Clinical Trials Register

Summary
EudraCT Number:	2014-000569-35
Sponsor's Protocol Code Number:	CLL2-BIG
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-10-16
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

Germany - PEI

A.2

EudraCT number

2014-000569-35

A.3

Full title of the trial

A prospective, open-label, multicentre phase-II trial to evaluate the efficacy and safety of a sequential regimen of bendamustine followed by GA101 and ibrutinib (BIG) followed by ibrutinib and GA101 maintenance in CLL patients (CLL2-BIG protocol)

A.3.1

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

A.3.2

Name or abbreviated title of the trial where available

CLL2-BIG

A.4.1

Sponsor's protocol code number

CLL2-BIG

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	University of Cologne
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	F. Hoffmann - La Roche
B.4.2	Country	Switzerland
B.4.1	Name of organisation providing support	Janssen - Cilag
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	German CLL Study Group
B.5.2	Functional name of contact point	Information Desk
B.5.3	Address:
B.5.3.1	Street Address	Gleueler Str. 176 - 178
B.5.3.2	Town/ city	Köln
B.5.3.3	Post code	50935
B.5.3.4	Country	Germany
B.5.4	Telephone number	00490221478 88220
B.5.5	Fax number	00490221478 86886
B.5.6	E-mail	cllstudie@uk-koeln.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	Bendamustine (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.3.1	Product name	Bendamustine hydrochloride
D.3.4	Pharmaceutical form	Concentrate and solvent 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.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Imbruvica®
D.2.1.1.2	Name of the Marketing Authorisation holder	Janssen-Cilag International NV
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	Ibrutinib
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.3.11 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: 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	Gazyvaro®
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche/Genentech
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	Obinutuzumab/GA101
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.3.11 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	Yes
D.3.11.13.1	Other medicinal product type	RO5072759 is a humanized and glycoengineered monoclonal antibody (mAB)

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

Fit and unfit patients with previously untreated or relapsed/refractory CLL requiring treatment

E.1.1.1

Medical condition in easily understood language

Fit and unfit patients with previously untreated or relapsed/refractory CLL requiring treatment

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	19.1
E.1.2	Level	PT
E.1.2	Classification code	10008958
E.1.2	Term	Chronic lymphocytic leukaemia
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

The primary objective of the study is to evaluate the efficacy of a regimen of two debulking cycles of bendamustine chemotherapy followed by a sequential combination therapy of GA101 (obinutuzumab) and ibrutinib for induction and maintenance therapy in CLL patients. For this, the overall response rate (ORR) at final restaging (RE) 12 weeks after start of the last cycle of induction therapy (end of induction treatment response = EOIT) will be used as primary parameter of efficacy. In the ORR all patients achieving a (clinical) complete response (CR) / complete response with incomplete recovery of the bone marrow (CRi), partial response (PR) and PR with lymphocytosis will be included. The response will be assessed according to the iwCLL criteria

E.2.2

Secondary objectives of the trial

Evaluate safety of bendamustine followed by GA101 + ibrutinib for induction + maintenance. Safety: by documentation of type, frequency, severity of AEs, registering relationship of AEs to study treatment.
Investigate feasibility of maintenance with GA101 + ibrutinib. Response: every 3 months during/at the end of maintenance. MRD at final restaging in patients responding to induction and every 3 months in patients with (clinical) CR and every 6 months in patients with PR during maintenance. A descriptive pairwise comparison of safety and efficacy between first line and relapse/ refractory patients + between physically fit and unfit patients.
Secondary endpoints: MRD, PFS, EFS, OS, duration of response in (clinical) CR/CRi or PR/PR with lymphocytosis patients, time to next CLL treatment, BRR 6 months after final restaging, ORR after debulking and after end of maintenance, in biological defined risk groups, (clinical) CR rate + relationship between baseline markers + clinical outcome

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Have documented CLL requiring treatment according to iwCLL criteria
2. Creatinine clearance ≥ 30 ml/min calculated according to the modified formula of Cockcroft and Gault or directly measured after 24 h urine collection
3. Adequate liver function as indicated by a total bilirubin ≤ 2 x, AST, and ALT ≤ 2.5 x the institutional ULN value, unless directly attributable to the patient’s CLL or to Gilbert’s Syndrome
4. Negative serological testing for hepatitis B (i.e. HBsAg negative and anti-HBc negative, patients positive for anti-HBc may be included if PCR for HBV DNA is negative and HBV-DNA PCR is performed every month until 3 months after last dosage of GA101), negative testing for hepatitis-C RNA and negative HIV test within 6 weeks prior to registration
5. Age at least 18 years
6. ECOG 0 – 2; ECOG 3 is only permitted if related to CLL (e.g. due to anaemia or severe constitutional symptoms)
7. Life expectancy ≥ 6 months
8. Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements

E.4

Principal exclusion criteria

1. Transformation of CLL (i.e. Richter’s transformation, prolymphocytic leukaemia)
2. Known central nervous system (CNS) involvement
3. Patients with a history of confirmed PML
4. Malignancies other than CLL currently requiring systemic therapies
5. Use of investigational agents which would interfere with the study drug within 28 days prior to registration
6. Active infection requiring systemic treatment
7. Any comorbidity or organ system impairment rated with a CIRS (cumulative illness rating scale) score of 4, excluding the eyes/ears/nose/throat/larynx organ system or any other life-threatening illness, medical condition or organ system dysfunction that – in the investigator´s opinion could comprise the patients safety or interfere with the absorption or metabolism of the study drugs
8. Known hypersensitivity to GA101 (obinutuzumab), ibrutinib or any of the excipients
9. Requirement of treatment with strong CYP3A4-inhibitors/-inducers or anticoagulant with warfarin or phenoprocoumon (marcumar)
10. History of stroke or intracranial haemorrhage within 6 months prior to randomization
11. Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of treatment)

12. Fertile men or women of childbearing potential unless:
a. surgically sterile or ≥ 2 years after the onset of menopause
b. willing to use two methods of reliable contraception including one highly effective (Pearl Index <1) and one additional effective (barrier) method during study treatment and for 12 months after end of study treatment.
13. Vaccination with a live vaccine a minimum of 28 days prior to randomization
14. Legal incapacity
15. Prisoners or subjects who are institutionalized by regulatory or court order
16. Persons who are in dependence to the sponsor or an investigator

E.5 End points

E.5.1

Primary end point(s)

Overall response rate (ORR)

E.5.1.1

Timepoint(s) of evaluation of this end point

at final restaging (RE; 3 months after the start of last course of induction therapy)

E.5.2

Secondary end point(s)

• Safety parameters: Type, frequency, and severity of adverse events (AEs) and adverse events of special interest (AESI) and their relationship to study treatment
• MRD levels (measured in peripheral blood at interim staging, final restaging and every 3 month during maintenance therapy)
• Overall response rate (ORR) in biological defined risk groups
• (Clinical) complete response rate
• Progression-free survival (PFS)
• Event-free survival 23
• Overall survival (OS)
• Duration of response in patients with (clinical) CR/ Cri and PR
• Time to next CLL treatment
• Evaluation of relationship between various baseline markers and clinical outcome parameters

E.5.2.1

Timepoint(s) of evaluation of this end point

ongoing evaluation during the trial

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

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

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 the clinical trial is defined as the time point once the last patient completed the maintenance phase and at minimum 2 follow up visits thereafter. This will take place approximately 40 months after the last patient entered the trial (registration).

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

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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.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)

After participation in the trial has ended no special treatment or care is needed.

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

2014-12-29

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-11-19

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-03-29

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