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

• Register: EUCTR
• Last refreshed on: 9 January 2023
• Main ID: EUCTR2014-001363-12-DE
• Date of registration: 21/10/2015
• Prospective Registration: Yes
• Primary sponsor: Klinikum der Universität München, Medizinische Klinik und Poliklinik III
• Public title: autologous Transplantation after a Rituximab/Ibrutinib/Ara-c containing iNduction in Generalized mantle cell Lymphoma – a randomized European MCL Network trial
• Scientific title: autologous Transplantation after a Rituximab/Ibrutinib/Ara-c containing iNduction in Generalized mantle cell Lymphoma – a randomized European MCL Network trial - TRIANGLE
• Date of first enrolment: 24/03/2016
• Target sample size: 870
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-001363-12
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: yes Other specify the comparator: Six alternating courses of R-CHOP/RDHAP followed by ASCT Number of treatment arms in the trial: 3
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Belgium, Croatia, Czech Republic, Czechia, Denmark, Finland, Germany, Israel, Italy, Netherlands, Norway, Poland, Portugal, Spain, Sweden, Switzerland, United Kingdom

Contacts

• Name: Head of Study Center for Hematology
• Affiliation: Klinikum der Universität München, Medizinische Klinik und Poliklinik III

• Name: Head of Study Center for Hematology
• Affiliation: Klinikum der Universität München, Medizinische Klinik und Poliklinik III

Key inclusion & exclusion criteria

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 one of the highly effective contraceptive methods (combined oral contraceptives using two hormones, contraceptive implants, injectables, intrauterine devices, sterilized partner) together with one of the barrier methods (latex condoms, diaphragms, contraceptive caps) while on study; this should be maintained for 90 days after the last dose of study drug and 12 months after the last dose of rituximab.
Are the trial subjects under 18? no
Number of subjects for this age range:
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) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
1. Major surgery within 4 weeks prior to randomization.
2. Requires anticoagulation with warfarin or equivalent vitamin K antagonists (e.g. 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.
6. Vaccinated with live, attenuated vaccines within 4 weeks prior to randomization.
7. Known CNS involvement of MCL.
8. Clinically significant hypersensitivity (e.g., anaphylactic or anaphylactoid reactions to the compound of ibrutinib itself or to the excipients in its formulation).
9. Known anti-murine antibody (HAMA) reactivity or known hypersensitivity to murine antibodies.
10. Previous lymphoma therapy with radiation, cytostatic drugs, anti-CD20 antibody or interferon except prephase therapy according to trial protocol.
11. 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).
12. 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 are eligible.
13. 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.
14. Patients with known HIV positive infection (mandatory test).
15.Prior organ, bone marrow or peripheral blood stem cell transplantation.
16. Concomitant or previous malignancies within the last 3 years other than basal cell skin cancer or in situ uterine cervix cancer.
17.Pregnancy or lactation.
18. Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow up schedule.
19. Subjects not able to give consent.
20. Subjects without legal capacity who are unable to understand the nature, scope, significance and consequences of this clinical trial.
21. Participation in another clinical trial within 30 days before randomization in this study.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Generalized mantle cell Lymphoma
MedDRA version: 21.0 Level: PT Classification code 10026805 Term: Mantle cell lymphoma stage IV System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 21.0 Level: PT Classification code 10026804 Term: Mantle cell lymphoma stage III System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 21.0 Level: PT Classification code 10026803 Term: Mantle cell lymphoma stage II System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]

Intervention(s)

Trade Name: Imbruvica
Product Name: Ibrutinib
Product Code: PCI-32765
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Ibrutinib
CAS Number: 936563-96-1
Other descriptive name: IBRUTINIB
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 140-

Primary Outcome(s)

Primary end point(s): FFS defined as time from randomization to stable disease at end of immuno-chemotherapy, progressive disease, or death from any cause.

Secondary Objective: 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.

Main Objective: 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).

Timepoint(s) of evaluation of this end point: End of immuno-chemotherapy, progressive disease, or death from any cause

Secondary Outcome(s)

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.

Timepoint(s) of evaluation of this end point: See E.5.2

Secondary ID(s)

TRIANGLE

Source(s) of Monetary Support

Janssen Pharmaceutica NV

Ethics review

Status: Approved
Approval date: 24/03/2016
Contact: