Clinical Trials Register

Summary
EudraCT Number:	2014-001363-12
Sponsor's Protocol Code Number:	TRIANGLE
National Competent Authority:	Finland - Fimea
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2018-06-06
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

Finland - Fimea

A.2

EudraCT number

2014-001363-12

A.3

Full title of the trial

autologous Transplantation after a Rituximab/Ibrutinib/Ara-c containing iNduction in Generalized mantle cell Lymphoma – a randomized European MCL Network trial

Vaiheen 3 tutkimus autologisesta kantasolusiirrosta rituksimabi/ Ibrutinibi/ sytarabiini/syklofosfamidi-doksorubisiini-vinkristiini-prednison-yhdistelmähoidon jälkeen manttelisolulymfoomassa (TRIANGLE, EudraCT no 2014-001363-12)

A.3.1

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

autologous Transplantation after a Rituximab/Ibrutinib/Ara-c containing iNduction in Generalized mantle cell Lymphoma – a randomized European MCL Network trial

Kantasolusiirto manttelisolulymfoomaa sairastavilla rituksimabi/ ibrutinib/ Ara-C hoitojen jälkeen.

A.3.2

Name or abbreviated title of the trial where available

TRIANGLE

A.4.1

Sponsor's protocol code number

TRIANGLE

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, Medizinische Klinik und Poliklinik III
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	Janssen Pharmaceutica NV
B.4.2	Country	Belgium
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Klinikum der Universität München, Medizinische Klinik und Poliklinik III
B.5.2	Functional name of contact point	Head of Study Center for Hematology
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	+4989440074900
B.5.5	Fax number	+4989440077900
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	Imbruvica
D.2.1.1.2	Name of the Marketing Authorisation holder	Janssen Research & Development, LCC and Pharmacyclics, LCC
D.2.1.2	Country which granted the Marketing Authorisation	Finland
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	EU/3/12/984 and EU/3/13/1115
D.3 Description of the IMP
D.3.1	Product name	Ibrutinib
D.3.2	Product code	PCI-32765
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.3.9.3	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

Generalized mantle cell Lymphoma

Manttelisolulymfooma

E.1.1.1

Medical condition in easily understood language

Generalized mantle cell Lymphoma

Manttelisolulymfooma eli imukudossyöpä

E.1.1.2

Therapeutic area

Diseases [C] - Blood and lymphatic diseases [C15]

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	10026805
E.1.2	Term	Mantle cell lymphoma 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	20.0
E.1.2	Level	PT
E.1.2	Classification code	10026804
E.1.2	Term	Mantle cell lymphoma stage III
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	10026803
E.1.2	Term	Mantle cell lymphoma stage II
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

To establish one of three study arms, R-CHOP/R-DHAP followed by ASCT (control arm A), R-CHOP+ibrutinib /R-DHAP followed by ASCT and ibrutinib maintenance (experimental armA+I), and R-CHOP+ibrutinib /R-DHAP followed by ibrutinib maintenance (experimental arm I) as future standard based on the comparison of the investigator-assessed failure-free survival (FFS).

E.2.2

Secondary objectives of the trial

To compare the efficacy of the three treatment arms in terms of secondary efficacy endpoints.
To determine the safety and tolerability of ibrutinib during induction immuno-chemotherapy and during maintenance and to compare the safety profile of the three treatment arms in terms of secondary toxicity endpoints.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Histologically confirmed diagnosis of MCL according to WHO classification
2. suitable for high-dose treatment including high-dose AraC
3. Stage II-IV (Ann Arbor)
4. Age >= 18 years and <= 65 years
5. Previously untreated MCL
6. At least 1 measurable lesion; in case of bone marrow infiltration only, bone marrow aspiration and biopsy is mandatory for all staging evaluations.
7. ECOG/WHO performance status <= 2
8. The following laboratory values at screening (unless related to MCL):
- Absolute neutrophil count (ANC) >=1000 cells/uL
- Platelets >=100,000 cells/uL
- Transaminases (AST and ALT) <= 3 x upper limit of normal (ULN)
- Total bilirubin <= 2 x ULN unless due to known Morbus Meulengracht [Gilbert-Meulengracht-Syndrome])
- Creatinine <=2 mg/dL or calculated creatinine clearance >= 50 mL/min
9. Written informed consent form according to ICH/EU GCP and national regulations
10. Sexually active men and women of child-bearing potential must agree to use highly effective contraceptives (eg, condoms, implants, injectables, combined oral contraceptives, intrauterine devices, sexual abstinence, or sterilized partner) while on study; this should be maintained for 90 days after the last dose of study drug.

E.4

Principal exclusion criteria

1. Major surgery within 4 weeks prior to randomization.
2. Requires anticoagulation with warfarin or equivalent vitamin K antagonists (eg phenprocoumon).
3. History of stroke or intracranial hemorrhage within 6 months prior to randomization.
4. Requires treatment with strong CYP3A4/5 inhibitors.
5. Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator’s opinion, could compromise the subject’s safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk.
4. Vaccinated with live, attenuated vaccines within 4 weeks prior to randomization.
5. Known CNS involvement of MCL.
6. Clinically significant hypersensitivity (eg, anaphylactic or anaphylactoid reactions to the compound of ibrutinib itself or to the excipients in its formulation).
7. Known anti-murine antibody (HAMA) reactivity or known hypersensitivity to murine antibodies.
8. Previous lymphoma therapy with radiation, cytostatic drugs, anti-CD20 antibody or interferon except prephase therapy according to trial protocol.
9. Serious concomitant disease interfering with a regular therapy according to the study protocol:
- Cardiac (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 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification or LVEF below LLN),
- Pulmonary (e.g. chronic lung disease with hypoxemia),
- Endocrinological (e.g. severe, not sufficiently controlled diabetes mellitus),
- Renal insufficiency (unless caused by the lymphoma): creatinine > 2x normal value and/or creatinin clearance < 50 ml/min),
- Impairment of liver function (unless caused by the lymphoma): transaminases > 3x normal or bilirubin > 2,0 mg/dl unless due to morbus Meulengracht (Gilbert-Meulengracht-Syndrome).
10. Patients with unresolved hepatitis B or C infection or known HIV positive infection (mandatory test).
11.Prior organ, bone marrow or peripheral blood stem cell transplantation.
12. Concomitant or previous malignancies within the last 3 years other than basal cell skin cancer or in situ uterine cervix cancer.
13.Pregnancy or lactation.
14. Any psychological, familiar, sociological, or geographical condition potentially hampering compliance with the study protocol and follow up schedule.
15. Subjects not able to give consent.
16. Subjects without legal capacity who are unable to understand the nature, scope, significance and consequences of this clinical trial.
17. Participation in another clinical trial within 30 days before randomization in this study.

E.5 End points

E.5.1

Primary end point(s)

FFS defined as time from start of treatment to stable disease at
end of immuno-chemotherapy, progressive disease, or death from any cause.

E.5.1.1

Timepoint(s) of evaluation of this end point

End of immuno-chemotherapy, progressive disease, or death from any cause

E.5.2

Secondary end point(s)

Secondary Efficacy Endpoints:
1. Overall survival (OS).
2. Progression-free survival (PFS) from randomization, from end of induction immuno-chemotherapy in patients with CR or PR at end of induction immuno-chemotherapy, and from the staging 6 weeks after end of induction assessment (at month 6).
3. Overall response and complete remission rates at midterm, at end of induction, 3 months after end of induction immunochemotherapy (at month 6).
4. PR to CR conversion rate during follow-up after end of induction immuno-chemotherapy.
Secondary Toxicity Endpoints:
1. Rates of AEs, SAEs, and SUSARs by CTC grade (Version 4.03) during induction immuno-chemotherapy and during periods of follow-up after response to immune-chemotherapy.
2. Cumulative incidence rates of SPMs.

E.5.2.1

Timepoint(s) of evaluation of this end point

See E.5.2

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)

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

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

Six alternating courses of R-CHOP/RDHAP followed by ASCT

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

230

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

Belgium

Croatia

Czech Republic

Denmark

Finland

Germany

Israel

Italy

Netherlands

Norway

Poland

Portugal

Spain

Sweden

Switzerland

United Kingdom

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

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:

870

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

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

800

F.4.2.2

In the whole clinical trial

870

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)

Patients will be treated according to the local standard care.

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	Deutsche Studiengruppe Niedrig Maligne Lymphome e.V. (GLSG), Klinikum Großhadern, Medizinische Klinik
G.4.3.4	Network Country	Germany
G.4 Investigator Network to be involved in the Trial: 2
G.4.1	Name of Organisation	Phase I/II platform e.V. of the European Mantle Cell Lymphoma Network, Klinikum der Universität München, Med. Klinik III
G.4.3.4	Network Country	European Union

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2018-06-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-08-08

P. End of Trial
P.	End of Trial Status	Ongoing

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