Combination Therapy for Mantle Cell Lymphoma

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: City of Hope Medical Center

Must not be taking: Warfarin, Strong CYP3A inhibitors

Disqualifiers: Illicit drug abuse, Organ transplant, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 63 days

50 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I/II trial tests the safety and effectiveness of glofitamab (with obinutuzumab pretreatment), venetoclax, and lenalidomide in treating patients with newly diagnosed, high risk mantle cell lymphoma. Glofitamab and obinutuzumab are monoclonal antibodies that may interfere with the ability of cancer cells to grow and spread. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Lenalidomide works by helping the immune system kill cancer cells and by helping the bone marrow to produce normal blood cells. Giving venetoclax, glofitamab with obinutuzumab, and lenalidomide together may kill more cancer cells in patients with newly diagnosed, high risk mantle cell lymphoma.

Will I have to stop taking my current medications?

The trial requires stopping certain medications, such as warfarin and strong or moderate CYP3A inhibitors or inducers, before starting the study drugs. If you are on these medications, you may need to stop them for a specific period before joining the trial. Please discuss your current medications with the study team to determine if any changes are needed.

What data supports the effectiveness of the drug combination therapy for Mantle Cell Lymphoma?

Research shows that adding venetoclax to lenalidomide and rituximab is safe and effective for untreated mantle cell lymphoma, with high response rates and durable remissions. Venetoclax has also been effective in relapsed mantle cell lymphoma, although resistance can develop. Additionally, venetoclax combined with obinutuzumab has shown improved outcomes in chronic lymphocytic leukemia, suggesting potential benefits in similar blood cancers. ^{1 2 3 4 5}

Is the combination therapy for Mantle Cell Lymphoma safe for humans?

Venetoclax, one of the drugs in the combination therapy, has been studied in various conditions and generally has a manageable safety profile. Common side effects include neutropenia (low white blood cell count), diarrhea, and fatigue, but these can often be managed with supportive care and dose adjustments. ^{1 5 6 7 8}

What makes the combination therapy for mantle cell lymphoma unique?

This combination therapy for mantle cell lymphoma is unique because it combines multiple drugs, including glofitamab, lenalidomide, obinutuzumab, and venetoclax, which target different aspects of the cancer cells, potentially leading to more effective treatment. Venetoclax, in particular, is a BCL-2 inhibitor that has shown promise in treating mantle cell lymphoma by targeting a protein that helps cancer cells survive. ^{2 4 9 10 11}

Research Team

Tycel J Phillips

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

This trial is for adults aged 18-80 with newly diagnosed, high-risk mantle cell lymphoma who haven't had cancer treatment before. Participants must be able to swallow pills, have certain blood counts and organ function levels, and agree to use effective birth control. People can't join if they've used certain drugs recently, have a history of other cancers or significant heart disease, active infections including hepatitis B/C or HIV, are pregnant/breastfeeding, or have CNS lymphoma.

Inclusion Criteria

Documented informed consent of the participant and/or legally authorized representative

Assent, when appropriate, will be obtained per institutional guidelines

My diagnosis of mantle cell lymphoma (MCL) is confirmed through specific tests.

Exclusion Criteria

I have not eaten grapefruit, Seville oranges, or star fruit in the last 3 days.

I am currently taking warfarin.

I am taking more than 30 mg/day of prednisone or its equivalent.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive venetoclax orally, obinutuzumab intravenously, glofitamab intravenously, and lenalidomide intravenously. Patients undergo bone marrow biopsy, blood sample collection, and CT/PET scans throughout the study.

Up to 63 days

Follow-up

Participants are monitored for safety and effectiveness after treatment. Follow-up includes monitoring every 3 months for the first two years, and then every 6 months starting in the third year until disease recurrence.

2 years

Treatment Details

Interventions

• Glofitamab
• Lenalidomide
• Obinutuzumab
• Venetoclax

Trial Overview The trial tests the combination of glofitamab (a monoclonal antibody), venetoclax (BCL-2 inhibitor), and lenalidomide in treating high-risk mantle cell lymphoma. It aims to see if this drug combo is safe and more effective than current treatments by stopping cancer cells from growing.

Participant Groups

Group I: Treatment (venetoclax, glofitamab, lenalidomide) Experimental Treatment 9 Interventions

Patients receive venetoclax PO, obinutuzumab IV, glofitamab IV, and lenalidomide IV on study. Patients undergo bone marrow biopsy, blood sample collection, and CT scan and/or PET scan throughout the study. Patients may undergo tumor biopsy throughout the study.

Glofitamab is already approved in United States for the following indications:

Approved in United States as COLUMVI for:

• Relapsed or refractory diffuse large B-cell lymphoma not otherwise specified (DLBCL), or large B-cell lymphoma (LBCL) arising from follicular lymphoma, after two or more lines of systemic therapy

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

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]

In a multicenter study of 28 patients with untreated mantle cell lymphoma (MCL), the combination of lenalidomide, rituximab, and venetoclax demonstrated a high overall response rate of 96% and a complete response rate of 86%, indicating strong efficacy for this treatment regimen.

The treatment was found to be safe, with no dose-limiting toxicities reported, although common side effects included neutropenia and thrombocytopenia, suggesting that this combination could be a promising option for patients who are ineligible for transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adding venetoclax to lenalidomide and rituximab is safe and effective in patients with untreated mantle cell lymphoma. Phillips, TJ., Bond, D., Takiar, R., et al.[2023]

In a study of 24 patients with relapsed mantle cell lymphoma (MCL) who had undergone multiple prior therapies, venetoclax treatment resulted in a 50% overall response rate and a 21% complete response rate, with a median follow-up of 17 months.

Genomic analysis revealed that resistance to venetoclax is linked to mutations in non-BCL2 genes, with specific alterations like SMARCA4 and KMT2C/D emerging after treatment progression, indicating a need for further research into combination therapies and the mechanisms of resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of venetoclax in high risk relapsed mantle cell lymphoma (MCL) - outcomes and mutation profile from venetoclax resistant MCL patients. Zhao, S., Kanagal-Shamanna, R., Navsaria, L., et al.[2020]

Bruton's tyrosine kinase inhibitors (BTKis) like ibrutinib, acalabrutinib, and zanubrutinib are effective as single-agent therapies for relapsed mantle cell lymphoma (MCL), but they have different toxicity profiles and dosing schedules, which is important for treatment planning.

CAR-T therapy, specifically brexucabtagene autoleucel, has been approved and shown to be highly effective for relapsed MCL, highlighting a significant advancement in treatment options for patients with this challenging condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relapsed Mantle Cell Lymphoma: Current Management, Recent Progress, and Future Directions. Bond, DA., Martin, P., Maddocks, KJ.[2023]

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 phase 2 study involving 49 adults with relapsed/refractory multiple myeloma, the combination of venetoclax, carfilzomib, and dexamethasone (VenKd) demonstrated an overall response rate of 80%, with even higher rates (92%) in patients with the t(11;14) genetic alteration.

The treatment was generally well tolerated, with a median progression-free survival of 22.8 months, although some patients experienced significant side effects, including diarrhea and fatigue.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 study of venetoclax plus carfilzomib and dexamethasone in patients with relapsed/refractory multiple myeloma. Costa, LJ., Davies, FE., Monohan, GP., et al.[2022]

In a phase 1/2 study involving 12 Japanese patients with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), venetoclax demonstrated a 100% objective response rate (ORR) in patients receiving monotherapy, with a complete remission (CR) rate of 17%.

When combined with rituximab, venetoclax achieved a 67% ORR and a 50% CR rate, indicating that both treatment strategies are effective and well-tolerated, with a safety profile consistent with previous studies in Western populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1/2 study of venetoclax, a BCL-2 inhibitor, in Japanese patients with relapsed or refractory chronic lymphocytic leukemia and small lymphocytic lymphoma. Izutsu, K., Yamamoto, K., Kato, K., et al.[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]

In a phase II study involving 8 patients with relapsed/refractory multiple myeloma, the combination of venetoclax, pomalidomide, and dexamethasone (VenPd) showed that 63% of patients had a confirmed response, with a median duration of response of 12.9 months.

The study highlighted significant safety concerns, as all patients experienced grade ≥ 3 adverse events, primarily neutropenia, indicating that while there may be efficacy, careful monitoring and dosing adjustments will be necessary in future trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase II Study of Venetoclax in Combination With Pomalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma. Gasparetto, C., Bowles, KM., Abdallah, AO., 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]

The maximum tolerated dose (MTD) of lenalidomide when combined with rituximab for treating relapsed or refractory mantle-cell lymphoma (MCL) was determined to be 20 mg, with the combination showing a manageable safety profile despite some grade 3-4 hematological toxicities.

In a phase 2 trial involving 44 patients, the combination therapy resulted in a 57% overall response rate, with 36% achieving a complete response and a median overall survival of 24.3 months, indicating its efficacy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenalidomide in combination with rituximab for patients with relapsed or refractory mantle-cell lymphoma: a phase 1/2 clinical trial. Wang, M., Fayad, L., Wagner-Bartak, N., et al.[2023]

References

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

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

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

Adding venetoclax to lenalidomide and rituximab is safe and effective in patients with untreated mantle cell lymphoma. [2023]

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

Efficacy of venetoclax in high risk relapsed mantle cell lymphoma (MCL) - outcomes and mutation profile from venetoclax resistant MCL patients. [2020]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Relapsed Mantle Cell Lymphoma: Current Management, Recent Progress, and Future Directions. [2023]

5. France pubmed.ncbi.nlm.nih.gov

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

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

Phase 2 study of venetoclax plus carfilzomib and dexamethasone in patients with relapsed/refractory multiple myeloma. [2022]

7. Japan pubmed.ncbi.nlm.nih.gov

Phase 1/2 study of venetoclax, a BCL-2 inhibitor, in Japanese patients with relapsed or refractory chronic lymphocytic leukemia and small lymphocytic lymphoma. [2021]

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

Venetoclax: First Global Approval. [2018]

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

A Phase II Study of Venetoclax in Combination With Pomalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma. [2022]

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

Cotargeting of BCL2 with Venetoclax and MCL1 with S63845 Is Synthetically Lethal In Vivo in Relapsed Mantle Cell Lymphoma. [2020]

11. England pubmed.ncbi.nlm.nih.gov

Lenalidomide in combination with rituximab for patients with relapsed or refractory mantle-cell lymphoma: a phase 1/2 clinical trial. [2023]