Venetoclax in combination with the BTK inhibitor Ibrutinib and Rituximab or conventional chemotherapy (Bendamustine) and Ibrutinib and Rituximab in patients with treatment naive Mantle Cell Lymphoma not eligible for high dose therapy
- Trial ID
- 2022-501808-96-00
- Protocol
- 20-01434
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this clinical study is to evaluate the **efficacy** of two treatment regimens in patients with treatment-naive **Mantle Cell Lymphoma** who are not eligible for high-dose therapy. The primary endpoint is Failure-Free Survival (FFS) at 30 months. This measure is clinically relevant as it provides insight into the duration patients remain free from treatment failure, which is critical for assessing the long-term effectiveness of the treatment options.
Secondary objectives include:
- Failure-free survival with continuous observation
- Progression-free survival
- Complete Remission rate (CR) and overall response rate (ORR: CR, PR) four weeks after the end of induction therapy
- Best response, time to best response, and time to first response
- Overall survival
- Overall survival of patients divided according to geriatric categories and treatment received
- Safety: adverse events and tolerability
- Quality of life during induction and maintenance therapy, assessed using the EORTC QLQ-C30 and the EORTC QLQ-NHL-HG29
- Molecular remission after induction and conversion during maintenance (exploratory)
- Immune reconstitution, including the persistence of anti-Covid19 immunity
- Safety and efficacy in different geriatric categories
These secondary objectives aim to provide a comprehensive evaluation of the treatment's impact on various clinical outcomes, including survival rates, response to therapy, safety, and quality of life, which are essential for understanding the broader implications of the treatment regimens in this patient population.
Participants
The clinical trial involves participants diagnosed with **Mantle Cell Lymphoma**. The study population includes both male and female subjects, with an age range primarily focused on individuals aged 60 years and older. Participants are required to have a histologically confirmed diagnosis of Mantle Cell Lymphoma according to the WHO classification and must not have received prior treatment for stages II-IV of the disease. The trial does not include a vulnerable population. Participants are expected to have a general health status that allows for an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, with specific laboratory criteria such as creatinine levels ≤ 2 mg/dL and an absolute neutrophil count (ANC) of at least 1000 cells/μL. The trial population was selected based on these criteria, ensuring that participants have at least one measurable lesion or, in cases of bone marrow infiltration, mandatory bone marrow aspiration and biopsy for staging evaluations. The sponsor has not provided information regarding the total number of participants in the study.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **venetoclax** in combination with the BTK inhibitor **ibrutinib** and **rituximab**, or conventional chemotherapy with **bendamustine**, **ibrutinib**, and **rituximab** in patients with treatment-naive Mantle Cell Lymphoma (MCL) who are not eligible for high-dose therapy. This is a Phase II, randomized, double-blind, controlled trial with an estimated duration extending until September 2028. The primary objective is to assess failure-free survival at 30 months, with secondary endpoints including progression-free survival, complete remission rate, overall response rate, and quality of life assessments.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed MCL, specific laboratory values, and performance status. Following randomization, participants will attend regular follow-up visits to monitor treatment response and safety, with assessments including imaging, laboratory tests, and quality of life questionnaires. The end-of-study visit will occur after the completion of the treatment period or upon early termination.
The expected length of participant involvement is up to 840 days, depending on the treatment arm and individual response. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. Participants will receive either oral or intravenous administration of the investigational products, with dosing regimens tailored to the specific treatment arm. The trial will adhere to ethical guidelines and regulatory requirements, ensuring the safety and well-being of all participants throughout the study duration.
Treatment
The clinical trial involves the administration of several **experimental medications** and non-experimental treatments to evaluate their efficacy in patients with treatment-naive Mantle Cell Lymphoma. The primary experimental medication is **Venetoclax**, a chemical compound provided in the form of a film-coated tablet. Venetoclax is administered orally with a maximum daily dose of 50 mg, and the total dose can reach up to 350 mg over a treatment period of 7 days. The pharmaceutical sponsor for Venetoclax is AbbVie Deutschland GmbH & Co. KG, and it is identified by the sponsor product code ABT-199.
Another experimental medication used in the trial is **Ibrutinib**, marketed as IMBRUVICA 140 mg hard capsules. Ibrutinib is also a chemical compound and is administered orally. The maximum daily dose is 560 mg, with a total dose of up to 470,400 mg over a treatment period of 840 days. The pharmaceutical sponsor for Ibrutinib is Janssen-Cilag International NV.
The trial also includes the administration of **Bendamustine**, a chemical compound provided for intravenous infusion. The maximum daily dose of Bendamustine is 90 mg/m², with a total dose of up to 1080 mg/m² over a treatment period of 168 days. Bendamustine serves as a comparator treatment in the study.
**Rituximab** is another non-experimental treatment used in the trial, provided for intravenous infusion. Rituximab is a protein-based compound with a maximum daily dose of 375 mg/m² and a total dose of up to 6750 mg/m² over a treatment period of 840 days. Rituximab is used in combination with other treatments to evaluate its efficacy in the study.
Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to assess the failure-free survival at 30 months in both treatment arms, providing valuable insights into the efficacy of these therapeutic combinations in patients with Mantle Cell Lymphoma.
Efficacy
The clinical trial aims to assess the efficacy of treatment regimens in patients with treatment-naive Mantle Cell Lymphoma who are not eligible for high-dose therapy. The primary endpoint for evaluating efficacy is **Failure-Free Survival (FFS)** at 30 months. Secondary endpoints include continuous observation of failure-free survival, progression-free survival, complete remission rate (CR), overall response rate (ORR), best response, time to best response, time to first response, overall survival, and overall survival of patients divided according to geriatric categories and treatment received. Additionally, safety and tolerability, quality of life during induction and maintenance therapy, molecular remission after induction, immune reconstitution, and safety and efficacy in different geriatric categories will be assessed.
Efficacy parameters will be measured and collected at specified timepoints, including four weeks after the end of induction therapy. The quality of life will be assessed using the EORTC QLQ-C30 and the EORTC QLQ-NHL-HG29 instruments. The trial is designed to provide comprehensive data on the efficacy and safety of the treatment regimens, with a focus on both clinical outcomes and patient-reported outcomes. The trial is expected to conclude by September 30, 2028, with recruitment having started on March 31, 2023.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Histologically confirmed diagnosis of MCL according to WHO classification
- previously untreated stage II-IV (Ann Arbor), previous local therapyi e.g. radiation therapy to single lesion is eligible, a limited pre-phase treatment with steroids for patients at need is allowed (s. treatment)
- ≥ 60 years and not suitable for autologous SCT
- At least 1 measurable lesion; in case of bone marrow infiltration only, bone marrow aspiration and biopsy is mandatory for all staging evaluations.
- ECOG performance status ≤ 2
- Absolute neutrophil count (ANC) ≥ 1000 cells/μL
- Platelets ≥75.000 cells/μL
- Transaminases (AST and ALT) ≤3 x ULN
- Total bilirubin ≤ 2 x ULN unless other reason known (Gilbert- Meulengracht-Syndrome)
- Creatinine ≤ 2 mg/dL or eGFR ≥ 50 mL/min
- Written informed consent form according to ICH/EU GCP and national regulations
- Sexually active men with female partners of child-bearing potential potential must agree to use highly effective contraceptives
Exclusion Criteria
- Major surgery within 4 weeks prior to first dose
- Patients with unresolved hepatitis B or C infection or known HIV positive infection (mandatory test) Concomitant or previous malignancies within the last 3 years other than basal cell skin cancer, Prostate cancer in remission with PSA within normal range or in situ uterine cervix cancer
- Requires anticoagulation with warfarin or equivalent vitamin K antagonists (e.g. phenprocoumon)
- History of stroke or intracranial hemorrhage within 6 months prior to first dose
- Treatment with strong or moderate CYP3A4/5 inhibitors/inducers within 7 days before first dose and during Venetoclax and Ibrutinib intake
- 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 first dose
- Known CNS involvement of MCL
- Known bleeding disorder (e.g. von Willebrand disease; hemophilia) 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)
- Patients requiring double platelet inhibition, e.g due to cardiovascular intervention
- clinically significant pulmonary dysfunction interfering with the conduct of the trial treatment
- any other significant medical condition interfering with the conduct of the trial treatment
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Recruiting | 31 Mar 2023 | 150 |
 Italy | Recruiting | 31 Mar 2023 | 85 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Venetoclax | Test | FILM-COATED TABLET | ORAL USE | 50 | 7 | PRD2186235 |
BENDAMUSTINE | Other | PHF00016MIG | INTRAVENOUS INFUSION | 90 | 168 | SCP60142978 |
Venetoclax | Test | FILM-COATED TABLET | ORAL USE | 400 | 826 | PRD2186236 |
IMBRUVICA 140 mg hard capsules | Test | HARD CAPSULES | ORAL USE | 560 | 840 | PRD1729393 |
RITUXIMAB | Other | PHF00230MIG | INTRAVENIOUS INFUSION | 375 | 840 | SCP24437829 |
Venetoclax | Test | FILM-COATED TABLET | ORAL USE | 20 | 7 | PRD2186234 |