Clinical Trials Register

Summary
EudraCT Number:	2013-000087-29
Sponsor's Protocol Code Number:	MO28543
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:	2013-07-12
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

2013-000087-29

A.3

Full title of the trial

A multicenter, open-label, single-arm, phase IIIb, international study evaluating the safety of Obinutuzumab alone or in combination with chemotherapy in patients with previously untreated or relapsed/refractory Chronic Lymphocytic Leukemia.

Estudio de fase IIIb multicéntrico, internacional, abierto, con un solo grupo de tratamiento para evaluar la seguridad de Obinutuzumab como agente único o en combinación con quimioterapia en pacientes con leucemia linfática crónica recurrente/refractaria o no tratados previamente.

A.3.1

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

International study evaluating safety of Obinutuzumab alone or in combination with chemotherapy in patients with Chronic Lymphocytic Leukemia.

Estudio internacional para evaluar la seguridad de Obinutuzumab como agente único o en combinación con quimioterapia en pacientes con leucemia linfática crónica.

A.4.1

Sponsor's protocol code number

MO28543

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	Roche Farma, S.A. , en nombre de 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	F.Hoffmann-La Roche Ltd.
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	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	4051
B.5.3.4	Country	Switzerland
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	Yes
D.2.5.1	Orphan drug designation number	EMA/OD/102/12
D.3 Description of the IMP
D.3.1	Product name	OBINUTUZUMAB
D.3.2	Product code	RO5072759
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.3.9.2	Current sponsor code	RO5072759
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	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	Levact
D.2.1.1.2	Name of the Marketing Authorisation holder	Astellas Pharma GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	RO5469113
D.3.4	Pharmaceutical form	Powder 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	BENDAMUSTINE HYDROCHLORIDE
D.3.9.1	CAS number	3543-75-7
D.3.9.2	Current sponsor code	RO5469113
D.3.9.4	EV Substance Code	SUB00696MIG
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	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

Chronic lymphocytic leukemia

Leucemia linfática crónica

E.1.1.1

Medical condition in easily understood language

leukemia

Leucemia

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	16.1
E.1.2	Level	LLT
E.1.2	Classification code	10008976
E.1.2	Term	Chronic lymphocytic leukemia
E.1.2	System Organ Class	100000004864

E.1.2 Medical condition or disease under investigation

E.1.2	Version	16.1
E.1.2	Level	LLT
E.1.2	Classification code	10008977
E.1.2	Term	Chronic lymphocytic leukemia recurrent
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

? To evaluate the safety and tolerability of obinutuzumab alone or in combination with chemotherapy

Evaluar la seguridad y la tolerancia de obinutuzumab administrado como agente único o en combinación con quimioterapia

E.2.2

Secondary objectives of the trial

? To evaluate the efficacy of obinutuzumab alone or in combination with chemotherapy in patients with previously untreated or relapsed/refractory, CLL, as measured by:
- Minimal residual disease (MRD)-negativity at the end of treatment (at the final response assessment)
- Overall response rate (ORR) at the end of treatment
- Progression-free survival (PFS)
- Time to Response (TTR)
- Event-free survival (EFS)
- Best overall response (BOR)
- Overall survival (OS)
- Time to new anti-leukemia therapy (TTNT)
- Duration of response (DoR)

Evaluar la eficacia de obinutuzumab administrado como agente único o en combinación con quimioterapia en pacientes con LLC no tratados previamente o con enfermedad recurrente/refractaria, que se determinará basándose en lo siguiente:
- Enfermedad mínima residual (EMR) negativa, confirmada por citometría de flujo al final del tratamiento
- Índice de respuesta global (IRG) al final del tratamiento
- Supervivencia libre de progresión (SLP)
- Tiempo hasta la respuesta (TR)
- Supervivencia libre de acontecimientos (SLA)
- Mejor respuesta global (MRG)
- Supervivencia glogal (SG)
- Tiempo hasta el nuevo tratamiento para la leucemia (TNTL)
- Duración de la respuesta (DR)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

? Documented CLL either previously untreated or relapsed and/or refractory'
? Age ? 18 years
? ECOG performance status 0?2
? Adequate haematological function

- LLC documentada tanto no tratada previamente como recurrente y/o refractaria.
- mayor igual a 18 años
- función hematológica adecuada

E.4

Principal exclusion criteria

? Patients who have received more than 3 previous CLL treatment lines
? Documented transformation of CLL to aggressive lymphoma (Richter?s transformation)
? Patients who are refractory to immunochemotherapy
?Calculated CrCl < 30 mL/min, or AST or ALT > 2.5 × ULN, or Total bilirubin ? 3 × ULN
? One or more individual organ/system impairment score of 4 as assessed by the CIRS definition
? Patients with a history of progressive multifocal leukoencephalopathy (PML)
? Regular treatment (i.e. more than 5 consecutive days) with corticosteroids during the 4 weeks prior to the start of Cycle 1, Day 1, unless administered for indications other than CLL at a dose equivalent to ? 30 mg/day prednisone
? Regular treatment with immunosuppressive medications following previous organ transplantation
? Vaccination with live vaccines within 28 days prior to start of treatment
? Positive test results for chronic hepatitis B, hepatitis C infections (HCV antibody are eligible only if PCR is negative for HCV RNA), history of HIV seropositive status, positive test results for HTLV 1 (un endemic areas)
? Women that are pregnant or lactating
? Fertile men or women of childbearing potential unless: (1) surgically sterile or (for women) ? 2 years after the onset of menopause; (2) willing to use a highly effective contraceptive method, during study and for 12 months (females) or 6 months (males) after end of treatment

- Pacientes que han recibido más de 3 regímenes de tratamiento previos para la LLC
-Transformación documentada de la LLC a linfoma agresivo (transformación de Richter)
- Pacientes refractarios a inmunoquimioterapia
- CCr calculado < 30 m/min, o AST O ALT mayor 2,5 x LSN, o bilirrubina total mayor o igual a 3 x LSN
- Puntuación 4 de deterioro en uno o varios órganos/sistemas individuales, evaluada basándose en la definición de la CIRS
- Pacientes con antecedentes de LMP confirmada
- 10. Tratamiento regular (es decir, durante más de 5 días consecutivos) con corticosteroides durante los 28 días previos al inicio del tratamiento el día 1 del ciclo 1, salvo que se administren para indicaciones distintas de LLC a una dosis equivalente a ? 30 mg/día de prednisona
. Tratamiento regular con inmunosupresores tras un trasplante de órganos previo
- Administración de vacunas vivas en los 28 días previos al inicio del tratamiento
- Resultado positivo de la prueba de detección de hepatitis B crónica, hepatitis C (anticuerpo contra VHC serán elegibles para el estudio únicamente si el resultado de la reacción en cadena de la polimerasa es negativo para el ARN de VHC), historia del estatus del VIH, resultado positivo HTLV 1 (en zonas endémicas)
- Mujeres embarazadas o en período de lactancia
- 21. Varones en edad fértil o mujeres potencialmente fértiles, a menos que: (1) estén esterilizados quirúrgicamente o, en el caso de las mujeres, hayan transcurrido ? 2 años desde el comienzo de la menopausia; (2) estén dispuestos a utilizar un método anticonceptivo altamente eficaz, durante el tratamiento del estudio y hasta 12 meses (mujeres) o 6 meses (hombres) después de finalizar el tratamiento.

E.5 End points

E.5.1

Primary end point(s)

? To evaluate the safety and tolerability of obinutuzumab alone or in combination with chemotherapy
? Incidence, type, and severity of all adverse events (AEs), based on the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI-CTCAE, v4.0)
? Serious adverse events (SAEs)
? AEs of special interest (AESIs; AEs associated with any obinutuzumab infusion [defined as any serious treatment-related AEs occurring during or within 24 hours of an obinutuzumab infusion], serious infections, serious neutropenia, and tumor lysis syndrome)
? Dose delays/discontinuations
? Abnormalities identified through physical examinations, vital signs, and laboratory assessments

- Evaluar la seguridad y la tolerancia de obinutuzumab administrado como agente único o en combinación con quimioterapia
- Incidencia, tipo y severidad de todos los acontecimientos adversos (AA), basándose en los Criterios de Terminología Común para Acontecimientos Adversos del National Cancer Institute, Versión 4.0 (NCI-CTCAE, v4.0)
- AA graves (AAG)
- AA de especial interés (AAEI; AA relacionados con las infusiones de obinutuzumab [que se definen como aquellos AA graves relacionados con el tratamiento que se manifiestan durante la infusión de obinutuzumab o en las 24 horas siguientes], infecciones graves, neutropenia grave y síndrome de lisis tumoral
- Aplazamientos/interrupciones del tratamiento
- Anomalías identificadas en las exploraciones físicas, las constantes vitales y las evaluaciones de laboratorio

E.5.1.1

Timepoint(s) of evaluation of this end point

Assessed at each visit: screening, days 1, 2, 8, 15, 29, 57, 85, 113, 141 during treatment, 169 then 225 and every 3 months until the end of study.

Evaluación en cada visita: screening, día 1, 2, 8, 15, 29, 57, 85, 113, 141 durante el tratamiento, 169 y 225 después y cada 3 meses hasta el final del estudio.

E.5.2

Secondary end point(s)

? To evaluate the efficacy of obinutuzumab alone or in combination with chemotherapy, as measured by:
- Minimal residual disease (MRD)-negativity by flow cytometry at the end of treatment
- Overall response rate (ORR) at the end of treatment
- Progression-free survival (PFS)
- Time to Response (TTR)
- Event-free survival (EFS)
- Best overall response (BOR)
- Overall survival (OS)
- Time to new anti-leukemia therapy (TTNT)
- Duration of response (DoR)

Evaluar la eficacia de obinutuzumab administrado como agente único o en combinación con quimioterapia, medido por:
- Enfermedad mínima residual (EMR) negativa evaluada en citometría de flujo al final del tratamiento.
- Índice de respuesta global (IRG) al final del tratamiento.
- Supervivencia libre de progresión (SLP)
- Tiempo hasta la respuesta (TR)
- Supervivencia libre de acontecimientos (SLA)
- Mejor respuesta global (MRG)
- Supervivencia global (SG)
- Tiempo hasta el nuevo tratamiento para la leucemia (TNTL)
- Duración de la respuesta (DR)

E.5.2.1

Timepoint(s) of evaluation of this end point

Assessed at: screening, day 57 during treatment, 169 then 225 and every 3 months until the end of study.

Evaluación en: screening, día 57 durante el tratamiento, 169 y 225 después y cada 3 meses hasta el final del estudio.

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

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

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

142

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

Canada

China

Romania

Slovakia

Bosnia and Herzegovina

Albania

Argentina

Brazil

Egypt

Estonia

Korea, Republic of

Latvia

Lithuania

Thailand

Uruguay

Israel

Macedonia, the former Yugoslav Republic of

Mexico

Poland

Russian Federation

Serbia

Slovenia

Switzerland

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

The study will end 30 months after the last patient has been enrolled, or earlier, if one of the following is documented for all treated patients: withdrawal from the study; loss to follow-up; death; or the study is prematurely terminated by the sponsor, whichever occurs first. The final analysis of OS and PFS will be conducted, and updated safety parameters will be summarized at this stage.

El estudio terminará 30 meses después de la inclusión del último paciente, o antes, si se documenta cualquiera de las circunstancias siguientes en todos los pacientes tratados: retirada del estudio, pérdida del seguimiento o muerte o terminación prematura del estudio por parte del promotor, según sea lo que ocurra antes. Se realizará el análisis final de la SG y la SLP y se resumirán los parámetros de seguridad actualizados en esta fase.

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:

530

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

270

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

560

F.4.2.2

In the whole clinical trial

800

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)

The Sponsor does not intend to provide obinutuzumab or other study interventions to patients after conclusion of the study or any earlier patient withdrawal.

El promotor no tiene intención de suministrar obinutuzumab u otros fármacos del estudio a los pacientes, una vez que haya concluido el estudio o después de que un paciente se haya retirado prematuramente.

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

2014-02-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-02-04

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-10-05

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IMP with orphan designation in the indication
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