Clinical Trials Register

Summary
EudraCT Number:	2015-001999-22
Sponsor's Protocol Code Number:	GO29834
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:	2016-01-04
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

2015-001999-22

A.3

Full title of the trial

A PHASE Ib/II STUDY EVALUATING THE SAFETY AND EFFICACY OF OBINUTUZUMAB IN COMBINATION WITH POLATUZUMAB VEDOTIN
AND LENALIDOMIDE IN PATIENTS WITH RELAPSED OR REFRACTORY FOLLICULAR OR DIFFUSE LARGE B-CELL LYMPHOMA

ESTUDIO DE FASE Ib/II PARA EVALUAR LA SEGURIDAD Y EFICACIA DE OBINUTUZUMAB EN COMBINACIÓN CON POLATUZUMAB VEDOTIN Y LENALIDOMIDA EN PACIENTES CON LINFOMA FOLICULAR O DIFUSO DE LINFOCITOS B GRANDES RECIDIVANTE O RESISTENTE

A.3.1

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

A Study of Safety and Efficacy of Obinutuzumab in Combination with Polatuzumab Vedotin and Lenalidomide in Patients with Relapsed or Refractory Follicular or Diffuse Large B-Cell Lymphoma

Un estudio para evaluar la seguridad y eficacia de Obinutuzumab en combinación con Polatuzumab Vedotin y lenalidomida en pacientes con con linfoma folicular o difuso de linfocitos B grandes recidivante o resistente

A.4.1

Sponsor's protocol code number

GO29834

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	F. Hoffmann-La Roche Ltd.
B.1.3.4	Country	Switzerland
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	Genentech Inc. c/o F. Hoffmann La Roche Ltd.
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	Genentech Inc. c/o F. Hoffmann La Roche Ltd.
B.5.2	Functional name of contact point	Trial Information Support Line-TISL
B.5.3	Address:
B.5.3.1	Street Address	Grenzacherstrasse 124
B.5.3.2	Town/ city	Basel
B.5.3.3	Post code	4070
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	34913257300
B.5.6	E-mail	global.rochegenentechtrials@roche.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	polatuzumab vedotin
D.3.2	Product code	DCDS4501A
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	POLATUZUMAB VEDOTIN
D.3.9.3	Other descriptive name	DCDS4501A
D.3.9.4	EV Substance Code	SUB177827
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	170
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Gazyvaro
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration Limited, UK
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.3.4	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	obinutuzumab
D.3.9.1	CAS number	949142-50-1
D.3.9.3	Other descriptive name	OBINUTUZUMAB
D.3.9.4	EV Substance Code	SUB32751
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	1000
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	Yes
D.3.11.13.1	Other medicinal product type	Gazyvaro is is a humanized and glycoengineered monoclonal antibody (mAB)
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.2.1.1.1	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	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.3.4	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	5
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.2.1.1.1	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	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.3.4	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: 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 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	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.3.4	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

Relapsed or refractory, follicular lymphoma (FL) or diffuse large B-cell lymphoma (DLBCL)

LINFOMA FOLICULAR O DIFUSO DE LINFOCITOS B GRANDES RECIDIVANTE O RESISTENTE

E.1.1.1

Medical condition in easily understood language

FL is a low grade tumor that develops slowly and DLBCL is an aggressive tumor that develops rapidly

LF es un tumor de bajo grado que se desarrolla lentamente y LDLBG es un tumor agresivo que se desarrolla rápidamente

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	18.1
E.1.2	Level	LLT
E.1.2	Classification code	10012857
E.1.2	Term	Diffuse large cell lymphoma (Diffuse large B-cell lymphoma) (Working Formulation) refractory
E.1.2	System Organ Class	100000004864

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.1
E.1.2	Level	LLT
E.1.2	Classification code	10012855
E.1.2	Term	Diffuse large cell lymphoma (Diffuse large B-cell lymphoma) (Working Formulation)
E.1.2	System Organ Class	100000004864

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.1
E.1.2	Level	LLT
E.1.2	Classification code	10012856
E.1.2	Term	Diffuse large cell lymphoma (Diffuse large B-cell lymphoma) (Working Formulation) recurrent
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

1. To determine the recommended Phase II dose (RP2Ds) for polatuzumab vedotin (Pola) and lenalidomide (Len) when given in combination with a fixed dose of obinutuzumab on the basis of incidence of dose limiting toxicities (DLTs) during the first cycle of study treatment
2. To evaluate the safety and tolerability of obinutuzumab+ Pola + Len based on nature, frequency, severity, timing of adverse events and DLTs, changes in vital signs, electrocardiogram (ECGs), and clinical laboratory results during and following study treatment administration
3. To evaluate the efficacy of induction treatment with obinutuzumab + Pola + Len based on complete response (CR) at end of induction (EOI), on the basis of positron emission tomography computerized tomography (PET CT) scans

1. Determinar las dosis recomendadas en la fase II (DRF2) de polatuzumab vedotin y lenalidomida administrados en combinación con una dosis fija de obinutuzumab sobre la base de la incidencia de toxicidad limitante de la dosis (TLD) durante el primer ciclo de tratamiento del estudio.
2. Evaluar la seguridad y tolerabilidad de G+ Pola + Len sobre naturaleza, frecuencia, intensidad y momento de aparición de los acontecimientos adversos, incluida la TLD, alteraciones en las constantes vitales, los ECG y los resultados de pruebas analíticas durante y después de la administración del tratamiento del estudio
3. Evaluación de la eficacia del tratamiento de inducción con G + Pola + Len basado en la respuesta completa (RC) al fin de la inducción (FI) sobre la base de tomografías de emisión positrónica (TEP) y las tomografías computarizadas (TC)

E.2.2

Secondary objectives of the trial

1. To evaluate the efficacy of induction treatment with obinutuzumab + Pola + Len based on CR at EOI, as determined by the investigator on the basis of PET-CT scans or CT scans alone, objective response (defined as a CR or PR at EOI) determined by the IRC and the Investigator on the basis of PET CT scans or CT scans alone, best response of CR or PR during the study determined by the Investigator on the basis of CT scans alone
2. To characterize the pharmacokinetic profiles of obinutuzumab + Pola + Len when given in combination based on the observed serum concentration of obinutuzumab, serum and plasma concentrations of Pola and its relevant analytes, and plasma concentration of Len at specified time points
3. To evaluate the immune response to obinutuzumab and to Pola based on incidence of human anti-human antibodies (HAHA) to obinutuzumab and anti-therapeutic antibody (ATA) to Pola during the study relative to the prevalence of HAHAs and ATAs at baseline, respectively

1. Evaluar la eficacia de del tto de inducción con G + Pola + Len sobre la base del RC al FI determinada por el IP a partir de las TEP-TC o de las TC exclusivamente, respuesta objetiva (definida como RC o RP) al FI determinada por el CIR y el IP a partir de las TEP-TC o de las TC exclusivamente, Mejor respuesta de RC o RP durante el estudio, determinada por el IP a partir de las TC exclusivamente
2. Caracterizar los perfiles perfiles FC del obi, el pola vedotin y la lenalidomida administrados en combinación basados en la concentración sérica de obi., concentración sérica y plasmática de pola y los analitos relevantes y la concentración plasmática de lenalidomida observada en los puntos temporales especificados.
3.3. Evaluar la respuesta inmunitaria al obi y al pola sobre la base de la Incidencia de anticuerpos antihumanos humanos (HAHA) contra el obi y anticuerpos antiterapéuticos (AAT) contra el pola durante el estudio en relación con la prevalencia de HAHA y AAT al inicio respect

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Age greater than or equal to (>=) 18 years
- Eastern Cooperative Oncology Group Performance Status of 0, 1, or 2
- For patients enrolled in the dose-escalation phase (DEP) and expansion phase (EP): Relapsed or refractory FL after treatment with at least one prior chemoimmunotherapy regimen that included an anti-CD20 monoclonal antibody and for which no other more appropriate treatment option exists as determined by the investigator
- For patients enrolled in the EP: Relapsed or refractory DLBCL after treatment with at least one prior chemoimmunotherapy regimen in patients who are not eligible for autologous stem-cell transplantation or who have experienced disease progression following treatment with high-dose chemotherapy plus autologous stem-cell transplantation
- Fluorodeoxyglucose (FDG)-avid lymphoma
- At least one bi-dimensionally measurable lesion (>1.5 cm in its largest dimension by CT scan or magnetic resonance imaging [MRI])
- Agreement to abstain from donating blood during the treatment period for 28 days after the last study dose
- For women of childbearing potential: Agreement to remain abstinent or use two adequate methods of contraception, including at least one method with a failure rate of < 1% per year, for at least 28 days prior to Day 1 of Cycle 1, during the treatment period and for at least 18 months after the last dose of study treatment
- For men: Agreement to remain abstinent or use contraceptive measures and agreement to refrain from donating sperm

- Edad >= 18 años
- Estado funcional 0, 1 o 2 del Grupo Oncológico Cooperativo de la Costa Este
- Para los pacientes incluidos en la fase de aumento escalonado de la dosis: LF recidivante o resistente tras un tratamiento con al menos un régimen de quimioinmunoterapia que incluya un anticuerpo monoclonal anti-CD20 y para el que no haya ninguna opción terapéutica más adecuada a criterio del investigador
- Para los pacientes incluidos en la fase de ampliación: LDLBG recidivante o resistente tras un tratamiento con al menos un régimen de quimioinmunoterapia en pacientes que no son aptos para trasplante autólogo de células madre o que han experimentado progresión de la enfermedad tras el tratamiento con quimioterapia en dosis altas más trasplante autólogo de células madre
- Linfoma con avidez por fluorodesoxiglucosa
- Al menos una lesión mensurable en dos dimensiones (> 1,5 cm en su mayor diámetro según TC o resonancia magnética)
- Compromiso de abstenerse de donar sangre durante el período de tratamiento y los 28 días posteriores a la última dosis de tratamiento del estudio
- En las mujeres fértiles: compromiso de practicar la abstinencia sexual (no mantener relaciones sexuales) o el uso de dos métodos anticonceptivos adecuados que incluyan al menos un método con un índice de fallo de < 1 % anual durante al menos 28 días antes del día 1 del ciclo 1, durante el período de tratamiento (incluidos los períodos de interrupción del tratamiento) y al menos 18 meses después de la última dosis de tratamiento del estudio
- En los hombres: compromiso de practicar la abstinencia sexual (no mantener relaciones sexuales) o el uso de métodos anticonceptivos y compromiso de no donar esperma

E.4

Principal exclusion criteria

- Known CD20-negative status at relapse or progression
- Central nervous system lymphoma or leptomeningeal infiltration
- Prior allogeneic stem-cell transplantation (SCT)
- Completion of autologous SCT within 100 days
- History of resistance to lenalidomide or response duration of <1 year
- Prior standard or investigational anti cancer therapy
- Clinically significant toxicity from prior therapy that has not resolved to Grade <=2 (per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.0)
- Treatment with systemic immunosuppressive medications
- History of severe allergic or anaphylactic reaction to humanized or murine monoclonal antibodies
- Known sensitivity or allergy to murine products
- History of erythema multiforme, Grade >=3 rash, or desquamation (blistering)
- Positive for hepatitis B surface antigen (HBsAg), total hepatitis B core antibody (HBcAb), or hepatitis C virus (HCV) antibody
- History of progressive multifocal leukoencephalopathy
- Contraindication to treatment for thromboembolism (TE) prophylaxis
- Life expectancy <3 months

- CD20 negativo en la recidiva o progresión
- Linfoma del sistema nervioso central o infiltración leptomeníngea
- Trasplante de células madre (TCM) alógeno previo
- Realización de TCM autólogo en los 100 días previos al día 1 del ciclo 1
- Antecedentes de resistencia a la lenalidomida o respuesta de < 1 año
- Tratamiento anticanceroso estándar o experimental previo
- Toxicidad clínicamente significativa de un tratamiento previo que no se haya resuelto hasta el grado <= 2 (según los CTCAE NCI, versión 4.0)
- Tratamiento con inmunodepresores sistémicos
- Antecedentes de reacción alérgica o anafiláctica grave a anticuerpos monoclonales humanizados o murinos
- Sensibilidad o alergia conocida a los productos murinos
- Antecedentes de eritema multiforme, exantema de grado >= 3 o descamación (vesiculación)
- Antígeno de superficie del virus de la hepatitis B, anticuerpo nuclear contra el virus de la hepatitis B o anticuerpo positivo contra el virus de la hepatitis C
- Antecedentes de leucoencefalopatía multifocal progresiva
- Contraindicación para el tratamiento profiláctico de TE
- Esperanza de vida < 3 meses

E.5 End points

E.5.1

Primary end point(s)

Safety:
1. Incidence of dose-limiting toxicities (DLTs) during Cycle 1 of study treatment
2. Incidence of adverse events
3. Changes in vital signs, ECG and clinical laboratory results

Efficacy:
4. CR at EOI, as determined by the IRC on the basis of PET-CT scans

Seguridad:
1. Incidencia de toxicidad limitante de la dosis (TLD) durante el primer ciclo de tratamiento del estudio
2. Incidencia de acontecimientos adversos
3. Alteraciones en las constantes vitales, los ECG y los resultados de pruebas analíticas

Eficacia:
4. RC al FI, determinada por el CIR a partir de las TEP-TC

E.5.1.1

Timepoint(s) of evaluation of this end point

Safety:
1. From Day 1 (D1) to D28 of Cycle 1 (C1)
2. From screening up to 5 Years
3. From screening up to 35 days after the last dose of maintenance/consolidation treatment

Efficacy:
4. 6?8 weeks after Day 1 of the last induction cycle

Seguridad:
1. Del Día 1 (D1) al D28 del Ciclo 1 (C1)
2. Desde el sreening hasta un máximo de 5 años
3. Desde el screanign hasta un máximo de 35 días después de la última dosis de matenimiento/consolidación del tratamiento

Eficacia:
4. 6-8 semanas despúes del Dia 1 del última ciclo de inducción

E.5.2

Secondary end point(s)

Efficacy:
1. CR at EOI, as determined by the investigator on the basis of PET-CT scans
2. CR at EOI, as determined by the investigator on the basis of CT scans alone
3. Objective response (defined as a CR or PR) at EOI, as determined by the IRC and by the investigator on the basis of PET-CT scans
4. Objective response (defined as a CR or PR) at EOI, as determined by the IRC and by the investigator on the basis of CT scans alone
5. Best response of CR or PR during the study, as determined by the investigator on the basis of CT scans alone

PK:
6. Observed serum obinutuzumab concentration at specified time points
7. Observed serum and plasma concentrations of Pola and its relevant analytes at specified time points
8. Observed plasma Len concentration at specified time points

Immunogenicity
9. Incidence of human anti-human antibodies (HAHA) to obinutuzumab during the study relative to the prevalence of HAHAs at baseline
10. Incidence of anti-therapeutic antibody (ATA) to Pola during the study relative to the prevalence of ATAs, at baseline

Eficacia:
1. RC al FI, determinada por el investigador a partir de las TEP-TC
2. RC al FI, determinada por el investigador a partir de las TC exclusivamente
3. Respuesta objetiva (definida como RC o RP) al FI, determinada por el CIR y el investigador a partir de las TEP-TC
4. Respuesta objetiva (definida como RC o RP) al FI, determinada por el CIR y el investigador a partir de las TC exclusivamente
5. Mejor respuesta de RC o RP durante el estudio, determinada por el investigador a partir de las TC exclusivamente

FC:
6. Concentración sérica de obinutuzumab observada en los puntos temporales especificados
7. Concentración sérica y plasmática de polatuzumab vedotin y los analitos relevantes en los puntos temporales especificados
8. Concentración plasmática de lenalidomida observada en los puntos temporales especificados

Inmunogenicidad
9. Incidencia de anticuerpos antihumanos humanos (HAHA) contra el obinutuzumab durante el estudio en relación con la prevalencia de HAHA al inicio
10. Incidencia de anticuerpos antiterapéuticos (AAT) contra el polatuzumab vedotin durante el estudio en relación con la prevalencia de AAT al inicio

E.5.2.1

Timepoint(s) of evaluation of this end point

Efficacy:
1-4. 6-8 weeks after Day 1 of the last induction cycle
5. Up to 5 years

PK:
6. Dose escalation phase (DP) and expansion phase (EP): C1D1, C2D1, C4D1, and C6D1; Maintenance phase (MP) and consolidation phase (CP): Month (M) 1D1, (M7D1, M13D1and M19D1 only for MP), at treatment discontinuation (TD), 120 days and 1 2 years after the last dose of obinutuzumab
7. DP and EP: C1D1, C1D8, C1D15, C2D1, C4D1, C6D1; MP and CP: at TD, 120 days and 1 2 years after the last dose of Pola
8. DP and EP: C1D1, C1D15, C6D1

Immunogenicity:
9. DP and EP: on C1D1, C6D1; MP and CP: at TD, 120 days and 1 2 years after the last dose of obinutuzumab
10. DP and EP: C1D1, C2D1, C4D1; MP and CP: at TD, 120 days and 1 2 years after the last dose of Pola

Eficacia:
1-4. 6-8 semanas después del Día 1 del último ciclo de inducción
5. Hasta 5 años

FC:
6. Fase de escalonado de la dosis (ED) y fase de expansión (FE): C1D1, C2D1, C4D1 y C6D1; Fase de mantenimiento (FM) y fase de consolidación (FC): Mes (M) 1D, (M7D1, M13D1and M19D1 solo FM), a la discontinuación del tratamiento (DT), 120 días y 1 2 años tras la última dosis de obinutuzumab
7. ED y FE: C1D1, C1D8, C1D15, C2D1, C4D1, C6D1; FM and FC: at DT, 120 días y 1 2 años tras la última dosis de Pola
8. ED y FE: C1D1, C1D15, C6D1

Inmunogenicidad
9. ED y FE: en C1D1, C6D1;FM y FC: al DT, 120 días y 1 2 años después de la última dosis de obinutuzumab
10. ED y FE: C1D1, C2D1, C4D1; FM y FC: al DT, 120 días y 1 2 años después de la última dosis de pola

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

Yes

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

Immunogenicity

Inmunogenecidad

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

Spain

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

The end of this study is defined as the time when both of the following criteria are met:
? All enrolled patients with FL have completed or discontinued study treatment (including induction treatment and maintenance treatment as applicable).
? All enrolled patients with DLBCL have been followed for at least 1 year after they have completed or discontinued study treatment (including induction treatment and consolidation treatment as applicable).

El fin del estudio se define como el momento en que se cumplen los dos criterios siguientes:
- Todos los pacientes con LF incluidos han finalizado o suspendido el tto del estudio (incluidos el tratamiento de inducción y el tratamiento de mantenimiento, según proceda).
- Todos los pacientes con LDLBG han sido objeto de seguimiento durante al menos 1 año tras la finalización o suspensión del tratamiento del estudio (incluidos el tto de inducción y el tto de consolidación, según proceda).

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)

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

116

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)

Currently, the Sponsor does not have any plans to provide obinutuzumab and polatuzumab vedotin or any other study treatments or interventions to patients who have completed the study. The Sponsor will evaluate whether to continue providing obinutuzumab and polatuzumab vedotin in accordance with the Roche Global Policy on Continued Access to Investigational Medicinal Product, available at the following Web site:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf

En la actualidad, el promotor no tiene previsto facilitar obinutuzumab, polatuzumab vedotin ni ningún otro tto o intervención del estudio a los pacientes que hayan finalizado el estudio.
El promotor estudiará si continúa suministrando obinutuzumab y pola vedotin de conformidad con la política global de Roche en materia de acceso continuado a los medicamentos en investigación, disponible en la página web siguiente:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf

G. Investigator Networks to be involved in the Trial

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2016-02-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-02-02

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-12-15

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Orphan Designation Number:
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