Randomized European Trial of Autologous Transplantation with Rituximab, Ibrutinib, and Ara-C Induction in Generalized Mantle Cell Lymphoma

Trial ID: 2024-511235-10-00
Protocol: TRIANGLE
Sponsor: Klinikum der Universitaet Muenchen AöR

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Diseases & Conditions

Mantle cell lymphoma stage II Mantle cell lymphoma stage III Mantle cell lymphoma stage IV

Objectives

The primary objective of this study is to establish one of three treatment arms as the future standard for patients with **generalized mantle cell lymphoma**. The study compares the investigator-assessed failure-free survival (FFS) among the following arms: R-CHOP/R-DHAP followed by autologous stem cell transplantation (ASCT) as the control arm (A), R-CHOP plus **ibrutinib**/R-DHAP followed by ASCT and ibrutinib maintenance as experimental arm (A+I), and R-CHOP plus ibrutinib/R-DHAP followed by ibrutinib maintenance as experimental arm (I). This comparison is clinically relevant as it aims to determine the most effective treatment regimen to improve patient outcomes in this aggressive form of lymphoma.

Secondary objectives include:

Comparing the efficacy of the three treatment arms in terms of secondary efficacy endpoints.
Determining the safety and tolerability of ibrutinib during induction immuno-chemotherapy and maintenance, and comparing the safety profile of the three treatment arms in terms of secondary toxicity endpoints.

Participants

The clinical trial involves a total of **38 participants** diagnosed with **generalized mantle cell lymphoma**. The study population includes both male and female subjects, aged between **18 and 65 years**, who are in generally good health as indicated by an **ECOG/WHO performance status** of 2 or less. Participants were selected based on specific criteria, including a histologically confirmed diagnosis of mantle cell lymphoma, suitability for high-dose treatment, and the presence of at least one measurable lesion. The trial does not include a vulnerable population. Participants are required to adhere to certain lifestyle considerations, such as the use of effective contraceptive methods for sexually active individuals of child-bearing potential. The trial excludes individuals with prior treatment for mantle cell lymphoma and those with significant laboratory abnormalities unrelated to the condition. The selection process ensures that participants are suitable for the study's high-dose treatment regimen, including high-dose Ara-C.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of different treatment regimens in patients with **generalized mantle cell lymphoma**. This is a randomized, controlled, and double-blind study, aiming to establish one of three study arms as the future standard based on the comparison of investigator-assessed failure-free survival (FFS). The trial includes a control arm (R-CHOP/R-DHAP followed by autologous stem cell transplantation (ASCT)) and two experimental arms (R-CHOP+ibrutinib/R-DHAP followed by ASCT and ibrutinib maintenance, and R-CHOP+ibrutinib/R-DHAP followed by ibrutinib maintenance). The trial is expected to run from October 2016 to October 2026, with participant involvement lasting up to 30 months.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed diagnosis of mantle cell lymphoma, age between 18 and 65 years, and suitable laboratory values. Follow-up visits will be scheduled to monitor treatment response and safety, with assessments including overall survival, progression-free survival, and response rates. The end-of-study visit will conclude the participant's involvement, evaluating the primary endpoint of FFS and secondary endpoints such as overall survival and adverse event rates.

Participants are expected to remain in the study for the full duration unless conditions arise that necessitate early termination, such as the development of stable disease at the end of immuno-chemotherapy, progressive disease, or any cause of death. The trial will adhere to strict eligibility criteria, including the requirement for participants to use effective contraceptive methods during and after the study period. The study will ensure compliance with ethical standards, including obtaining written informed consent from all participants.

Treatment

The clinical trial involves the use of **Ibrutinib**, a chemical-origin medication, as part of the experimental treatment regimen. **Ibrutinib** is administered in an oral pharmaceutical form, identified by the code PHF00082MIG. The maximum daily dose of **Ibrutinib** is 560 mg, with a total maximum dose of 441,000 mg over the course of the treatment period. The treatment duration is capped at 30 days. **Ibrutinib** is utilized in two experimental arms of the study: one involving R-CHOP plus **Ibrutinib** followed by R-DHAP and autologous stem cell transplantation (ASCT) with **Ibrutinib** maintenance, and the other involving R-CHOP plus **Ibrutinib** followed by R-DHAP with **Ibrutinib** maintenance.

The study also includes a control arm, which consists of the standard-of-care therapy R-CHOP followed by R-DHAP and ASCT without the addition of **Ibrutinib**. This arm serves as a comparator to evaluate the efficacy of the experimental treatments. The trial aims to establish one of the three study arms as the future standard based on the comparison of investigator-assessed failure-free survival (FFS).

Efficacy

Efficacy in the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **failure-free survival (FFS)**, defined as the time from randomization to stable disease at the end of immuno-chemotherapy, progressive disease, or death from any cause. Secondary endpoints include overall survival (OS), progression-free survival (PFS) from randomization, from the end of induction immuno-chemotherapy in patients with complete response (CR) or partial response (PR) at the end of induction, and from the staging 6 weeks after the end of induction assessment (at month 6). Additionally, overall response and complete remission rates will be evaluated at midterm, at the end of induction, and 3 months after the end of induction immuno-chemotherapy (at month 6). The conversion rate from PR to CR during follow-up after the end of induction immuno-chemotherapy will also be assessed.

Other secondary endpoints include the rates of adverse events (AEs), serious adverse events (SAEs), and suspected unexpected serious adverse reactions (SUSARs) by Common Terminology Criteria (CTC) grade (Version 4.03) during induction immuno-chemotherapy and during follow-up periods after response to immune-chemotherapy. Cumulative incidence rates of secondary primary malignancies (SPMs) will also be monitored. These efficacy parameters will be collected and analyzed at specified timepoints throughout the trial to determine the effectiveness of the treatment regimens being studied.

Inclusion and Exclusion Criteria

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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/- 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
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

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Exclusion Criteria

Major surgery within 4 weeks prior to randomization.
Previous lymphoma therapy with radiation, cytostatic drugs, anti-CD20 antibody or interferon except prephase therapy according to 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 (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)
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
Requires anticoagulation with warfarin or equivalent vitamin K antagonists (e.g. phenprocoumon).
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.
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

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Belgium	Not Recruiting	01 Oct 2016	14
Czechia	Not Recruiting	01 Oct 2016	16
Denmark	Not Recruiting	01 Oct 2016	33
Finland	Not Recruiting	01 Oct 2016	2
Germany	Not Recruiting	01 Oct 2016	286
Italy	Not Recruiting	01 Oct 2016	206
The Netherlands	Not Recruiting	01 Oct 2016	—
Norway	Not Recruiting	01 Oct 2016	18
Poland	Not Recruiting	01 Oct 2016	38
Portugal	Not Recruiting	01 Oct 2016	4