This study has been transitioned to CTIS with ID 2024-511235-10-00 check the CTIS register for the current data. 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…
ID
Source
Brief title
Condition
- Lymphomas non-Hodgkin's B-cell
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
FFS defined as time from randomization to stable disease at end of
immuno-chemotherapy, progressive disease, or death from any cause.
Secondary outcome
Secondary Efficacy Endpoints:
-Overall survival (OS)
-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)
-Overall response and complete remission rates at midterm, at end of induction,
3 months after end of induction immuno-chemotherapy (at month 6)
-PR to CR conversion rate during follow-up after end of induction
immuno-chemotherapy
Secondary Toxicity Endpoints:
-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
-Cumulative incidence rates of SPMs
Background summary
According to current European guidelines, the standard of care in younger
patients with mantle cell lymphoma (MCL) is a dose-intensified approach with a
cytarabine containing immunochemotherapy induction followed by autologous
transplantation. Ibrutinib has recently shown impressive efficacy data in
relapsed MCL while tolerability was rather favorable.
Based on these prerequisites, our study proposal challenges the current
standard of care and questions, whether the addition of ibrutinib (arm A+I) to
the standard (control arm A) results in a superior clinical outcome. In
addition, we investigate whether ASCT which sometimes is hampered by short and
long term toxicity is still superior to a (hopefully much better tolerated)
conventional treatment without ASCT and with the addition of ibrutinib in
induction and maintenance (duration 2 years, arm I and A+I). As so far
combination data are only available with the R-CHOP regimen but not for the
alternating R-DHAP regimen.16 Ibrutinib will be only given during the R-CHOP
regimen, and during an initial safety run-in phase 50 patients randomized will
be closely monitored for the observed toxicities during induction therapy.
Analysis of minimal residual disease (MRD) will play a critical role in
identifying specific patient subpopulations which may be especially prone to
one of the three therapeutical strategies.
Finally, the recently completely recruited LyMa trial has proven a benefit of
rituximab maintenance after an ASCT. Therefore, rituximab maintenance will be
added to all 3 study arms in the Netherlands.
Study objective
This study has been transitioned to CTIS with ID 2024-511235-10-00 check the CTIS register for the current data.
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).
Study design
Randomized, three-arm, parallel-group, open label, international phase III
trial comparing six alternating courses of R-CHOP/R-DHAP (one cycle every 21
days) followed by ASCT versus the combination with ibrutinib in induction and
maintenance (2 years) or the experimental arm without ASCT
Intervention
Arm A: standard of care. Alternating 3 cycles R-CHOP / 3 cycles R-DHAP
induction followed by ASCT.
Experimental arm A+I. Alternating 3 cycles R-CHOP+Ibrutinib / 3 cycles R-DHAP
induction, followed by ASCT and 2 years Ibrutinib-Maintenance.
Experimental Arm I. Alternating 3 cycles R-CHOP + Ibrutinib / 3 cycles R-DHAP
induction, followed by 2 years ibrutinib-maintenance.
Study burden and risks
Participation in this study will be associated with extra investigations
compared to standard patient care.
Although most investigations are standard care, patients will have to visit the
hospital more frequently.
During maintenance/observation a CT-scan will be performed regularly.
When given consent, extra investigations consist of MRD measurement in blood
and bone marrow.
It is possible that the patient will experience different adverse events in
comparison to standard care.
Marchioninistr. 15
Munchen 81377
DE
Marchioninistr. 15
Munchen 81377
DE
Listed location countries
Age
Inclusion criteria
-Histologically confirmed diagnosis of MCL according to WHO classification
-Suitable for high-dose treatment including high-dose Ara-C
-Stage II-IV (Ann Arbor)
-Age >= 18 years and <= 65 years
-Previously untreated MCL
-At least 1 measurable lesion; in case of bone marrow infiltration only, bone
marrow aspiration and biopsy is mandatory for all staging evaluations.
-ECOG/WHO performance status <= 2
-The following laboratory values at screening (unless related to MCL):
-Absolute neutrophil count (ANC) >=1000 cells/µL
-Platelets >=100,000 cells/µL
-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
-Written informed consent form according to ICH/EU GCP and national
regulations
-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
-Major surgery within 4 weeks prior to randomization.
-Requires anticoagulation with warfarin or equivalent vitamin K antagonists
(e.g. phenprocoumon).
-History of stroke or intracranial hemorrhage within 6 months prior to
randomization.
-Requires treatment with strong CYP3A4/5 inhibitors.
-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.
-Vaccinated with live, attenuated vaccines within 4 weeks prior to
randomization.
-Known CNS involvement of MCL
-Clinically significant hypersensitivity (e.g., anaphylactic or anaphylactoid
reactions to the compound of ibrutinib itself or to the excipients in its
formulation)
-Known anti-murine antibody (HAMA) reactivity or known hypersensitivity to
murine antibodies
-Previous lymphoma therapy with radiation, cytostatic drugs, anti-CD20 antibody
or interferon except prephase therapy outlined in this trial protocol
-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 (chronic lung disease with hypoxemia)
-Endocrinological (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)
-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.
-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.
-Patients with known HIV positive infection (mandatory test).
-Prior organ, bone marrow or peripheral blood stem cell transplantation
-Concomitant or previous malignancies within the last 3 years other than basal
cell skin cancer or in situ uterine cervix cancer
-Pregnancy or lactation
-Any psychological, familial, sociological, or geographical condition
potentially hampering compliance with the study protocol and follow up schedule
-Subjects not able to give consent
-Subjects without legal capacity who are unable to understand the nature,
scope, significance and consequences of this clinical trial
-Participation in another clinical trial within 30 days before randomization in
this study.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2024-511235-10-00 |
| EudraCT | EUCTR2014-001363-12-NL |
| CCMO | NL56406.078.16 |