Ibrutinib + Rituximab + Chemotherapy for Mantle Cell Lymphoma

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Warfarin, Strong CYP3A inhibitors

Disqualifiers: Uncontrolled hypertension, Diabetes, HIV, Hepatitis, 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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 24

131 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot participate if you require treatment with strong CYP3A inhibitors or anticoagulation with warfarin. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug combination Ibrutinib, Rituximab, and Chemotherapy for Mantle Cell Lymphoma?

Research shows that Ibrutinib combined with Rituximab has shown promising results in treating mantle cell lymphoma, with studies indicating that this combination can lead to remission and reduce the need for extensive chemotherapy. Additionally, Ibrutinib with Bendamustine and Rituximab has shown clinical benefits in older patients with untreated mantle-cell lymphoma. ^{1 2 3 4 5}

Is the combination of Ibrutinib, Rituximab, and Chemotherapy safe for humans?

The combination of Ibrutinib, Rituximab, and Chemotherapy has been studied in patients with mantle cell lymphoma, showing some safety concerns. Ibrutinib can cause side effects like diarrhea, serious infections, bleeding issues, and heart problems such as irregular heartbeat. It's important to discuss these potential risks with your healthcare provider. ^{1 3 5 6 7}

How is the drug combination of Ibrutinib, Rituximab, and Chemotherapy unique for treating mantle cell lymphoma?

This treatment is unique because it combines Ibrutinib and Rituximab, which are targeted therapies, with chemotherapy to potentially reduce the amount of chemotherapy needed, aiming for remission with fewer side effects. This approach is different from traditional treatments that rely heavily on chemotherapy alone. ^{1 3 5 6 8}

What is the purpose of this trial?

This phase II trial studies how well ibrutinib, rituximab, and consolidation chemotherapy consisting of cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, dexamethasone, methotrexate, and cytarabine work in treating young patients with newly diagnosed mantle cell lymphoma. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as rituximab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, dexamethasone, methotrexate, and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving more than one drug (combination chemotherapy) may kill more cancer cells. Giving ibrutinib together with rituximab and consolidation chemotherapy may be a better treatment for mantle cell lymphoma.

Research Team

Luhua (Michael) Wang

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for young patients under 65 with newly diagnosed mantle cell lymphoma, who need immediate treatment and have measurable disease. They should be in good physical condition (ECOG <=2), have proper organ function, no serious medical conditions or active infections, and not be pregnant. High-risk factors like blastoid/pleomorphic variant or certain genetic mutations qualify them.

Inclusion Criteria

I am 65 years old or younger.

My cancer can be measured in two dimensions.

My biopsy shows I have mantle cell lymphoma with CD20 positive.

Exclusion Criteria

I have a serious medical condition.

I am HIV positive.

I have an active hepatitis B or C infection.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Ibrutinib Plus Rituximab

Patients receive ibrutinib orally once daily and rituximab intravenously over several hours. Treatment repeats every 28 days for up to 12 cycles.

Up to 48 weeks

Monthly visits for 12 cycles

Consolidation Therapy

Patients receive a combination of rituximab, dexamethasone, cyclophosphamide, doxorubicin, vincristine, methotrexate, and cytarabine. Treatment repeats every 28 days for up to 8 cycles.

Up to 32 weeks

Monthly visits for 8 cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

Up to 6 years

Every 4 months for 2 years, every 6 months for 2 years, then annually

Treatment Details

Interventions

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

Trial Overview The study tests a combination of the drug Ibrutinib with Rituximab and other chemotherapy drugs to see if they work better together for treating mantle cell lymphoma. It aims to block cancer growth enzymes, help the immune system attack cancer cells, and kill or stop cancer cells from dividing.

Participant Groups

Group I: Treatment (ibrutinib, rituximab, consolidation chemotherapy) Experimental Treatment 11 Interventions

PART I (IBRUTINIB PLUS RITUXIMAB): Patients receive ibrutinib PO QD on days 1-28 and rituximab IV over 6-8 hours on days 1, 8, 15, and 22 of cycle 1 and then over 4 hours on day 1 of cycles 3-12. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity or until patients achieve complete response. PART II (CONSOLIDATION THERAPY): 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; doxorubicin hydrochloride IV over 15-30 minutes on day 5; and vincristine sulfate IV over 15-30 minutes on day 5 of cycles 1, 3, 5, and 7. 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 and 4 of cycles 2, 4, 6, and 8. Treatment repeats every 28 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity.

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

Approved in European Union as Imbruvica for:

• Chronic lymphocytic leukemia
• Mantle cell lymphoma
• Waldenström's macroglobulinemia
• Marginal zone lymphoma
• Graft-versus-host disease

Approved in United States as Imbruvica for:

• Chronic lymphocytic leukemia/small lymphocytic lymphoma
• Mantle cell lymphoma
• Waldenström's macroglobulinemia
• Marginal zone lymphoma
• Graft-versus-host disease

Approved in Canada as Imbruvica for:

• Chronic lymphocytic leukemia
• Mantle cell lymphoma
• Waldenström's macroglobulinemia
• Marginal zone lymphoma

Approved in Japan as Imbruvica for:

• Chronic lymphocytic leukemia
• Mantle cell lymphoma
• Waldenström's macroglobulinemia

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+

Findings from Research

In a phase 2 trial involving 50 patients with relapsed or refractory mantle cell lymphoma, the combination of ibrutinib, lenalidomide, and rituximab resulted in a high overall response rate of 76%, with 56% achieving a complete response, suggesting this triplet therapy is effective.

While the treatment showed promising efficacy, it was associated with significant adverse events, including neutropenia in 38% of patients and three treatment-related deaths, highlighting the need for careful monitoring and further evaluation in randomized controlled trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib, lenalidomide, and rituximab in relapsed or refractory mantle cell lymphoma (PHILEMON): a multicentre, open-label, single-arm, phase 2 trial. Jerkeman, M., Eskelund, CW., Hutchings, M., et al.[2022]

In a phase 2 study involving 50 patients with relapsed or refractory mantle cell lymphoma, the combination of ibrutinib and rituximab resulted in an impressive 88% objective response rate, with 44% of patients achieving a complete response.

The treatment was generally well tolerated, with the most common serious side effect being atrial fibrillation in 12% of patients, indicating that while effective, monitoring for cardiac issues is important during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib in combination with rituximab in relapsed or refractory mantle cell lymphoma: a single-centre, open-label, phase 2 trial. Wang, ML., Lee, H., Chuang, H., et al.[2021]

Bruton's tyrosine kinase inhibitors, such as ibrutinib, acalabrutinib, and zanubrutinib, are effective and well-tolerated treatment options for patients with mantle cell lymphoma who have already undergone one line of therapy.

These inhibitors offer a promising alternative for patients who experience relapse or drug resistance after initial chemo-immunotherapy, highlighting the need for novel treatment strategies in this aggressive lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of Bruton's tyrosine kinase inhibitors in the management of mantle cell lymphoma. Hanna, KS., Campbell, M., Husak, A., et al.[2021]

In a network meta-analysis of three randomized controlled trials involving 1459 patients with newly diagnosed mantle-cell lymphoma (MCL) ineligible for intensive therapy, the combination of ibrutinib plus bendamustine and rituximab (Ibru + BR) significantly improved progression-free survival (PFS) compared to other regimens like VR-CAP and R-CHOP.

Ibru + BR had a 94.9% probability of being the best treatment option for prolonging PFS, with no significant differences in adverse events compared to the other treatment regimens, indicating its efficacy and safety for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Superiority of ibrutinib plus bendamustine and rituximab in newly diagnosed patients with mantle-cell lymphoma ineligible for intensive therapy: A network meta-analysis. Sheng, Z., Wang, L.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Ibrutinib, lenalidomide, and rituximab in relapsed or refractory mantle cell lymphoma (PHILEMON): a multicentre, open-label, single-arm, phase 2 trial. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Ibrutinib plus Bendamustine and Rituximab in Untreated Mantle-Cell Lymphoma. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Ibrutinib in combination with rituximab in relapsed or refractory mantle cell lymphoma: a single-centre, open-label, phase 2 trial. [2021]

4. Germany pubmed.ncbi.nlm.nih.gov

[scRNA-sequencing uncovers metabolism and CD52 as new targets in ibrutinib-surviving mantle cell lymphoma cells]. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Ibrutinib-rituximab followed by R-HCVAD as frontline treatment for young patients (≤65 years) with mantle cell lymphoma (WINDOW-1): a single-arm, phase 2 trial. [2022]

6. France pubmed.ncbi.nlm.nih.gov

Ibrutinib (Imbruvica). Relapsed chronic lymphocytic leukaemia and mantle cell lymphoma: uncertain impact on survival. [2021]

7. England pubmed.ncbi.nlm.nih.gov

The role of Bruton's tyrosine kinase inhibitors in the management of mantle cell lymphoma. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Superiority of ibrutinib plus bendamustine and rituximab in newly diagnosed patients with mantle-cell lymphoma ineligible for intensive therapy: A network meta-analysis. [2023]