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

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, but you cannot take certain drugs that affect liver enzymes (CYP3A inhibitors or inducers) within one week before starting the trial treatment.

What data supports the effectiveness of the drug combination of Venetoclax, Lenalidomide, and Rituximab for treating Mantle Cell Lymphoma?

A study showed that adding Venetoclax to Lenalidomide and Rituximab was safe and effective for patients with untreated Mantle Cell Lymphoma, with 96% of patients responding to the treatment and 86% achieving complete response. ^{1 2 3 4 5}

Is the combination of Venetoclax, Lenalidomide, and Rituximab safe for humans?

The combination of Venetoclax, Lenalidomide, and Rituximab has been found to be safe in patients with untreated mantle cell lymphoma, with common side effects including low white blood cell counts (neutropenia) and low platelet counts (thrombocytopenia). Venetoclax, when used alone or with Rituximab, has also shown a manageable safety profile in patients with chronic lymphocytic leukemia. ^{1 3 4 6 7}

What makes the drug combination of Venetoclax, Lenalidomide, and Rituximab unique for treating Mantle Cell Lymphoma?

This drug combination is unique because it combines Venetoclax, a BCL-2 inhibitor, with Lenalidomide and Rituximab to enhance treatment effectiveness for untreated Mantle Cell Lymphoma, achieving high response rates and minimal residual disease undetectability, which is not commonly seen with other treatments. ^{1 3 4 7 8}

What is the purpose of this trial?

The purpose of this study is to determine if giving an experimental drug called venetoclax in combination with lenalidomide and rituximab is safe and effective for treating people with Mantle Cell Lymphoma (MCL).

Research Team

Tycel Phillips, M.D.

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

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

Pregnant or breastfeeding women

My cancer has spread to my brain or spinal cord.

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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 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]

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 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]

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]

References

1. 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]

2. 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]

3. France pubmed.ncbi.nlm.nih.gov

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

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

Addition of rituximab in relapsed/refractory chronic lymphocytic leukemia after progression on venetoclax monotherapy. [2022]

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

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

6. 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]

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

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . [2018]

8. England 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. [2018]