Ibrutinib + Rituximab + Venetoclax + Chemo for Mantle Cell Lymphoma

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: Uncontrolled hypertension, Diabetes, HIV, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 30

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of drugs, including ibrutinib, rituximab, venetoclax, and chemotherapy, to evaluate their effectiveness in treating newly diagnosed mantle cell lymphoma. Mantle cell lymphoma affects white blood cells, and the trial seeks a more effective treatment strategy by combining these medications. Individuals newly diagnosed with mantle cell lymphoma who experience symptoms like large tumors or pain may be suitable candidates for this study. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group, providing an opportunity to contribute to advancements in treatment strategies.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot take certain medications like strong CYP3A inhibitors or inducers, and you should avoid grapefruit, Seville oranges, and star fruit within a few days before starting the trial. It's best to discuss your current medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that a combination of the drugs ibrutinib, rituximab, and venetoclax, with or without chemotherapy, is under study for safety in treating mantle cell lymphoma. Ibrutinib and rituximab together have slowed disease progression in older patients with this type of lymphoma.

Adding venetoclax has generally been well-tolerated. One study found that using venetoclax with lenalidomide and rituximab was safe and effective for patients who had not been treated before.

Chemotherapy drugs like cyclophosphamide, doxorubicin, vincristine, and methotrexate are well-known in cancer treatment. While they can cause side effects, they are commonly used in standard cancer care.

This trial is in Phase 2, indicating that the treatment showed promise in earlier studies. While this doesn't guarantee complete safety, it suggests the combination is safe enough for further testing. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of ibrutinib, rituximab, and venetoclax for treating Mantle Cell Lymphoma (MCL) because it offers a novel approach compared to traditional chemotherapy regimens. Unlike standard treatments that primarily use chemotherapy to target rapidly dividing cells, this combination includes targeted therapies like ibrutinib and venetoclax, which specifically disrupt cancer cell survival pathways and enhance the immune response. Ibrutinib blocks a key protein in cancer cell growth, while venetoclax targets proteins that prevent cancer cell death. This targeted strategy not only aims to be more effective but also potentially reduces the harsh side effects often associated with conventional chemotherapy, offering a more tailored and potentially tolerable treatment option for patients with MCL.

What evidence suggests that this trial's treatments could be effective for mantle cell lymphoma?

Research shows that combining ibrutinib, rituximab, and venetoclax holds promise for treating mantle cell lymphoma. Studies have found that this combination can lead to long-lasting responses and extended periods without treatment. In this trial, participants in Group I and Group II will receive ibrutinib, rituximab, and venetoclax along with chemotherapy, potentially enhancing their effectiveness in stopping tumor growth. Meanwhile, participants in Group III will receive ibrutinib, rituximab, and venetoclax without chemotherapy. Ibrutinib, when added to other cancer treatments, has been shown to help patients live longer without disease progression. Venetoclax blocks a protein that cancer cells need to survive, while rituximab helps stop cancer cells from growing and spreading. This combination is being studied as a potentially strong option for people with mantle cell lymphoma. ^{1 2 3 4 5}

Who Is on the Research Team?

Luhua (Michael) Wang

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with newly diagnosed mantle cell lymphoma who need treatment and have no prior therapy. They must be in good physical condition, not pregnant or breastfeeding, willing to use birth control, and free of serious medical conditions like uncontrolled hypertension or active infections.

Inclusion Criteria

Specific blood count requirements

My kidney function is above the required level.

My heart's pumping ability is within the normal range.

Exclusion Criteria

I do not have any uncontrolled health conditions.

I have not taken any medications or substances that are not allowed in the study recently.

I have had a recent infection.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Part I

Participants receive ibrutinib, rituximab, and venetoclax. Treatment repeats every 28 days for up to 12 cycles.

12 cycles (approximately 12 months)

Monthly visits for drug administration and monitoring

Treatment Part II - Combination Chemotherapy

Participants receive combination chemotherapy with rituximab, dexamethasone, cyclophosphamide, doxorubicin, vincristine, methotrexate, and cytarabine. Treatment repeats every 28 days for up to 4 cycles.

4 cycles (approximately 4 months)

Monthly visits for chemotherapy administration

Maintenance Therapy

Participants receive ibrutinib, venetoclax, and rituximab. Cycles repeat every 28 days for up to 24 months.

24 months

Bi-monthly visits for drug administration

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

Up to 5 years

Follow-up at 30 days, every 4 months for 2 years, every 6 months for 2 years, then annually

What Are the Treatments Tested in This Trial?

Interventions

• Cyclophosphamide
• Cytarabine
• Dexamethasone
• Doxorubicin Hydrochloride
• Ibrutinib
• Methotrexate
• Rituximab
• Venetoclax
• Vincristine Sulfate

Trial Overview The study tests a combination of drugs (ibrutinib, rituximab, venetoclax) with chemotherapy (cytarabine, cyclophosphamide, dexamethasone, methotrexate) against mantle cell lymphoma. It aims to see if this mix can better halt cancer growth compared to current treatments.

How Is the Trial Designed?

Group I: Group III (ibrutinib, rituximab, venetoclax) Experimental Treatment 3 Interventions

Patients receive ibrutinib, rituximab, venetoclax as in part I. Patients then receive maintenance therapy as in group I.

Group II: Group II (ibrutinib, rituximab, venetoclax, chemotherapy) Experimental Treatment 9 Interventions

Patients receive ibrutinib, rituximab, and venetoclax as in part I. Patients receive combination chemotherapy as in group I. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive maintenance therapy as in group I.

Group III: Group I (ibrutinib, rituximab, venetoclax, chemotherapy) Experimental Treatment 9 Interventions

Patients receive ibrutinib, rituximab, and venetoclax as described in part I. COMBINATION CHEMOTHERAPY: Patients receive rituximab IV over 6 hours on day 1, dexamethasone PO or IV on days 1-4, cyclophosphamide IV over 3 hours BID on days 2-4, and doxorubicin hydrochloride IV over 24 hours and vincristine sulfate IV over 15-30 minutes on day 5 of odd-numbered cycles (1 and 3). Patients also receive rituximab IV over 6 hours on day 1, methotrexate IV over 24 hours on day 2, and cytarabine IV over 2 hours BID on days 3-4 of even-numbered cycles (2 and 4). Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive ibrutinib and venetoclax PO QD on days 1-28, and rituximab IV over 4-8 hours on day 1 of every other month. Cycles repeat every 28 days for up to 24 months in the absence of disease progression or unacceptable toxicity.

Cyclophosphamide is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Cytoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in European Union as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Canada as Neosar for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Japan as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a phase 3 trial with 523 patients, the combination of ibrutinib and venetoclax significantly improved progression-free survival compared to the traditional FCR treatment, with only 12 patients experiencing disease progression or death in the ibrutinib-venetoclax group versus 75 in the FCR group.

The study also found that 65.9% of patients on ibrutinib-venetoclax achieved undetectable measurable residual disease (MRD) in bone marrow after 5 years, indicating effective disease control, although there was a higher incidence of serious cardiac adverse events in this group compared to FCR.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic Lymphocytic Leukemia Therapy Guided by Measurable Residual Disease. Munir, T., Cairns, DA., Bloor, A., et al.[2023]

The combination of venetoclax, ibrutinib, and obinutuzumab is well tolerated in patients with relapsed and untreated mantle cell lymphoma (MCL), with no dose-limiting toxicities reported and a maximum tolerated dose of 400 mg per day established for venetoclax.

High response rates were observed, with a complete response rate of 67% in relapsed patients and 86.6% in untreated patients, along with significant minimal residual disease clearance in 71.5% of relapsed and 100% of untreated patients after three cycles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib, obinutuzumab, and venetoclax in relapsed and untreated patients with mantle cell lymphoma: a phase 1/2 trial. Le Gouill, S., Morschhauser, F., Chiron, D., et al.[2021]

The combination of venetoclax with rituximab showed remarkable efficacy and a manageable safety profile in treating chronic lymphocytic leukemia (CLL), both in relapsed/refractory cases and as a first-line therapy for high-risk patients.

Similarly, the combination of ibrutinib with venetoclax also demonstrated striking efficacy, suggesting that these combinations could become new standard treatment options for CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic lymphocytic leukemia at ASH 2017. Wanner, D., Steurer, M.[2020]

In a safety run-in cohort of 21 patients with relapsed/refractory mantle cell lymphoma, the combination of ibrutinib and venetoclax showed an impressive overall response rate of 81%, with 62% achieving a complete response after a median follow-up of 31 months.

The study indicated that concurrent administration of ibrutinib and venetoclax is safe, with only three dose-limiting toxicities observed and no new safety concerns, allowing the trial to proceed without an ibrutinib lead-in.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concurrent ibrutinib plus venetoclax in relapsed/refractory mantle cell lymphoma: the safety run-in of the phase 3 SYMPATICO study. Wang, M., Ramchandren, R., Chen, R., et al.[2021]

In a retrospective analysis of 4 patients with relapsed/refractory mantle-cell lymphoma (MCL), the combination of ibrutinib and venetoclax resulted in a 50% complete response rate, demonstrating its potential efficacy as a treatment option.

All patients who responded to the treatment were able to undergo allogeneic stem cell transplantation, with two patients remaining in complete remission, indicating that this combination therapy may be a viable bridge to transplant for MCL patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib in association with venetoclax for the treatment of mantle-cell lymphoma: a multicenter case series. Fabbri, A., Cencini, E., Congiu, AG., et al.[2021]

The combination of venetoclax (VEN) and ibrutinib (IBR) showed a high overall response rate of 93.8% at the optimal dosing of VEN 200 mg and IBR 420 mg in treating relapsed mantle cell lymphoma (MCL) among 35 participants.

The study found that higher doses of VEN and IBR did not improve efficacy and were associated with increased toxicity, highlighting the importance of dose optimization in combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose-finding study of ibrutinib and venetoclax in relapsed or refractory mantle cell lymphoma. Portell, CA., Wages, NA., Kahl, BS., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03710772

Ibrutinib, Rituximab, Venetoclax, and Combination ... Giving ibrutinib, rituximab, and venetoclax together with combination chemotherapy may work better in treating patients with mantle cell lymphoma. Detailed ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S0140673625014321

Ibrutinib and rituximab versus immunochemotherapy in ... Ibrutinib, a Bruton tyrosine kinase inhibitor, prolongs progression-free survival when added to immunochemotherapy as first line treatment.

3. bmccancer.biomedcentral.com bmccancer.biomedcentral.com/articles/10.1186/s12885-025-14803-8

The MCL elderly III trial protocol: an international, randomized ... Ibrutinib plus venetoclax in relapsed or refractory mantle cell lymphoma (SYMPATICO): A.multicentre, randomised, double-blind, placebo ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12376325/

The MCL elderly III trial protocol: an international, randomized ... The MCL elderly III trial of the European MCL Network is an international phase II trial evaluating the efficacy of the combination of ibrutinib ...

5. ashpublications.org ashpublications.org/blood/article/144/8/867/515901/Seven-year-outcomes-of-venetoclax-ibrutinib

Seven-year outcomes of venetoclax-ibrutinib therapy in ... Seven-year outcomes of venetoclax-ibrutinib therapy in mantle cell lymphoma: durable responses and treatment-free remissions