Venetoclax + Lenalidomide + Rituximab for Mantle Cell Lymphoma

Recruiting at 4 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: City of Hope Medical Center

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: Chemotherapy, Pregnancy, Cardiovascular disease, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 12 cycles

28 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether a combination of three drugs—venetoclax (a targeted therapy), lenalidomide, and rituximab—is safe and effective for treating Mantle Cell Lymphoma (MCL), a type of blood cancer. The researchers aim to determine if these drugs, when used together, can help manage or reduce MCL symptoms. This trial may suit individuals diagnosed with MCL who have not received prior chemotherapy for it and can swallow pills. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to contribute to groundbreaking research.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot take certain drugs that affect liver enzymes (CYP3A inhibitors or inducers) within one week before starting the trial treatment.

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

Research has shown that adding venetoclax to lenalidomide and rituximab is safe for patients with untreated Mantle Cell Lymphoma (MCL). Studies have found that this combination does not cause serious side effects requiring early discontinuation. Patients can take the full dose without major issues.

Overall, using these three drugs together is both safe and effective for treating MCL. This is encouraging for those considering joining a clinical trial to explore new treatment options. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment combination for mantle cell lymphoma because it brings together three powerful drugs: Venetoclax, Lenalidomide, and Rituximab. Unlike standard treatments, Venetoclax specifically targets and inhibits the BCL-2 protein, which helps cancer cells survive, potentially improving effectiveness. Lenalidomide not only fights cancer cells directly but also boosts the immune system, adding another layer of attack. Rituximab, already a staple in lymphoma treatment, works by targeting CD20 on B-cells, and when combined with the other drugs, it may enhance overall outcomes. This multi-drug approach aims to tackle the cancer from different angles, potentially leading to better results than current single or dual-drug therapies.

What evidence suggests that this trial's treatments could be effective for Mantle Cell Lymphoma?

Research has shown that using venetoclax, lenalidomide, and rituximab together, as studied in this trial, effectively treats mantle cell lymphoma (MCL). Studies have found this combination safe and effective for patients who have not previously received treatment for MCL. In some cases, venetoclax alone helped 40% of high-risk patients with recurrent MCL. It also works well against certain B-cell cancers, including MCL. This suggests that this drug combination could be very promising for managing the disease. ^{1 2 4 6 7}

Who Is on the Research Team?

Tycel Phillips, M.D.

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

This trial is for adults over 18 with untreated Mantle Cell Lymphoma, who are in relatively good health (ECOG ≤2), not pregnant or breastfeeding, and can take oral medication. They must join the Revlimid REMS® program, agree to pregnancy testing if applicable, use contraception, and have no recent strong drug interactions or other cancers within 2 years.

Inclusion Criteria

I agree to follow the pregnancy testing schedule as required.

My tests show I have mantle cell lymphoma.

I can swallow pills.

Exclusion Criteria

My cancer has spread to my brain or spinal cord.

Pregnant or breastfeeding women

I have had cancer before, but it was either skin cancer treated successfully, cervical cancer that did not spread, or any cancer I've been free from for 2+ years.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive venetoclax, lenalidomide, and rituximab. Rituximab is administered on specific days across multiple cycles, lenalidomide is given in varying doses across cycles, and venetoclax is administered with a ramp-up dose in cycle 1 and a consistent dose in cycles 2-12.

12 cycles

Multiple visits per cycle for drug administration

Follow-up

Participants are monitored for safety and effectiveness after treatment, with assessments including PET, CT scans, and bone marrow examinations.

Up to 4 years

What Are the Treatments Tested in This Trial?

Interventions

• Lenalidomide
• Rituximab
• Venetoclax

Trial Overview The study tests a combination of venetoclax with lenalidomide and rituximab for safety and effectiveness against MCL. Participants will receive this experimental treatment to see how well it works compared to current treatments.

How Is the Trial Designed?

Group I: Venetoclax, Lenalidomide, Rituximab Experimental Treatment 3 Interventions

Rituximab 375 mg/m2 IV day 1, 8, 15, 22 of 1st cycle then on day 1 for cycles 2, 4, 6, 8, 10, 12 Lenalidomide 10 mg day 1-7 of and 15 mg day 8-14 cycle #1. 20 mg PO day day 15-21 of cycle #1 and days 1-21 cycles 2-12. Venetoclax PO days 8 - 28 cycles during cycle 1 only. Starting with ramp-up dose as follows (50 mg x 7 days then 100mg x 7 days then 200 mg x 7 days then 400 mg for remainder of therapy). Will be given days 1-28 at a dose of 400 mg cycle 2-12.

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

Approved in European Union as Revlimid for:

• Multiple myeloma
• Myelodysplastic syndromes
• Mantle cell lymphoma
• Follicular lymphoma
• Marginal zone lymphoma

Approved in United States as Revlimid for:

• Multiple myeloma
• Myelodysplastic syndromes
• Mantle cell lymphoma
• Follicular lymphoma
• Marginal zone lymphoma

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

University of Michigan Rogel Cancer Center

Lead Sponsor

Trials

303

Recruited

20,700+

Published Research Related to This Trial

In a study of 323 patients with relapsed or refractory chronic lymphocytic leukemia (CLL), a daily dose of 400 mg of venetoclax resulted in a median progression-free survival (PFS) of 1.8 years.

The addition of 6 cycles of rituximab to venetoclax treatment significantly increased the median PFS to 3.9 years, demonstrating a synergistic effect that enhances treatment efficacy beyond increasing the venetoclax dose alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relationship between venetoclax exposure, rituximab coadministration, and progression-free survival in patients with relapsed or refractory chronic lymphocytic leukemia: demonstration of synergy. Freise, KJ., Jones, AK., Menon, RM., et al.[2018]

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]

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 involving 10 patients with relapsed/refractory chronic lymphocytic leukemia (CLL), the addition of rituximab to venetoclax therapy resulted in a 50% response rate, with three patients achieving complete responses and two achieving partial responses.

The combination treatment was well tolerated, suggesting that adding rituximab after progression on venetoclax may provide a beneficial option for some patients with R/R CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Addition of rituximab in relapsed/refractory chronic lymphocytic leukemia after progression on venetoclax monotherapy. Handunnetti, S., Anderson, MA., Roberts, AW., et al.[2022]

In the phase III AUGMENT trial, lenalidomide combined with rituximab significantly improved progression-free survival in patients with relapsed or refractory follicular lymphoma compared to placebo, showing particular benefit for elderly patients.

Lenalidomide has an acceptable safety profile, although it can cause more frequent cases of severe neutropenia, which can be managed with dosage adjustments and growth factor support.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenalidomide: A Review in Previously Treated Follicular Lymphoma. Blair, HA.[2021]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10425679/

Adding venetoclax to lenalidomide and rituximab is safe ... The combination of lenalidomide, rituximab, and venetoclax is a safe and effective regimen in patients with untreated MCL. This trial was registered at www.

2. ashpublications.org ashpublications.org/bloodadvances/article-abstract/doi/10.1182/bloodadvances.2023009992/495202/Adding-venetoclax-to-lenalidomide-and-rituximab-is

Adding venetoclax to lenalidomide and rituximab is safe and ... Adding venetoclax to lenalidomide and rituximab is safe and effective in patients with untreated mantle cell lymphoma Available. Clinical Trials & Observations.

3. sciencedirect.com sciencedirect.com/science/article/pii/S2473952923000952

A multicenter analysis of the outcomes with venetoclax ... In high-risk patients with relapsed MCL, most of whom received prior BTKi, venetoclax resulted in ORR of 40% and median PFS of 3.7 months.

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

Treatment Landscape of Relapsed/Refractory Mantle Cell ... In a recent retrospective study on 81 heavily-pretreated patients with R/R MCL, venetoclax was given as monotherapy in 62% of patients, among ...

5. nejm.org nejm.org/doi/full/10.1056/NEJMoa1715519

Ibrutinib plus Venetoclax for the Treatment of Mantle-Cell ... In a phase 1 study, venetoclax had greatest single-agent activity, among B-cell cancers, against chronic lymphocytic leukemia and mantle-cell ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10320213/

A multicenter analysis of the outcomes with venetoclax in ... In high-risk patients with relapsed MCL, most of whom received prior BTKi, venetoclax resulted in ORR of 40% and median PFS of 3.7 months.

7. clinicaltrials.gov clinicaltrials.gov/study/NCT03523975

Venetoclax, Lenalidomide and Rituximab in Patients With ... Adding venetoclax to lenalidomide and rituximab is safe and effective in patients with untreated mantle cell lymphoma. Blood Adv. 2023 Aug 22;7(16):4518 ...