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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Klinikum der Universitaet Muenchen AöR

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

25 Jul 2016 → 23 Dec 2025

Decision date (initial)

2024-11-12

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-511235-10-00

EudraCT number

2014-001363-12

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety, Efficacy

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 arm A+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).

Secondary objectives 2

1. To compare the efficacy of the three treatment arms in terms of secondary efficacy endpoints
2. 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

Conditions and MedDRA coding

Generalized mantle cell Lymphoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Histologically confirmed diagnosis of MCL according to WHO classification
2. suitable for high-dose treatment including high-dose Ara-C
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/- Platelets ≥100,000 cells/- Transaminases (AST and ALT) ≤3 x upper limit of normal (ULN) Total bilirubin 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

Exclusion criteria 21

1. Major surgery within 4 weeks prior to randomization.
2. Previous lymphoma therapy with radiation, cytostatic drugs, anti-CD20 antibody or interferon except prephase therapy according to trial protocol
3. 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 creatinine 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)
4. 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
5. 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
6. Patients with known HIV positive infection (mandatory test)
7. Prior organ, bone marrow or peripheral blood stem cell transplantation
8. Concomitant or previous malignancies within the last 3 years other than basal cell skin cancer or in situ uterine cervix cancer
9. Pregnancy or lactation
10. Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow up schedule
11. Requires anticoagulation with warfarin or equivalent vitamin K antagonists (e.g. phenprocoumon).
12. Subjects not able to give consent
13. Subjects without legal capacity who are unable to understand the nature, scope, significance and consequences of this clinical trial
14. Participation in another clinical trial within 30 days before randomization in this study.
15. History of stroke or intracranial hemorrhage within 6 months prior to randomization.
16. Requires treatment with strong CYP3A4/5 inhibitors.
17. 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
18. Vaccinated with live, attenuated vaccines within 4 weeks prior to randomization.
19. Known CNS involvement of MCL
20. Clinically significant hypersensitivity (e.g., anaphylactic or anaphylactoid reactions to the compound of ibrutinib itself or to the excipients in its formulation)
21. Known anti-murine antibody (HAMA) reactivity or known hypersensitivity to murine antibodies

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

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

Secondary endpoints 6

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
5. 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
6. Cumulative incidence rates of SPMs

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Klinikum der Universitaet Muenchen AöR

Sponsor organisation

Klinikum der Universitaet Muenchen AöR

Address

Marchioninistrasse 15, Hadern Hadern

City

Munich

Postcode

81377

Country

Germany

Scientific contact point

Organisation

Klinikum der Universitaet Muenchen AöR

Contact name

Martin Dreyling

Public contact point

Organisation

Klinikum der Universitaet Muenchen AöR

Contact name

Martin Dreyling

Third parties 6

Locations

12 EU/EEA countries · 147 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 62 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications