Linfoma difuso de células grandes B refractarios.

E.1.1.1

Medical condition in easily understood language

Sort of cancer (Large B cells lymphoma) from specific haematological cells (from the blood).

Tipo de cáncer (Linfoma de cálulas B grandes) que afecta a determinadas células hematológicas (de la sangre)

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	17.0
E.1.2	Level	PT
E.1.2	Classification code	10012822
E.1.2	Term	Diffuse large B-cell lymphoma refractory
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 determine the response rate with the combination of lenalidomide and chemotherapy type R-GDP (Rituximab, Gemcitabine, Dexamethasone and Cisplatin) in patients with relapsed or refractory diffuse large B-cell lymphoma not candidates for high-dose chemotherapy nor transplantation of cells hematopoietic progenitors.

Determinar la tasa de respuesta obtenida con la combinación de lenalidomida y quimioterapia tipo R-GDP (Rituximab, Gemcitabina, Cisplatino y Dexametasona) en pacientes con linfoma difuso de células grandes B refractarios o en recaída no candidatos a quimioterapia a altas dosis y transplante de células progenitoras hematopoyéticas.

E.2.2

Secondary objectives of the trial

-Overall survival
-Progression free survival
-Safety
-Biomarker analysis in tumor tissue, associated with the immune response.
-Genomic analysis of oncogenic mutations
-Serum immunophenotypic study using flow cytometry
-Correlate data taken from translational research to clinical data, paying special attention to the subgroup of long-responders

-Supervivencia Global
-Supervivencia Libre de Progresión
-Seguridad
-Análisis de biomarcadores, en tejido tumoral, relacionados con la repuesta inmune.
-Estudio Genómico de mutaciones oncogénicas
-Estudio de inmunofenotipo sérico mediante citometría de flujo.
-Correlacionar los datos extraídos del estudio traslacional con los datos clínicos, poniendo especial atención al subgrupo de largos respondedores

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Patients over 18 years old.
2. Patients with diffuse large cell lymphoma (DLBCL) diagnosed by biopsy, including immunohistochemical positivity for CD20 study.
3. Patients with relapsed or refractory DLBCL (DLBCL r / r) after receiving at least a first line of treatment that included chemotherapy and anti-CD20 monoclonal antibodies. Biopsy recommended but not mandatory.
4. Patients who are not candidates for autologous hematopoietic cell transplantation according to the investigator´s criteria.
5. ECOG Performance Status ? 2.
6. Life expectancy over 3 months.
7. All patientsmust accept common contraception methods in clinical trials with lenalidomide.
8. Women of childbearing potential must have a negative pregnancy test result at screening.
9. Signed informed consent.

1. Pacientes con edad igual o mayor a 18 años
2. Linfoma B difuso de células grandes (LBDCG) diagnosticado mediante biopsia, incluyendo estudio inmunohistoquímico y con demostración de positividad a CD20.
3. Pacientes con LBDCG refractarios o en recaída (LBDCG r/r) tras haber recibido al menos una primera línea de tratamiento que incluyese quimioterapia y anticuerpos monoclonales anti-CD20. Biopsia de recaída recomendable pero no obligatoria.
4. Pacientes no candidatos a transplante autólogo de células hematopoyéticas, a criterio del médico responsable.
5. ECOG Performance Status ? 2.
6. Expectativa de esperanza de vida superior a 3 meses.
7. Todos los pacientes incluidos aceptarán las medidas de anticoncepción habituales en los ensayos realizados con lenalidomida.
8. Las mujeres potencialmente fértiles deberán acreditar un test negativo para embarazo en el momento del screening.
9. Haber firmado el Consentimiento Informado para inclusión en el estudio.

E.4

Principal exclusion criteria

1. Patients who may be susceptible of autologous bone marrow transplant during the evolution of the disease according to investigator´s criteria.
2. Patients with inadequate renal, hepatic or haematological function, and / or showing any of the following laboratory parameters (It is not allowed the use of colony stimulating factors and other similar measures for the inclusion of patients):
- ANC < 1000 células/mm3
- Platelets < 75.000/ mm3
- GOT o GPT > 5 normal level
- Total bilirubin > 2 mg/dl o conjugated bilirubin > 0.8mg/dl, except if hemolytic anemia.
- Creatinine clearance < 30 ml/minute
3. ECOG Performance Status 3 ó 4.
4. Any other serious medical condition, laboratory abnormality, or psychiatric illness that hinders obtaining informed consent from the patient.
5. Systemic infection not solved> 2 months before starting experimental treatment despite adequate anti-infective treatment.
6. Pregnant or lactating women.
7. Rejection of contraceptive methods according to the protocol.
8. Patients who had received any experimental therapy within 28 days prior to inclusion in the clinical trial.
9. Involvement of central nervous system confirmed by cerebrospinal fluid cytology or imaging test.
10. Previous history of malignant disease unless the patient has been free of disease ? 3 years. The following neoplasia are excluded:
- Basal cell carcinoma of skin
- Squamous cell carcinoma of skin
- Carcinoma in situ of the cervix
- Carcinoma in situ of breast
- Incidentally diagnosed prostate carcinoma (T1a or T1b)
11. Seropositivity for HIV, Hepatitis B or Hepatitis C
12. Uncontrolled intercurrent illness, such as:
- Active infection requiring parenteral antibiotics
- Uncontrolled diabetes mellitus
- Chronic heart failure (class III or IV NYHA)
- Unstable angina or angioplasty, stent or heart attack in the last 6 months
- Thromboembolic disease grade 3-4 in the past 6 months
- Prior neuropathy grade ? 2
13. Patients who have received any of the following treatments in the specified period prior day 1:
- Any chemotherapy in the previous 2 weeks
- Nitrosoureas in the previous 6 weeks
- Monoclonal antibodies in previous 8 weeks
- External radiotherapy in the previous 3 weeks
- Radioimmunoconjugates in the previous 12 weeks

1. Pacientes que a criterio de los investigadores puedan ser susceptibles de transplante autólogo de médula ósea en algún momento de la evolución de la enfermedad.
2. Pacientes con función renal, hepática o hematológica inadecuada, y/o mostrando alguna de los siguientes parámetros de laboratorio (no está permitido el uso de factores estimulantes de colonias ni otras medidas de soporte para la inclusión de los pacientes):
- ANC < 1000 células/mm3
- Plaquetas < 75.000/ mm3
- GOT o GPT > 5 veces el nivel normal
- Bilirrubina total > 2 mg/dl o bilirrubina conjugada > 0.8mg/dl, excepto si existe anemia hemolítica.
- Aclaramiento de creatinina < 30 ml/minuto
3. ECOG Performance Status 3 ó 4.
4. Alguna otra condición médica grave, anomalía de laboratorio o enfermedad psiquiátrica que dificulte la obtención del consentimiento informado por parte del paciente.
5. Infección sistémica que no se haya resuelto > 2 meses antes de iniciar el tratamiento de ensayo a pesar de tratamiento anti-infeccioso adecuado.
6. Mujeres embarazadas o en periodo de lactancia.
7. Rechazo a utilización de métodos anticonceptivos recomendados según protocolo.
8. Haber recibido algún tratamiento experimental en los 28 días previos a iniciar el tratamiento de ensayo.
9. Afectación de sistema nervioso central confirmada por citología de líquido cefalorraquídeo o pruebas de imagen.
10. Historial previo de enfermedad maligna, salvo que el paciente haya estado libre de enfermedad ? 3 años. Se exceptúan las siguientes neoplasias:
- Carcinoma basocelular de piel.
- Carcinoma escamoso de piel.
- Carcinoma in situ del cervix.
- Carcinoma in situ de la mama.
- Carcinoma de próstata diagnosticado incidentalmente (T1a o T1b).
11. Seropositividad para HIV, hepatitis B o hepatitis C.
12. Enfermedad intercurrente no controlada, como por ejemplo:
- Infección activa que requiera antibióticos parenterales.
- Diabetes mellitus no controlada.
- Insuficiencia cardiaca crónica sintomática (clase III o IV de la NYHA).
- Angina de pecho inestable o realización de angioplastia, stent o infarto de miocardio en los últimos 6 meses.
- Enfermedad tromboembólica grado 3-4 en los últimos 6 meses.
- Neuropatía previa grado ? 2.
13. Haber recibido alguno de los siguientes tratamientos en el periodo especificado previo al día 1 del estudio:
- Cualquier quimioterapia en las 2 semanas previas.
- Nitrosoureas en las 6 semanas previas.
- Anticuerpos monoclonales en las 8 semanas previas.
- Radioterapia externa en las 3 semanas previas.
- Radioinmunoconjugados en las 12 semanas previas.

E.5 End points

E.5.1

Primary end point(s)

Overall Response Rate obtained after the period or phase induction obtained with the combination of lenalidomide and immunochemotherapy (R2-GDP) in patients with DLBCL R / R.

The Overall Response Rate is defined as the addition of the rate of complete response plus partial response rate obtained, according to Cheson criteria 2007.

Tasa de Respuesta Global obtenida tras el periodo o fase de inducción obtenida con la combinación de lenalidomida e inmunoquimioterapia (R2-GDP) en pacientes con LDCGB R/R.

La Tasa de Respuesta Global se define como la suma de la tasa de respuestas completas más la tasa de respuestas parciales que se obtengan, según Criterios de Cheson 2007

E.5.1.1

Timepoint(s) of evaluation of this end point

At the end of the induction phase. 180 days.

Al final del periodo de inducción. 180 días.

E.5.2

Secondary end point(s)

- Overall survival: from recruitment or the start of treatment to the date of patient´s death or last date known as the patient was alive.
- Progression-free survival: from recruitment or the start of treatment to recurrence of disease.
- Safety: collection and assessment of all adverse events occurring since the signing of informed consent until the last patient visit (SPM last visit at 36 months since the last dose of Lenalidomide).
- Biomarker analysis in tumor tissue, associated with the immune response.
- Genomic Study of oncogenic mutations.
- Serum flow cytometric immunophenotypic studies.
- Relationship between data taken from translational research and clinical data, paying special attention to the subgroup of long-responders (sustained response over 2 years after receiving the treatment).

- Supervivencia Global: desde la entrada en el estudio o el inicio del tratamiento hasta la fecha de la muerte del paciente o la última fecha en que se tuvo conocimiento de que el paciente estaba vivo.
- Supervivencia Libre de Progresión: desde la entrada en el estudio o el inicio del tratamiento hasta la progresión recidiva de la enfermedad.
- Seguridad: recogida y valoración de todos los acontecimientos adversos que ocurran desde la firma del consentimiento informado hasta la última visita del paciente (última visita SPM a los 36 meses de la última toma de Lenalidomida)
- Análisis de biomarcadores, en tejido tumoral, relacionados con la repuesta inmune.
- Estudio Genómico de mutaciones oncogénicas.
- Estudio de inmunofenotipo sérico mediante citometría de flujo.
- Correlacionar los datos extraídos del estudio traslacional con los datos clínicos, poniendo especial atención al subgrupo de largos respondedores (respuesta mantenida más de 2 años después de recibir el tratamiento).

E.5.2.1

Timepoint(s) of evaluation of this end point

Until disease progression, unacceptable toxicity or complete response confirmed by PET after 2 years of treatment.

Hasta progresión de la enfermedad, toxicidad inaceptable o respuesta completa confirmada mediante PET tras 2 años de tratamiento.

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

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

Biomarkers analysis in tumoral tissue

Análisis de biomarcadores en tejido tumoral

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)

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

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

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

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

At 36 months of the last dose of Lenalidomide

A los 36 meses de la última dosis de Lenalidomida

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

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)

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.4.2.2

In the whole clinical trial

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)

Patients will be treated according to the common clinical practice

Los pacientes serán tratados según la practica clinica habitual

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2014-10-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-10-16

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

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