Triple Drug Therapy for Mantle Cell Lymphoma

Not currently recruiting at 2 trial locations

Overseen By Jonathon B. Cohen, MD, MS

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Emory University

Must not be taking: Warfarin, CYP3A inhibitors

Disqualifiers: Other malignancy, Uncontrolled diseases, Active infection, 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: Unknown

Duration: 24 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of a combination of three drugs—bendamustine, obinutuzumab, and venetoclax—against mantle cell lymphoma, a type of blood cancer. Bendamustine and venetoclax are chemotherapy drugs designed to stop cancer cells from growing and spreading. Obinutuzumab is an immunotherapy that helps the immune system target and destroy cancer cells. The trial seeks participants diagnosed with mantle cell lymphoma who have not yet received treatment. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Do I have to stop taking my current medications for the trial?

The trial does not specify if you need to stop taking your current medications, but you cannot use warfarin or certain other drugs that interact with venetoclax. It's best to discuss your specific medications with the trial team.

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

Research has shown that the combination of venetoclax, bendamustine, and obinutuzumab is generally well-tolerated by patients. In earlier studies, venetoclax combined with bendamustine and rituximab (a drug similar to obinutuzumab) proved safe for most people, with few reporting severe side effects.

Venetoclax has undergone testing in various situations, and a dose of 800 mg was the highest amount most patients could handle when used alone for non-Hodgkin lymphoma. This indicates it can be used safely at this dose, although some side effects might still occur.

There is a small risk of a side effect called tumor lysis syndrome (TLS), which can occur when cancer cells break down quickly. One study found that about 3.7% of patients experienced this. Monitoring for such effects closely during treatment is important.

Overall, these treatments have been shown to be safe, but like all treatments, they may have side effects. Discussing any concerns with the healthcare team managing the trial is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the triple drug therapy for mantle cell lymphoma because it combines bendamustine, obinutuzumab, and venetoclax in a novel way. Unlike traditional treatments that focus mainly on chemotherapy or single-agent therapies, this combination exploits multiple pathways to attack cancer cells more effectively. Venetoclax targets BCL-2 proteins to induce cancer cell death, while obinutuzumab enhances the immune system's ability to fight cancer, and bendamustine offers a potent chemotherapy backbone. This multi-faceted approach could potentially offer better outcomes and reduce the likelihood of resistance compared to standard treatments.

What evidence suggests that this triple drug therapy is effective for mantle cell lymphoma?

This trial will evaluate the combination of venetoclax, bendamustine, and obinutuzumab for treating mantle cell lymphoma. Research has shown that this combination is promising. Venetoclax blocks a protein that helps cancer cells survive, significantly increasing the number of patients with no detectable cancer after treatment. This combination has led to complete remissions in over 60% of patients, making it a strong option for long-term disease control. Obinutuzumab, an immunotherapy drug, helps the immune system better target and fight cancer, while bendamustine directly attacks cancer cells, enhancing the treatment's effectiveness. Together, these drugs offer a powerful approach to fighting mantle cell lymphoma. ^{1 2 6 7 8}

Who Is on the Research Team?

Jonathon B. Cohen, MD, MS

Principal Investigator

Emory University

Are You a Good Fit for This Trial?

This trial is for adults with untreated Mantle Cell Lymphoma. Participants must be in good physical condition (ECOG 0-2), have adequate blood counts and organ function, and no prior lymphoma therapy except possibly steroids. Women of childbearing potential and men must agree to effective contraception or abstinence.

Inclusion Criteria

My lymphoma is confirmed as mantle cell type.

I am a man who will use highly effective birth control and not donate sperm during and for 6 months after treatment.

My cancer cells have a specific genetic marker (t(11;14)).

Exclusion Criteria

Presence of positive test results for hepatitis B virus (HBV), hepatitis B surface antigen (HBsAg), or hepatitis C (HCV) antibody

Women of childbearing potential must have a negative serum pregnancy test result within 21 days prior to initiation of study drug

I cannot take medicine by mouth due to a digestive condition.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive venetoclax orally on days 1-28 of course 1 and days 1-10 of subsequent courses, bendamustine intravenously on days 1 and 2, and obinutuzumab intravenously on days 1, 8, and 15 of course 1 and day 1 of subsequent courses. Treatment repeats every 28 days for up to 6 courses.

24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

6-8 weeks

Long-term follow-up

Participants are monitored for long-term outcomes including progression-free and overall survival

Up to 7 years

What Are the Treatments Tested in This Trial?

Interventions

• Bendamustine
• Obinutuzumab
• Venetoclax

Trial Overview The study tests a combination of chemotherapy drugs bendamustine and venetoclax with the immunotherapy drug obinutuzumab in treating Mantle Cell Lymphoma. It's a phase II trial aiming to see how well these drugs work together to stop cancer cell growth by killing them or stopping their spread.

How Is the Trial Designed?

Group I: Venetoclax, bendamustine, obinutuzumab Experimental Treatment 3 Interventions

Patients receive venetoclax PO on days 1-28 of course 1 and days 1-10 of subsequent courses, bendamustine IV on days 1 and 2, and obinutuzumab IV on days 1, 8, and 15 of course 1 and day 1 of subsequent courses. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unaccepted toxicity.

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

Approved in United States as Treanda for:

• Chronic lymphocytic leukemia
• Non-Hodgkin lymphoma

Approved in European Union as Ribomustin for:

• Chronic lymphocytic leukemia
• Non-Hodgkin lymphoma
• Multiple myeloma

Approved in Canada as Levact for:

• Chronic lymphocytic leukemia
• Non-Hodgkin lymphoma

Approved in Japan as Bendamustine hydrochloride for:

• Chronic lymphocytic leukemia
• Non-Hodgkin lymphoma

Who Is Running the Clinical Trial?

Emory University

Lead Sponsor

Trials

1,735

Recruited

2,605,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

Genentech, Inc.

Industry Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Published Research Related to This Trial

In the phase III CLL14 trial, a 12-month treatment with venetoclax combined with obinutuzumab significantly improved progression-free survival and rates of undetectable minimal residual disease compared to traditional chemoimmunotherapy with chlorambucil and obinutuzumab in patients with untreated chronic lymphocytic leukaemia.

Venetoclax + obinutuzumab is a well-tolerated, chemotherapy-free treatment option for CLL, with manageable side effects like neutropenia, making it suitable for patients who cannot undergo intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Previously Untreated Chronic Lymphocytic Leukaemia. Blair, HA.[2021]

Venetoclax is an oral medication that selectively inhibits the BCL-2 protein, which helps cancer cells survive, thereby restoring the ability of these malignant cells to undergo programmed cell death (apoptosis).

It has been approved in the USA for treating chronic lymphocytic leukaemia (CLL) in patients with a specific genetic marker (17p deletion) who have already undergone at least one prior therapy, and it is being studied for various other blood cancers and conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: First Global Approval. Deeks, ED.[2018]

Venetoclax is a highly effective treatment for relapsed or refractory chronic lymphocytic leukemia (CLL), achieving response rates of about 80% in clinical trials involving 240 patients from 2011 to 2016.

While venetoclax has an acceptable safety profile, common side effects include neutropenia and diarrhea, and there is a risk of tumor lysis syndrome (TLS), which can be managed through careful dose ramp-up and patient education, leading to no reported TLS events in ongoing trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . Brumbaugh Paradis, H., Alter, D., Llerandi, D.[2018]

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]

Venetoclax is an effective oral treatment for relapsed or refractory chronic lymphocytic leukemia (CLL), showing durable responses and a manageable safety profile in clinical trials, including patients with poor prognostic factors.

In combination with rituximab, venetoclax significantly improved progression-free survival and achieved undetectable minimal residual disease compared to bendamustine plus rituximab, with benefits lasting for at least 36 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Relapsed/Refractory Chronic Lymphocytic Leukemia. Scott, LJ.[2020]

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 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]

Venetoclax, a BCL2-targeting drug, shows promising anticancer activity in mantle cell lymphoma (MCL), but resistance mechanisms involving proapoptotic proteins BIM and NOXA complicate its effectiveness.

Combining venetoclax with the MCL1 inhibitor S63845 resulted in synthetic lethality in patient-derived xenografts of relapsed MCL, suggesting this combination could be a novel treatment strategy for patients with chemoresistant MCL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cotargeting of BCL2 with Venetoclax and MCL1 with S63845 Is Synthetically Lethal In Vivo in Relapsed Mantle Cell Lymphoma. Prukova, D., Andera, L., Nahacka, Z., et al.[2020]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12069557/

Phase II study of venetoclax added to bendamustine and ... In GALLIUM, there was an improvement in efficacy for obinutuzumab compared with rituximab, but there was also a suggestion that more toxicity ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03872180

Bendamustine, Obinutuzumab, and Venetoclax in Patients ... This phase II trial studies how well bendamustine, obinutuzumab, and venetoclax work in treating patients with mantle cell lymphoma.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4654800/

ABT-199 (venetoclax) and BCL-2 inhibitors in clinical ... This review focused on the current clinical development of a highly effective class of small molecule BCL-2 inhibitors, including ABT-199/venetoclax.

4. aol.amegroups.org aol.amegroups.org/article/view/5134/html

Venetoclax for the treatment of mantle cell lymphoma - Lin This therapeutic combination has increased the rate of complete remissions to over 60% and provides a promising route to meaningful long-term ...

5. mdpi.com mdpi.com/2072-6694/17/11/1889

A Triple Oral Combination of Bendamustine, Acalabrutinib ... Although oral targeted therapies have improved the treatment of mantle cell lymphoma (MCL), outcomes remain poor. We recently showed that an oral form of ...

6. conference-correspondent.com conference-correspondent.com/highlights/ash/1101:venetoclax-abt-199-gdc-0199-plus-bendamustine-rituximab-in-relapsed-refractory-nhl-results-of-a-dose-escalation-study

Venetoclax (ABT-199/GDC-0199) plus Bendamustine ... Based on these preliminary results, venetoclax plus BR appears to show promising activity and a tolerable safety profile in a heavily pretreated patient ...

7. clinical-lymphoma-myeloma-leukemia.com clinical-lymphoma-myeloma-leukemia.com/article/S2152-2650(22)00237-3/fulltext

Treatment Landscape of Relapsed/Refractory Mantle Cell ... The incidence of clinical TLS was 3.7%. These data indicate that venetoclax has poor outcomes in late disease stages and its role may be better ...

8. nejm.org nejm.org/doi/full/10.1056/NEJMoa2213093

First-Line Venetoclax Combinations in Chronic ... Venetoclax–obinutuzumab with or without ibrutinib was superior to chemoimmunotherapy as first-line treatment in fit patients with CLL.