Chemotherapy Combinations for Mantle Cell Lymphoma

Recruiting at 520 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: ECOG-ACRIN Cancer Research Group

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: Pregnancy, Active infections, Cardiac disease, 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: Unknown

Duration: 12-24 weeks

360 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that patients switch from proton pump inhibitors to an alternative drug before starting acalabrutinib. Additionally, patients must not take strong or moderate CYP3A inhibitors or inducers within 7 days before the first dose of the study drug. If you are on these medications, you may need to stop or switch them.

What data supports the effectiveness of the drug combination for mantle cell lymphoma?

Research shows that combining rituximab, bendamustine, and cytarabine is effective for treating mantle cell lymphoma, with high response rates and prolonged survival in patients. Additionally, bendamustine and rituximab together have been shown to be effective with a favorable safety profile in treating this type of lymphoma. ^{1 2 3 4 5}

Is the chemotherapy combination for mantle cell lymphoma safe for humans?

The combination of rituximab, bendamustine, and cytarabine has shown high activity but also high blood-related side effects in mantle cell lymphoma. Acalabrutinib, another drug in the combination, has been approved for mantle cell lymphoma and is considered to have minimal off-target effects, suggesting a favorable safety profile. ^{1 2 4 6 7}

What makes the chemotherapy combination of Acalabrutinib, Bendamustine, Cytarabine, and Rituximab unique for treating mantle cell lymphoma?

This treatment is unique because it combines Acalabrutinib, a newer drug that targets specific proteins in cancer cells, with a regimen of Bendamustine, Cytarabine, and Rituximab, which have shown effectiveness in mantle cell lymphoma but can have high toxicity. The inclusion of Acalabrutinib may offer a novel approach to enhance treatment efficacy while potentially managing side effects. ^{1 2 4 8 9}

What is the purpose of this trial?

This phase II trial compares three chemotherapy regimens consisting of bendamustine, rituximab, high dose cytarabine, and acalabrutinib and studies how well they work in treating patients with newly diagnosed mantle cell lymphoma. Drugs used in chemotherapy, such as bendamustine 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. Monoclonal antibodies, such as rituximab, may interfere with the ability of cancer cells to grow and spread. Acalabrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. This study is being done to find out if one the drug combinations of bendamustine, rituximab, high dose cytarabine, and acalabrutinib is better or worse than the usual approach for mantle cell lymphoma.

Research Team

Nina D Wagner-Johnston

Principal Investigator

ECOG-ACRIN Cancer Research Group

Eligibility Criteria

This trial is for adults with newly diagnosed mantle cell lymphoma. Participants should be in good physical condition (ECOG score 0-2), have acceptable blood counts, liver and kidney function, and not be pregnant or breastfeeding. They must agree to use contraception and cannot have certain heart conditions, active infections, bleeding disorders, severe allergies to the drugs being tested, or be on specific medications that affect drug metabolism.

Inclusion Criteria

You are not eligible for the study if you have any of the following conditions: problems with absorbing nutrients, a history of bleeding disorders or anemia, autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura that is not under control, taking blood thinners such as warfarin within 7 days of starting the study drug, significant cerebrovascular disease or events within 6 months before starting the study drug, active infections that are not responding to treatment, severe allergic reaction to similar drugs like rituximab, bendamustine, cytarabine, or acalabrutinib.

My heart function is classified as class 2B or better, despite any history of heart issues or treatments.

I haven't taken strong or moderate CYP3A inhibitors or inducers in the last week.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive one of three chemotherapy regimens: bendamustine, rituximab, and cytarabine; bendamustine, rituximab, cytarabine, and acalabrutinib; or bendamustine, rituximab, and acalabrutinib. Treatment cycles repeat every 28 days.

12-24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up occurs every 3 months for 3 years, then every 6 months until year 10.

10 years

Treatment Details

Interventions

• Acalabrutinib
• Bendamustine
• Cytarabine
• Rituximab

Trial Overview The study compares three chemotherapy regimens using bendamustine, rituximab, high dose cytarabine, and acalabrutinib to see which works best for treating mantle cell lymphoma. It aims to determine if these combinations are more effective than current treatments by stopping cancer cells from growing.

Participant Groups

Group I: Arm C (acalabrutinib, bendamustine, rituximab) Experimental Treatment 4 Interventions

Patients receive acalabrutinib PO BID on days 1-28, bendamustine IV on days 1 and 2, and rituximab IV on day 1 or 2. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

Group II: Arm B (acalabrutinib, bendamustine, rituximab, cytarabine) Experimental Treatment 5 Interventions

Patients receive PO BID on days 1-28, bendamustine IV on days 1 and 2, and rituximab IV on day 1 or 2. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Beginning cycle 4, patients receive acalabrutinib PO BID on days 1-7 and 22-28, rituximab IV on day 1, and cytarabine IV Q12 hours on days 1 and 2. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity.

Group III: Arm A (bendamustine, rituximab, cytarabine) Experimental Treatment 4 Interventions

Patients receive bendamustine IV on days 1 and 2 and rituximab IV on day 1 or 2. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Beginning cycle 4, patients receive rituximab IV on day 1 and cytarabine IV every Q12 hours on days 1 and 2. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity.

Acalabrutinib is already approved in United States, European Union for the following indications:

Approved in United States as Calquence for:

• Mantle cell lymphoma
• Chronic lymphocytic leukemia
• Small lymphocytic lymphoma

Approved in European Union as Calquence for:

• Chronic lymphocytic leukemia
• Small lymphocytic lymphoma
• Mantle cell lymphoma

Who Is Running the Clinical Trial?

ECOG-ACRIN Cancer Research Group

Lead Sponsor

Trials

122

Recruited

160,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

The RBAC500 regimen, which combines rituximab, bendamustine, and low-dose cytarabine, showed a high efficacy in treating elderly patients with mantle cell lymphoma, with 91% of patients achieving a complete response after treatment.

While the treatment did not meet the predefined safety criteria due to manageable hematological toxicities, such as neutropenia and thrombocytopenia, it was deemed effective and safe enough to warrant further investigation in phase 3 trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab, bendamustine, and low-dose cytarabine as induction therapy in elderly patients with mantle cell lymphoma: a multicentre, phase 2 trial from Fondazione Italiana Linfomi. Visco, C., Chiappella, A., Nassi, L., et al.[2018]

The combination of bendamustine and rituximab (BR) showed a high overall response rate of 90% in 63 patients with mantle cell or low-grade lymphomas, with a complete remission rate of 60%.

The median progression-free survival was 24 months, indicating that BR is an effective treatment option for patients in their first to third relapse or refractory to previous treatments, although myelosuppression was noted as a significant side effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bendamustine plus rituximab is effective and has a favorable toxicity profile in the treatment of mantle cell and low-grade non-Hodgkin's lymphoma. Rummel, MJ., Al-Batran, SE., Kim, SZ., et al.[2022]

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]

Acalabrutinib (Calquence®) has received accelerated approval from the US FDA for treating mantle cell lymphoma, based on promising results from a phase II study.

Phase III trials are currently ongoing for acalabrutinib in mantle cell lymphoma and chronic lymphocytic leukaemia, indicating its potential for broader application in treating hematological cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib: First Global Approval. Markham, A., Dhillon, S.[2018]

Acalabrutinib demonstrated significantly higher overall response rates (ORR) and complete response (CR) rates compared to other targeted therapies for relapsed/refractory mantle cell lymphoma (MCL), indicating its efficacy in treating this condition.

The safety profile of acalabrutinib was comparable or better than that of other monotherapies, although it did show increased risks of infection and anemia compared to certain combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Matching-adjusted Indirect Comparisons of the Efficacy and Safety of Acalabrutinib Versus Other Targeted Therapies in Relapsed/Refractory Mantle Cell Lymphoma. Telford, C., Kabadi, SM., Abhyankar, S., et al.[2021]

References

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

Rituximab, bendamustine, and low-dose cytarabine as induction therapy in elderly patients with mantle cell lymphoma: a multicentre, phase 2 trial from Fondazione Italiana Linfomi. [2018]

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

Combination of rituximab, bendamustine, and cytarabine for patients with mantle-cell non-Hodgkin lymphoma ineligible for intensive regimens or autologous transplantation. [2022]

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

Rituximab/bendamustine and rituximab/cytarabine induction therapy for transplant-eligible mantle cell lymphoma. [2022]

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

Bendamustine plus rituximab is effective and has a favorable toxicity profile in the treatment of mantle cell and low-grade non-Hodgkin's lymphoma. [2022]

5. 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]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Acalabrutinib: First Global Approval. [2018]

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

Matching-adjusted Indirect Comparisons of the Efficacy and Safety of Acalabrutinib Versus Other Targeted Therapies in Relapsed/Refractory Mantle Cell Lymphoma. [2021]

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

A phase 2 study of Rituximab-Bendamustine and Rituximab-Cytarabine for transplant-eligible patients with mantle cell lymphoma. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Bortezomib is synergistic with rituximab and cyclophosphamide in inducing apoptosis of mantle cell lymphoma cells in vitro and in vivo. [2015]