Clinical Trials Register

Summary
EudraCT Number:	2017-002139-41
Sponsor's Protocol Code Number:	R1979-ONC-1625
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Temporarily Halted
Date on which this record was first entered in the EudraCT database:	2019-07-26
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

2017-002139-41

A.3

Full title of the trial

An Open-Label Study to Assess the Anti-Tumor Activity and Safety of REGN1979, an anti CD20 x anti-CD3 Bispecific Antibody, in Patients with Relapsed or Refractory Follicular Lymphoma

Estudio abierto para evaluar la actividad antitumoral y la seguridad de REGN1979, un anticuerpo biespecífico anti-CD20 y anti-CD3 en pacientes con linfoma folicular recidivante o resistente al tratamiento

A.3.1

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

A Study to Assess the Anti-Tumor Activity and Safety of REGN1979 in patients with Follicular Lymphoma that has been previously treated

Estudio para evaluar la actividad antitumoral y la seguridad de REGN1979 en pacientes con linfoma folicular que se ha tratado previamente

A.4.1

Sponsor's protocol code number

R1979-ONC-1625

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	Regeneron Pharmaceuticals, 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	Regeneron Pharmaceuticals, 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	Regeneron Pharmaceuticals, Inc.
B.5.2	Functional name of contact point	Clinical Trial Information
B.5.3	Address:
B.5.3.1	Street Address	777 Old Saw Mill River Road
B.5.3.2	Town/ city	Tarrytown, NY
B.5.3.3	Post code	10591
B.5.3.4	Country	United States
B.5.6	E-mail	clinicaltrials@regeneron.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.3.2	Product code	REGN1979
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	REGN1979
D.3.9.2	Current sponsor code	REGN1979
D.3.9.3	Other descriptive name	REGN1979
D.3.9.4	EV Substance Code	SUB179367
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	2
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	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Follicular lymphoma

Linfoma folicular

E.1.1.1

Medical condition in easily understood language

Cancer (Follicular lymphoma)

Cáncer (Linfoma folicular)

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	22.0
E.1.2	Level	PT
E.1.2	Classification code	10029547
E.1.2	Term	Non-Hodgkin's lymphoma
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

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of this study is to assess the anti-tumor activity of single agent REGN1979, as measured by objective response rate (ORR) according to the Lugano Classification of response in malignant lymphoma by independent central review, in patients with relapsed or refractory follicular lymphoma (FL) previously treated with at least 2 prior lines of systemic therapy, including an anti-CD20 antibody and an alkylating agent.

El objetivo principal de este estudio es evaluar la actividad antitumoral del agente único REGN1979, medida por la tasa de respuesta objetiva (TRO) de acuerdo con la Clasificación de Lugano de la respuesta en el linfoma maligno por una revisión central independiente, en pacientes con linfoma folicular (LF) recidivante o resistente al tratamiento tratados previamente con al menos 2 líneas anteriores de tratamiento sistémico, incluidos un anticuerpo anti-CD20 y un agente alquilante.

E.2.2

Secondary objectives of the trial

The secondary objectives include:
•To assess the anti-tumor activity of single agent REGN1979 in patients with relapsed or refractory FL, as measured by:
o ORR according to the Lugano Classification (Cheson, 2014) as assessed by local investigator evaluation
o CR rate according to the Lugano Classification as assessed by:
Independent central review, and Local investigator evaluation
o PFS according to Lugano Classification as assessed by:
Independent central review, and Local investigator evaluation
o OS

Refer to protocol for the full list of Secondary objectives of the trial

Los objetivos secundarios del estudio son:
•Evaluar la actividad antitumoral del agente único REGN1979 en pacientes con LF recidivante o resistente al tratamiento, medida por:
o TRO de acuerdo con la Clasificación de Lugano (Cheson, 2014) según la evaluación del investigador local
o Tasa de respuesta completa (RC) de acuerdo con la Clasificación de Lugano, evaluada mediante:
Revisión central independiente y Evaluación del investigador local
o Supervivencia sin progresión (SSP) de acuerdo con la Clasificación de Lugano evaluada mediante:
Revisión central independiente y Evaluación del investigador local
o Supervivencia general (SG)
Refiéranse a la lista completa de objetivos secundarios del estudio incluida en el protocolo

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

There is an optional Genomics sub-study. The purpose of the genomic analyses is to identify genomic associations with clinical or biomarker response, other clinical outcome measures, and possible AEs. In addition, associations between genomic variants and prognosis or progression of FL as well as other related diseases may also be studied.

Hay un sub-estudio opcional de genómica. El propósito de los análisis genómicos es identificar asociaciones genómicas con respuesta clínica o de biomarcadores, otras medidas de resultados clínicos y posibles EA. Además, también se pueden estudiar las asociaciones entre las variantes genómicas y el pronóstico o la progresión de FL, así como otras enfermedades relacionadas.

E.3

Principal inclusion criteria

Principal inclusion in the study are:
1. Age 18 years or greater
2. Central histopathologic confirmation of the FL Grade 1 to 3a diagnosis must be obtained before study enrollment. Patients with FL grade 3b are ineligible. Follicular lymphoma subtyping is based on the World Health Organization (WHO) classification (Swerdlow, 2017).
3. Must have received at least 2 prior lines of therapy, including an anti-CD20 antibody and an alkylating agent.
4. Measurable disease on cross sectional imaging (defined as at least 1 bi dimensionally measurable nodal lesion of ≥1.5 cm in the greatest transverse diameter (GTD) regardless of the short axis diameter) documented by diagnostic imaging (computed tomography [CT], or magnetic resonance imaging [MRI]).
5. Eastern Cooperative Oncology Group (ECOG) performance status 0 or1.
6. Adequate bone marrow function as documented by:
a. Platelet count ≥50 x 109/L. A patient may not have received platelet transfusion within 7 days prior to first dose of REGN1979 in order to meet the platelet eligibility criterion.
b. Hemoglobin ≥9.0 g/dL
c. Absolute neutrophil count (ANC) ≥1.0 x 109/L. A patient may not have received granulocyte colony stimulating factor within 2 days prior to first dose of REGN1979 in order to meet the ANC eligibility criterion.
7. Adequate hepatic function

Refer to protocol for the full list of inclusion criteria of the trial

Los principales criterios de inclusion son:
1. 18 o más años de edad.
2. Confirmación por el laboratorio central de histopatología deldiagnóstico de LF de grado 1 a 3a antes de la inclusión en el estudio. Los pacientes con LF de grado 3b no son aptos. La caracterización del linfoma folicular en subtipos se basa en la clasificación de la Organización Mundial de la Salud (OMS) (Swerdlow, 2017).
3. Haber recibido al menos 2 líneas previas de tratamiento, incluidos un anticuerpo anti-CD20 y un agente alquilante.
4. Enfermedad medible en imagen axial (definida como la presencia de al menos 1 lesión ganglionar medible en dos dimensiones con un diámetro transverso máximo [DTM] ≥1,5 cm, independientemente del diámetro del eje corto) documentada por técnicas de diagnóstico por la imagen (tomografía axial computarizada [TAC] o resonancia magnética [RM]).
5. Estado funcional según el Grupo Oncológico Cooperativo de la Costa Este (Eastern Cooperative Oncology Group, ECOG) de 0 o 1.
6. Función de médula ósea adecuada documentada por los siguientes
parámetros:
a. Recuento de plaquetas ≥50 × 109/l. Para cumplir el criterio de aptitud relativo a las plaquetas, los pacientes no pueden haber recibido una transfusión plaquetaria en los 7 días anteriores a la primera dosis de REGN1979.
b. Hemoglobina ≥9,0 g/dl.
c. Recuento absoluto de neutrófilos (RAN) ≥1,0 × 109/l. Para cumplir el criterio de aptitud relativo al RAN, los pacientes no pueden haber recibido factor estimulante de colonias de granulocitos en los 2 días anteriores a la primera dosis de REGN1979.
7. Función hepática adecuada:

Refiéranse a la lista completa de criterios de inclusion incluida en el
protocolo

E.4

Principal exclusion criteria

Principal exclusion criteria are:
1. Primary central nervous system (CNS) lymphoma or known involvement by non-primary CNS NHL (suspected CNS lymphoma should be evaluated by lumbar puncture, as appropriate, in addition to the mandatory head CT or MRI).
2. Treatment with any systemic anti lymphoma therapy within 5 half-lives or within 28 days prior to first administration of study drug, whichever is shorter.
3. History of allogeneic stem cell transplantation
4. Prior treatment with any chimeric antigen receptor T-cell (CAR-T) therapy
5. Continuous systemic corticosteroid treatment with more than 10 mg per day of prednisone or anti-inflammatory equivalent within 72 hours of start of study drug
6. History of neurodegenerative condition or CNS movement disorder
7. Vaccination within 28 days prior to first study drug administration with a vector that has replicative potential

Refer to protocol for the full list of exclusion criteria of the trial

Los principales criterios de exclusión son:
1. Linfoma primario del sistema nervioso central (SNC) o afectación
conocida por LNH no primario del SNC (la sospecha de linfoma del SNC
se debe evaluar mediante punción lumbar, según corresponda, además
de la TAC o RM obligatoria de cabeza).
2. Tratamiento sistémico contra el linfoma en las 5 semividas o los 28
días anteriores a la primera administración del fármaco del estudio, lo
que suponga menos tiempo.
3. Antecedentes de alotrasplante de células madre.
4. Tratamiento previo de linfocitos T con receptores de antígenos
quiméricos (CAR-T).
5. Tratamiento continuo con corticoesteroides sistémicos a una dosis
superior a 10 mg/día de prednisona o antiinflamatorio equivalente en las
72 horas antes del inicio del fármaco del estudio.
6. Antecedentes de trastorno neurodegenerativo o trastorno motor del
SNC.
7. Vacunación en los 28 días anteriores a la primera administración del
fármaco del estudio con un vector que tenga potencial de replicación.

Refiéranse a la lista completa de criterios de exclusión incluida en el
protocolo

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint of the study is ORR from first dose until 194 weeks following the first dose, as measured by the Lugano Classification of response in malignant lymphoma (Cheson, 2014) and according to independent central review, in patients with relapsed or refractory FL previously treated with at least 2 prior lines of systemic therapy, including an anti-CD20 antibody and an alkylating agent.

El criterio de valoración principal de este estudio es la TRO desde la primera dosis hasta 194 semanas después de la primera dos, medida de acuerdo con la Clasificación de Lugano de la respuesta en el linfoma maligno (Cheson, 2014) y de acuerdo con una revisión central independiente, en pacientes con LF recidivante o resistente al tratamiento tratados previamente con al menos 2 líneas anteriores de tratamiento sistémico, incluidos un anticuerpo anti-CD20 y un agente alquilante.

E.5.1.1

Timepoint(s) of evaluation of this end point

194 weeks

194 Semanas

E.5.2

Secondary end point(s)

Secondary endpoints include:
• ORR according to the Lugano Classification, as assessed by local investigator evaluation, from first dose until 194 weeks following the first dose
• CR rate from first dose until 194 weeks following the first dose, according to the Lugano Classification, as assessed by:
o Independent central review, and
o Local investigator evaluation
• PFS from first dose until 194 weeks following the first dose, according to the Lugano Classification, as assessed by:
o Independent central review, and
o Local investigator evaluation
• OS from first dose until 194 weeks following the first dose
• DOR from first dose until 194 weeks following the first dose, according to the Lugano Classification, as assessed by:
o Independent central review, and
o Local investigator evaluation
• DCR from first dose until 194 weeks following the first dose, according to the Lugano Classification, as assessed by:
o Independent central review, and
o Local investigator evaluation
• DDC from first dose until 194 weeks following the first dose, according to the Lugano Classification, as assessed by:
o Independent central review, and
o Local investigator evaluation
• Incidence and severity of TEAEs from first dose until 194 weeks following the first dose
• Changes in scores of patient-reported outcomes from first dose until 194 weeks following the first dose, as measured by the validated instruments EORTC QLQ C30 and EQ-5D-3L

Los criterios de valoración secundarios son:
• TRO de acuerdo con la Clasificación de Lugano, evaluada por el investigador local, desde la primera dosis hasta 194 semanas después de la primera dosis.
• Tasa de RC desde la primera dosis hasta 194 semanas después de la primera dosis, de acuerdo con la Clasificación de Lugano, evaluada mediante:
o Revisión central independiente y
o Evaluación del investigador local
• SSP desde la primera dosis hasta 194 semanas después de la primera dosis, de acuerdo con la Clasificación de Lugano, evaluada mediante:
o Revisión central independiente y
o Evaluación del investigador local
• SG desde la primera dosis hasta un máximo de 194 semanas después de la primera dosis.
• DR desde la primera dosis hasta 194 semanas después de la primera dosis, de acuerdo con la Clasificación de Lugano, evaluada mediante:
o Revisión central independiente y
o Evaluación del investigador local
• DCR desde la primera dosis hasta 194 semanas después de la primera dosis, de acuerdo con la Clasificación de Lugano, evaluada mediante:
o Revisión central independiente y
o Evaluación del investigador local
• DCE desde la primera dosis hasta 194 semanas después de la primera dosis, de acuerdo con la Clasificación de Lugano, evaluada mediante:
o Revisión central independiente y
o Evaluación del investigador local
• Incidencia e intensidad de los acontecimientos adversos surgidos durante el tratamiento (AAST) desde la primera dosis hasta 194 semanas después de la primera dosis.
• Cambios en las puntuaciones de los resultados notificados por el paciente desde la primera dosis hasta 194 semanas después de la primera dosis medidos por los instrumentos validados QLQ-C30 de la EORTC y el cuestionario EQ-5D-3L.

E.5.2.1

Timepoint(s) of evaluation of this end point

194 weeks

194 Semanas

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

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

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.8.3

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

Italy

Korea, Democratic People's Republic of

Poland

Singapore

Spain

Taiwan

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

LVLS

Última visita del último paciente

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

112

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)

None

Ninguno

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

2019-07-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-07-09

P. End of Trial
P.	End of Trial Status	Temporarily Halted

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IMP with orphan designation in the indication
Orphan Designation Number:
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