Clinical Trials Register

Summary
EudraCT Number:	2014-003893-17
Sponsor's Protocol Code Number:	SAKK36/13
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:	2017-07-24
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 - BfArM

A.2

EudraCT number

2014-003893-17

A.3

Full title of the trial

Combination of ibrutinib and bortezomib followed by ibrutinib maintenance to treat patients with relapsed and refractory mantle cell lymphoma;
a multicenter Phase I/II trial

Kombinationstherapie von Ibrutinib mit Bortezomib mit nachfolgender Erhaltungstherapie mit Ibrutinib zur Behandlung von Patienten mit wiederauftretendem oder therapieresistentem Mantelzell-Lymphom; eine multizentrische Phase I/II Studie

A.3.1

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

Combination of ibrutinib and bortezomib followed by ibrutinib to treat patients with relapsed and refractory mantle cell lymphoma

Kombinationstherapie von Ibrutinib mit Bortezomib gefolgt von Ibrutinib zur Behandlung von Patienten mit wiederauftretendem oder therapieresistentem Mantelzell-Lymphom

A.4.1

Sponsor's protocol code number

SAKK36/13

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02356458

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	SAKK, Swiss Group for Clinical Cancer Research
B.1.3.4	Country	Switzerland
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	Janssen Cilag Pharma
B.4.2	Country	Switzerland
B.4.1	Name of organisation providing support	State Secretariat for Education, Reasearch and Innovation
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	CROLLL GmbH
B.5.2	Functional name of contact point	Scientific Head
B.5.3	Address:
B.5.3.1	Street Address	Wörnitzstr. 115a
B.5.3.2	Town/ city	Nürnberg
B.5.3.3	Post code	90449
B.5.3.4	Country	Germany
B.5.4	Telephone number	004991125268846
B.5.5	Fax number	004991125268840
B.5.6	E-mail	tobias.leidig@crolll.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	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	Bortezomib
D.3.4	Pharmaceutical form	Lyophilisate 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.3.9.4	EV Substance Code	SUB20020
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	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	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	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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	IBRUTINIB
D.3.9.1	CAS number	936563-96-1
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

Histologically confirmed mantle cell lymphoma in need of systemic
treatment
Refractory or relapsed disease after pretreatment of non-bortezomib containing
chemotherapy including high-dose therapy

Histologisch bestätigtes Mantelzell-Lymphom das einer systemischen
Therapie bedarf
Therapieresistente oder wiederauftretende Krankheit nach
Vorbehandlung mit einer Chemotherapie, die nicht Bortezomib enthielt,
inklusive Hochdosistherapie

E.1.1.1

Medical condition in easily understood language

Mantle cell Lymphoma in relapse or refractory

Therapieresistentes oder wiederauftretendes Mantelzell-Lymphom

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	20.0
E.1.2	Level	PT
E.1.2	Classification code	10026801
E.1.2	Term	Mantle cell lymphoma refractory
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	20.0
E.1.2	Level	PT
E.1.2	Classification code	10026800
E.1.2	Term	Mantle cell lymphoma recurrent
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 phase II is to define the efficacy of
ibrutinib in combination with bortezomib in patients with relapsed or
refractory Mantle cell Lymphoma

Ziel der Studie ist es herauszufinden, ob Ibrutinib und Bortezomib eine gemeinsame Wirkung in der Behandlung von Patienten mit wiederauftretendem oder therapieresistentem Mantelzell-Lymphom aufweisen.

E.2.2

Secondary objectives of the trial

The secondary objectives of this trial are
• to determine the safety and tolerability of the RP2D of ibrutinib in
combination with bortezomib
• to determine the efficacy of ibrutinib in combination with
bortezomib in patients with relapsed MCL followed by an ibrutinib
maintenance therapy.

Die sekundären Endpunkte der Studie sind
• Untersuchung der Sicherheit und Verträglichkeit der RP2D von Ibrutinib in Kombination mit Bortezomib
• Untersuchung der Wirksamkeit von Ibrutinib in Kombination mit
Bortezomib in Patienten mit wiederauftretendem MCL, gefolgt von einer Ibrutinib Erhaltungstherapie.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

6.1.1 Patient must give written informed consent before registration
indicating that the patient understands the purpose of the procedures
required for the trial and is willing to participate in the trial.
6.1.2 Histologically confirmed mantle cell lymphoma with either
overexpression of cyclin D1 protein or evidence of t(11;14)(q13;q32)
assessed by cytogenetics, by fluorescence, in situ hybridization (FISH)
or by polymerase chain reaction (PCR).
6.1.3 Refractory or relapsed disease in need of systemic therapy after
pretreatment with non-bortezomib-containing chemotherapy (including
high-dose therapy plus autologous stem cell support; induction and
consolidation with high-dose chemotherapy is considered one line of
chemotherapy.)
6.1.4 At least one measurable lesion ≥11 mm in its greatest
transverse diameter measured with CT scan
(contrast enhanced) or MRI (in case of the disease cannot be
adequately imaged using CT and if contrast is not appropriate for
patients according to the treating physician).
6.1.5 WHO performance status 0-2 (see 0)
6.1.6 Age ≥ 18 years
6.1.7 Adequate hematological values:
o Absolute neutrophil count (ANC) ≥ 1.0 x 10^9/L independent of
growth factor support
o Platelets ≥ 100 x 10^9/L or ≥ 50 x 10^9/L if bone marrow
involvement independent of transfusion support in either situation,
o Hb ≥ 80 g/L
6.1.8 Adequate hepatic function:
o Total bilirubin ≤1.5xupper limit of normal (ULN) unless bilirubin is
due to Gilbert`s syndrome ≤ 5.0 x ULN
o Aspartate aminotransferase (AST) and alanine aminotransferase
(ALT) ≤3xULN
6.1.9 Adequate renal function: Body surface area (BSA) corrected
creatinine clearance ≥40mL/min/1.73m^2 (calculated according to the
corrected formula of Cockcroft-Gault, see 0)
6.1.10 Women of childbearing potential and men who are sexually
active must be practicing a highly effective method of birth control
during and after the trial (see below) consistent with local regulations
regarding the use of birth control methods for patients participating in
clinical trials. Men must agree to not donate sperm
during and after the trial. These restrictions apply for
o Ibrutinib: 3 month after the last dose of trial drug for males and 1
month for females.
o Bortezomib: during trial treatment (for males and females): no
restrictions of birth control after last dose of trial drug. Donation of
sperm: 6 month after the last dose of trial drug.
6.1.11 Women of childbearing potential must have a negative serum
(beta-human chorionic gonadotropin [β-hCG]) or urine pregnancy test
at baseline. Women who are pregnant or breastfeeding are ineligible
for this trial.

E.4

Principal exclusion criteria

6.2.1 Prior therapy with ibrutinib or bortezomib
6.2.2 Adverse event neuropathy of prior therapy grade ≥2 (according
to CTCAE criteria Version 4.0) at registration
6.2.3 Previous malignancy within 5 years with the exception of
adequately treated in situ cervical cancer or localized non-melanoma
skin cancer.
6.2.4 Presence or history of CNS disease (either CNS lymphoma or
lymphomatous meningeosis)
6.2.5 Evidence of ongoing systemic infections of all kind
6.2.6 Exclusion of the following prior treatments prior to trial
registration
o major surgery within 4 weeks
o concurrent treatment with other experimental drugs or treatment in
a clinical trial within 30 days.
o treatment with chemotherapy and radiotherapy within 3 weeks
o vaccinated with live, attenuated vaccines within 4 weeks
6.2.7 History of stroke or intracranial hemorrhage within 6 months
prior to trial registration.
6.2.8 Requires anticoagulation with warfarin or equivalent vitamin K
antagonists (e.g. phenprocoumon)
6.2.9 Requires treatment with strong or moderate CYP3A inhibitors
(see http://medicine.iupui.edu/clinpharm/ddis/main-table and also
chapter 9.11.1.2 of the study protocol)
6.2.10 Clinically significant cardiovascular disease such as congestive
heart failure NYHA III or IV (as defined by the New York Heart
Association Functional Classification), uncontrolled or
symptomatic arrhythmias, significant QT-prolongation, unstable angina
pectoris myocardial infarction within 6 months of prior to registration,
6.2.11 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 treatment.
6.2.12 Prior allogeneic bone marrow or solid organ transplantation
6.2.13 Any life-threatening illness, medical condition, or organ system
dysfunction which, in the investigator's opinion,
o could impair the ability of the patient to participate in the trial
o could compromise the patient's safety,
o could interfere with the absorption or metabolism of ibrutinib
capsules, or
o could put the trial outcomes at undue risk
o could prevent compliance with trial treatment.
6.2.14 Psychiatric disorder precluding understanding of trial
information, giving informed consent, or interfering with compliance
for oral drug intake.
6.2.15 Known hypersensitivity to trial drug(s) or hypersensitivity to
any other component of the trial drugs.
6.2.16 Any concomitant drugs contraindicated for use with the trial
drugs according to the approved product information.
6.2.17 Any psychological, familial, sociological or geographical
condition potentially hampering compliance with the trial protocol and follow-up.

E.5 End points

E.5.1

Primary end point(s)

Overall response (OR) (combination therapy)

Ansprechrate (OR) (Kombinationstherapie)

E.5.1.1

Timepoint(s) of evaluation of this end point

6 months after treatment start

6 Monate nach Beginn der Behandlung

E.5.2

Secondary end point(s)

• Adverse events (AE) until 30 days after end of trial therapy
• OR based on best response observed during treatment
(combination and maintenance therapy)
• Progression-free survival (PFS)
• Time to treatment failure (TTF)
• Duration of objective response

• Nebenwirkungen bis 30 Tage nach Ende der Studienbehandlung
• Ansprechrate basierend auf dem besten Ansprechen das während der Behandlung beobachtet wurde (Kombinations- und Erhaltungstherapie)
• Progressions-freies Überleben
• Zeit bis zum Therapieversagen
• Dauer des objektiven Ansprechens auf die Therapie

E.5.2.1

Timepoint(s) of evaluation of this end point

-OR at 1 1/2 years after patient registration.
-all other secondary endpoints estimated after 2 years

-Ansprechrate 1 1/2 Jahre nach Registrierung des Patienten
-alle anderen sekundären Endpunkte nach 2 Jahren

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

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

Germany

Italy

Switzerland

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

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

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)

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.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)

After maintenance, there is a follow up phase but no active treatment is performed. After progressive disease is established, subsequent therapy is permitted at the investigator’s discretion.

Nach der Erhaltungstherapie folgt eine Follow-Up Phase in der aber keine aktive Behandlung erfolgt. Nach dem Fortschreiten der Krankheit erfolgt die nachfolgende Therapie nach dem Ermessen des behandelnden Arztes.

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

2017-11-23

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-11-08

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-03-30

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IMP with orphan designation in the indication
Orphan Designation Number:
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