Clinical Trials Register

Summary
EudraCT Number:	2016-000755-27
Sponsor's Protocol Code Number:	GABe2016
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-07-07
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

Germany - BfArM

A.2

EudraCT number

2016-000755-27

A.3

Full title of the trial

FIRST LINE THERAPY OF ADVANCED STAGE FOLLICULAR LYMPHOMA
IN PATIENTS < 60 YEARS NOT ELIGIBLE FOR
STANDARD IMMUNOCHEMOTHERAPY AND ALL PATIENTS ≥ 60 YEARS
Prospective randomized evaluation of single agent
GA101 versus GA101 plus Bendamustine followed by GA101

Primärtherapie fortgeschrittener Follikulärer Lymphome bei Patienten < 60 Jahren die für eine Standard-Immunochemotherapie nicht in Frage kommen und für alle Patienten ≥ 60 Jahre
Eine prospektive randomisierte Untersuchung einer GA101- Monotherapie und GA101 plus Bendamustin jeweils gefolgt von GA101 bei Patienten in höherem Lebensalter bzw. bei Patienten mit Komorbiditäten und/oder Einschränkungen von Organfunktionen und/oder schlechtem Allgemeinzustand

A.3.1

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

First line therapy of patients < 60 years suffering from advanced follicular lymphoma who are not in the state of health for the standard immunochemotherapy or for all patients ≥ 60 years. It is a forward-looking comparison of two therapy schemes wherein the patients are assigned to the particular test group according to a special mathematical based principle. In arm 1 only GA 101 and in arm 2 GA 101 and Bendamustin is administered. After the initial therapy only GA 101 is given in both arms.

Therapie bei Patienten < 60 Jahren mit Erstdiagnose eines fortgeschrittenen FL, deren allgemeiner Gesundheitszustand eine Standard- Immunchemotherapie nicht zulässt oder bei Patienten ≥ 60 Jahren. Die Studie untersucht prospeltiv zwei therapeutischer Ansätze, wobei die Testpatienten der jeweiligen Testgruppe gemäß dem Zufallsprinzip zugeordnet werden: in Arm 1 wird GA 101 allein und in Arm 2 GA 101 plus Bendamustin verabreicht. In der Folgetherapie wird in beiden Armen nur GA 101 verabreicht.

A.3.2

Name or abbreviated title of the trial where available

GABe2016

A.4.1

Sponsor's protocol code number

GABe2016

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03492775

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	Klinikum der Universität München
B.1.3.4	Country	Germany
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	Roche Pharma AG
B.4.2	Country	Germany
B.4.1	Name of organisation providing support	Mundipharma GmbH
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Klinikum der Universität München, Med Klinik III
B.5.2	Functional name of contact point	Studienzentrale für Hämatologie
B.5.3	Address:
B.5.3.1	Street Address	Marchioninistr. 15
B.5.3.2	Town/ city	Munich
B.5.3.3	Post code	81377
B.5.3.4	Country	Germany
B.5.4	Telephone number	004989440074900
B.5.5	Fax number	004989440077900
B.5.6	E-mail	studyce@med.uni-muenchen.de

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	Gazyvaro®
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Pharma AG
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Gazyvaro®, Obinutuzumab®
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	Monoclonal Antibody
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, Munich
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.3.1	Product name	Levact®, Ribomustine®
D.3.2	Product code	Bendamustin
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	BENDAMUSTINE HYDROCHLORIDE
D.3.9.1	CAS number	3543-75-7
D.3.9.4	EV Substance Code	SUB00696MIG
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	2.5
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.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

Evaluation of the efficacy and toxicity of GA 101 versus GA 101 plus Bendamustin, followed by GA 101 in medically non-fit patients < 60 years and in all patients ≥ 60 years as first line therapy of advanced stage follicular lymphoma

Untersuchung der Monotherapie von GA 101 gegen GA 101 plus Bendamustin in der Erstlinie bei gesundheitlich beeinträchtigten Patienten < 60 Jahren und bei allen Patienten ≥ 60 Jahren mit fortgeschrittenem follikulären Lymphom

E.1.1.1

Medical condition in easily understood language

Evaluation of GA 101 versus GA 101 plus Bendamustin followed by GA 101 in patients < 60 y not eligible for standard immunochemotherapy and in all patients ≥ 60 y suffering from an advanced stage FL

Untersuchung der Einzeltherapie von GA 101 gegen GA 101 plus Bendamustin als Ersttherapie bei Patienten < 60 J mit schlechtem Allgemeinzustand und bei allen Patienten ≥ 60 J mit fortgeschrittenem FL

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	21.1
E.1.2	Level	PT
E.1.2	Classification code	10016908
E.1.2	Term	Follicle centre lymphoma, follicular grade I, II, III stage II
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10016910
E.1.2	Term	Follicle centre lymphoma, follicular grade I, II, III stage IV
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10016909
E.1.2	Term	Follicle centre lymphoma, follicular grade I, II, III stage III
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

Primary objective:
The objective of this study is to test the efficacy and toxicity of a combined OBINUTUZUMAB/bendamustine therapy or single agent OBINUTUZUMAB in younger (< 60 years) medically non-fit, ‘compromised’ patients and in all older patients (≥ 60 years) i. For the assessment of the anti-lymphoma activity the “overall response rate (ORR)” will be applied as primary endpoint. Overall response is defined as complete or partial response after 19 – 21 weeks

E.2.2

Secondary objectives of the trial

Secondary objectives are to compare OBINUTUZUMAB/bendamustine with single agent OBINUTUZUMAB in terms of additional measures of anti-lymphoma activity, treatment related toxicities, treatment compliance, quality of life, and comorbidities, and the evaluation of geriatric and co-morbidity scores in the included medically non-fit FL population.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- „Medically non-fit“ patients < 60 years defined by
ECOG > 2 or ECOG 0-2 with co-morbidities excluding intensive therapy according to local investigator’s discretion
- All patients ≥ 60 years in case of decision of investigator and patient to apply a reduced Treatment

- Documentation of the CIRS-G, G8, IADL and ECOG Scores before start of treatment

- Histologically confirmed follicular lymphoma grade I, II or IIIa with material available for central pathology review.

- Stage III/IV and stage II without the option of curative radiotherapy

- Age > 18 years

- No prior therapy

- Presence of at least one of the following symptoms or conditions requiring initiation of treatment:

- Bulky disease according to the GELF criteria: nodal or extranodal mass > 7cm in its greater diameter

- B symptoms (fever, drenching night sweats, or unintentional weight loss of >10% of normal body weight over a period of 6 months or less)

- Hematopoietic insufficiency (at least one of the following: granulocytopenia < 1.500 cells/µl, Hb < 10 g/dl, thrombocytopenia < 100.000 cells/µl)

- Compressive syndrome

- Pleural/peritoneal effusion

- Symptomatic nodal or extranodal manifestations

- At least one bi-dimensionally measurable lesion (> 1,5 cm in its largest dimension by CT scan or MRI)

- Adequate hematologic function (unless abnormalities are related to NHL), defined as follows:

--hemoglobin ≥ 9.0 g/dl

--absolute neutrophil count ≥ 1500 /µL

--platelet count ≥75000 /µl

- Women who are not breast feeding, are using effective contraception, are not pregnant and agree not to become pregnant during participation in the trial and during the 18 months thereafter.

- Men who agree not to father a child during participation in the trial and during the 18 months thereafter.

- Written informed consent form

E.4

Principal exclusion criteria

- Medically fit” patient < 60 years with the option for more intensive induction therapy such as R-CHOP

- Transformation to high-grade lymphoma (secondary to “low-grade” follicular lymphoma)

- Grade IIIb follicular lymphoma

- Presence or history of CNS disease (either CNS lymphoma or lymphomatous meningitis).

- Regular use of corticosteroids during the last 4 weeks, unless administered at a dose equivalent to < 20 mg/day prednisone.

- Prior (< 3 years) or concomitant malignancies except non-melanoma skin cancer or adequately treated in situ cervical cancer.

- Major surgery (excluding lymph node biopsy) within 28 days prior to registration.

- Necessity of rapid cytoreduction

- Serious underlying medical conditions, which could impair the ability of the patient to tolerate the therapy offered in this trial (e.g. ongoing infection, uncontrolled diabetes mellitus, gastric ulcers, active autoimmune disease).

- Severe hepatic impairment (serum bilirubin > 3.0 mg/dl)

- Known sensitivity or allergy to murine products

- Known hypersensitivity to any of the study drugs

- Treatment within a clinical lymphoma trial within 30 days prior to trial entry

- Positive test results for chronic HBV infection (defined as positive HBsAg serology) (mandatory testing) Patients with occult or prior HBV infection (defined as negative HBsAg and positive total HBcAb) may be included if HBV DNA is undetectable, provided that they are willing to undergo monthly DNA testing. Patients who have protective titers of hepatitis B surface antibody (HBSAb) after vaccination or prior but cured hepatitis B are eligible.

- Positive test results for hepatitis C (mandatory hepatitis C virus [HCV] antibody serology testing) Patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA.

- Known history of HIV seropositive status.

- Patients with a history of confirmed PML

- Vaccination with a live vaccine within 28 days prior to registration

- Prior organ, bone marrow or peripheral blood stem cell transplantation

- Any other co-existing medical or psychological condition that will preclude participation in the study or compromise the ability to understand its nature, meaning and implications

E.5 End points

E.5.1

Primary end point(s)

Overall response rate (ORR) defined as complete or partial response after 19-21 weeks.

E.5.1.1

Timepoint(s) of evaluation of this end point

Staging at week 19-21

E.5.2

Secondary end point(s)

● event free survival (EFS)
● CR Rate Time to Treatment Failure (TTF)
● Progression-free survival (PFS)
● Duration of Remission (RD)
● Time to next anti-lymphoma treatment
● Overall Survival (OS)
● Toxicities
● Frequency and Duration of Hospitalization
● Supportive Care
● Incidence of secondary transformation to aggressivelymphoma
● Incidence of secondary malignancies
● Treatment Compliance
● Quality of Life analysis (QoL)
● Geriatric and Comorbidity Scores
lymphoma
Incidence of secondary malignancies
Treatment Compliance
Quality of Life analysis (QoL)
Geriatric and Comorbidity Scores

E.5.2.1

Timepoint(s) of evaluation of this end point

Staging at week 19-21 and 4-6 weeks after completion of the last OBINUTUZUMAB application (week 49-51).

Follow-Up evaluation every three months during the first year and then every 6 months the subsequent years until documentation of disease progression or death.

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

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

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

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

Yes

E.8.2.3.1

Comparator description

Monotherapie versus Kombinationstherapie

monotherapy versus combination

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

LVLS
observation until end of trial, but 1 year follow-up is for every patient mandatory
max. duration: 60 months

Beobachtung bis zum Ende der Studie (maximale Dauer: 60Monate); mindestens 1 Jahr Nachbeobachtung für jeden Patienten ist zwingend vorgesehen

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

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)

Follow-up treatment according local standard of care for this patient group.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	GLSG Studienzentrale, Klinikum der Universität
G.4.3.4	Network Country	Germany

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2016-09-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-01-17

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2022-12-31

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