Clinical Trials Register

Summary
EudraCT Number:	2015-003429-32
Sponsor's Protocol Code Number:	ImbruVeRCHOP-Trial
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:	2016-08-19
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

2015-003429-32

A.3

Full title of the trial

“Ibrutinib (Imbruvica®), Bortezomib (Velcade®) s.c., Rituximab, CHOP for the treatment of elderly patients (age 61-80 years) with CD20+ diffuse large B-cell lymphoma, IPI ≥ 2”

„Eine Phase-I/II-Studie zur Untersuchung von Ibru-tinib (Imbruvica®), Bortezomib (Velcade®) s.c., Rituximab, CHOP in der Behandlung von älteren Patienten (Alter 61-80 Jahre) mit CD20+ diffus großzelligem Lymphom (DLBCL) und IPI ≥ 2“

A.3.1

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

“Ibrutinib (Imbruvica®), Bortezomib (Velcade®) s.c., Rituximab, CHOP for the treatment of elderly patients (age 61-80 years) with CD20+ diffuse large B-cell lymphoma, IPI ≥ 2”

A.3.2

Name or abbreviated title of the trial where available

ImbruVeRCHOP-Trial

A.4.1

Sponsor's protocol code number

ImbruVeRCHOP-Trial

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	Charité - Universitätsmedizin Berlin
B.1.3.4	Country	Germany
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	Janssen-Cilag GmbH
B.4.2	Country	Germany
B.4.1	Name of organisation providing support	Deutsches Konsortium für translationale Krebsforschung (DKTK)
B.4.2	Country	Germany
B.4.1	Name of organisation providing support	Preclinical Comprehensive Cancer Center (PCCC)
B.4.2	Country	Germany
B.4.1	Name of organisation providing support	Berlin Institute of Health (BIH)
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	Charité - Universitätsmedizin Berlin
B.5.2	Functional name of contact point	CVK, Hematology, Oncology and Tumor
B.5.3	Address:
B.5.3.1	Street Address	Augustenburger Platz 1
B.5.3.2	Town/ city	Berlin
B.5.3.3	Post code	13353
B.5.3.4	Country	Germany
B.5.4	Telephone number	+4930450 553 896
B.5.5	Fax number	+4930450 553 986
B.5.6	E-mail	clemens.schmitt@charite.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	Velcade
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	Belgium
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	Velcade
D.3.4	Pharmaceutical form	Powder for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	BORTEZOMIB
D.3.9.1	CAS number	179324-69-7
D.3.9.3	Other descriptive name	VELCADE
D.3.9.4	EV Substance Code	SUB20020
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	3,5
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: 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	Belgium
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	IMBRUVICA
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	IMBRUVICA
D.3.9.1	CAS number	936563-96-1
D.3.9.3	Other descriptive name	IBRUTINIB
D.3.9.4	EV Substance Code	SUB120863
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	140
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

untreated CD20-positive DLBCL-like aggressive Non-Hodgkin’s lymphoma, 61-80 years of age with unfavorable risk profile (IPI ≥ 2)

E.1.1.1

Medical condition in easily understood language

CD20-positive diffuse large B-cell lymphoma, IPI ≥ 2

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

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 main objective of this clinical trial is to assess the efficacy of the treatment determined as the 2-year PFS for patients with DLBCL. The regimen will be considered unacceptable if ≤ 60 % of patients (i.e. ≤ 36 patients in a cohort of 60 patients) are progression-free at 2 years. With this decision rule, the regimen will be correctly rejected with at least 95% power if true 2-year PFS rate falls below 50%. If true 2-year PFS rate is 75%, the treatment will be rejected erroneously with a 0.007 probability. “Responders” (i.e. patients achieving a CR or a PR) vs. “Non-Responders” are based on the Revised Response Criteria for Malignant Lymphoma.

E.2.2

Secondary objectives of the trial

• Feasibility & assessment of toxicity
• 1-year PFS & 2-year PFS for patients substratified by their different cell-of-origin (c-o-o) subtypes (i.e. GCB vs
ABC by GEP)
• CRR, ORR, DFS, OS in all patients & the GCB vs. ABC subgroups
• Frequency of secondary CNS involvement
• Protocol adherence
• Predictive value of an IHC-based prediction score compared to a GEP-based c-o-o signature (GCB DLBCL, ABC/non-GCB DLBCL )
• Predictive value of MRD (minimal residual disease) Levels or MRD reduction after two cycles
• Correlation of response & outcome with GEP-based gene subsets under therapy (cycle 1 and 3) & with
specific mutations identified by sequencing analysis of candidate loci
• Targeted re-sequencing of primary lymphoma material & whole-exome or whole-genome sequencing in a subset of
the patients
• Establishment of patient-derived xenograft (PDX) mouse models
• Proteome and metabolome analyses of patient primary (or PDX) lymphoma material & serum
• Analyses of relapses

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Written informed consent indicating that they understand the purpose of and procedures required for the study, including biomarkers and are willing to participate in the study
• Age ≥ 61 years and ≤ 80 years
• CD20-positive diffuse large B-cell lymphoma (DLBCL); including T-cell-rich large B-cell lymphoma, anaplastic large B-cell lymphoma; follicular lymphoma grade 3b or primary transformed follicular lymphoma at initial diagnosis or high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements or high-grade B-cell lymphoma NOS
• Lymphoma biopsy native, fresh-frozen for genome-wide transcriptome array or RNA-Seq analyses (gene expression profiling [GEP]) for molecular subtype diagnosis
• Willingness to consent to a re-biopsy in C1/day d2, and – in case of a residual lesion by interim CT – in C3/d2 if it can be obtained without inadequate risk
• Unfavorable risk profile according to the IPI score (IPI ≥ 2)
• Performance status (ECOG) 0-2
• Bi-dimensionally measurable disease (measurable by CT scan or MRI)
• Cardiac ejection fraction ≥ 50 % without clinically significant abnormalities
• Adequate hematological function: hemoglobin ≥ 9 g/dL absolute neutrophil count ≥ 1,00/μL independent of growth factor support and platelet count ≥ 100,000/μL or ≥50,000/μL if bone marrow involvement independent of transfusion support in either situation
• Adequate renal function as documented by serum creatinine level < 2 x ULN or estimated GFR ≥ 40ml/min/1,73m²
• Adequate hepatic function (total bilirubin ≤ 1,5 x ULN unless bilirubin rise is due to Gilbert’s syndrome or of nonhepatic
origin, alanine aminotransferase ALT and aspartate aminotransferase AST ≤ 3 x ULN)
• Life expectancy > 6 months
• Women of childbearing potential must have a negative serum (beta-human chorionic gonadotropin [ß-hCG]) or
urine pregnancy test at screening. Women who are pregnant or breastfeeding are ineligible for this study.
• Women of childbearing potential and men who are sexually active must be practicing a highly effective method of birth
control during and after the study consistent with local regulations regarding the use of birth control methods for
subjects participating in clinical trials. Men must agree to not donate sperm during and after the study. For females,
these restrictions apply for 1 month after the last dose of study drug. For males, these restrictions apply for 3 month
after the last dose of study drug

E.4

Principal exclusion criteria

• Unable to sign informed consent
• Secondary transformed B-NHL or types of NHL other than DLBCL and its subtypes according to WHO classification
• Prior therapy for DLBCL
• Known central nervous system lymphoma
• CNS involvement by lymphoma or any evidence of spinal cord compression. Brain CT/MRI is only mandatory (within 4 weeks prior to study entrance) in case of clinical suspicion of CNS involvement by lymphoma
• Major surgery within 4 weeks of study entrance
• History of stroke or intracranial hemorrhage within 6 months prior to study entrance
• Anticoagulation with Warfarin or equivalent vitamin K antagonists (e.g, Phenprocoumon)
• Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure or myocardial infarction within 6 months of Screening or any class 3 or 4 cardiac disease as defined by NYHA
• Treatment with strong CYP3A inhibitors
• Known history of human immunodeficiency virus HIV or active Hepatitis C virus or active Hepatitis B virus infection
or any uncontrolled active systemic infection requiring intravenous iv antibiotics
• Vaccination with live, attenuated vaccines within 3 weeks of study entrance
• History of solid organ transplantation
• Pregnant or nursing females
• Prior malignancy (except adequately treated basal cell carcinoma and squamous cell carcinoma of the skin, cervical cancer in situ, or any other cancer for which the patient has been in remission for at least 5 years)
• Known hypersensitivity or contraindication to any of the study drugs, its ingredients or recombinant human
antibodies and contrast agents
• Pre-existing polyneuropathy of any kind > grade I
• Severe chronic obstructive pulmonary disease with hypoxemia
• Current or recent (within the last 30 days prior to enrollment) treatment with another investigational drug or participation in another clinical trial
• Evidence of any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug, or patient at high risk from treatment complications
• Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigators opinion, could compromise the subjects safety, interfere with the absorption or metabolism of ibrutinib capsules or put the study outcomes at undue risk
• Any co-existing medical or psychological condition that would compromise the ability to give informed consent
• Subjects who are legally detained in an official institution
• Subjects who may be dependent on the sponsor, the investigator or the trial sites, have to be exclude from the trial
• Lack of willingness to storage and disclosure of pseudonymous disease data in the context of the clinical trial

E.5 End points

E.5.1

Primary end point(s)

Primary endpoint is the 2-year progression-free survival (PFS) for all patients.

E.5.1.1

Timepoint(s) of evaluation of this end point

A first analysis (after enrollment of approximately 40 patients) is planned for publication and/or congress presentation in 2019

E.5.2

Secondary end point(s)

Secondary endpoints are feasibility and assessment of toxicity, the 1-year PFS and 2-year PFS stratified by DLBCL c-o-o subtypes (GCB vs. ABC by GEP), calculated from d1 of C1. CR, ORR, DFS, OS of ABC and GCB DLBCL and correlation with GEP or other molecular signatures, PET results (given a PET amendment), MRD levels and the frequency of secondary CNS Manifestation at different time points

E.5.2.1

Timepoint(s) of evaluation of this end point

Please see above E.5.2.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

Yes

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

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

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

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

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.1.3

Elderly (>=65 years)

Yes

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.4.2

For a multinational trial

F.4.2.1

In the EEA

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 termination of this study patients will be treated with standard care or standard followup
assessments will be done.

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

2017-01-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-02-09

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2024-11-12

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