Venetoclax + Lenalidomide + Rituximab for Non-Hodgkin's Lymphoma

Overseen By Ubaldo Martinez-Outschoorn, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Thomas Jefferson University

Must be taking: Aspirin

Must not be taking: Warfarin, CYP3A inhibitors

Disqualifiers: CNS involvement, Other malignancy, Infections, others

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

Compensation: Varies

Number of Visits: 12

Duration: 12 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the safest dose and potential side effects of a three-drug combination—venetoclax, lenalidomide, and rituximab—for treating certain types of non-Hodgkin's lymphoma that have returned or not responded to initial treatment. Venetoclax, a targeted therapy, attacks a protein that helps cancer cells survive, while lenalidomide and rituximab work with the immune system to attack cancer cells. Individuals with follicular or marginal zone lymphoma that has relapsed or resisted previous treatments might be suitable candidates. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

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 use warfarin or certain other drugs like strong CYP3A inhibitors or inducers. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

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

Research shows that combining venetoclax with lenalidomide and rituximab is generally safe for people with relapsed or non-responding follicular lymphoma. Studies have found that the most common side effects include low levels of white blood cells (neutropenia) and low levels of platelets (thrombocytopenia), which can impact the immune system and blood clotting. Despite these side effects, the treatment has been very successful. Specifically, one study found that 96% of patients responded to the treatment, and 86% had a complete response, meaning no cancer was detected.

Overall, while some side effects occur, many patients have tolerated the combination treatment well. Potential trial participants should discuss these findings with their healthcare provider to understand what this might mean for them. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this combination treatment for Non-Hodgkin's Lymphoma because it brings together three powerful drugs: venetoclax, lenalidomide, and rituximab. Unlike standard treatments, which often rely solely on rituximab or chemotherapy, this regimen includes venetoclax, which works differently by targeting and inhibiting a specific protein (BCL-2) that cancer cells need to survive. Additionally, the use of rituximab hyaluronidase allows for subcutaneous administration, potentially making the treatment more comfortable and convenient for patients compared to traditional intravenous infusions. This combination aims to enhance the effectiveness while possibly reducing side effects and improving patient quality of life.

What evidence suggests that this trial's treatments could be effective for relapsed or refractory non-Hodgkin's lymphoma?

Research has shown that combining venetoclax, lenalidomide, and rituximab can help treat certain types of non-Hodgkin lymphoma. Specifically, studies with mantle cell lymphoma found this combination to be safe and effective. Venetoclax blocks a protein that helps cancer cells survive, while lenalidomide and rituximab enhance the immune system's ability to fight cancer. In this trial, participants will receive this combination to halt cancer growth and potentially shrink tumors in patients whose lymphoma has returned or not responded to treatment. ^{1 2 3 5 6}

Who Is on the Research Team?

Ubaldo R Martinez-Outschoorn, MD

Principal Investigator

Thomas Jefferson University

Are You a Good Fit for This Trial?

This trial is for adults with certain slow-growing lymphomas, like follicular and marginal zone lymphoma, that have either returned after treatment or haven't responded to previous therapy. Participants must have had at least one prior systemic therapy, be able to swallow pills whole, take daily aspirin or equivalent for blood clot prevention, and meet specific health criteria.

Inclusion Criteria

I agree to follow the pregnancy testing schedule as required.

You must have a certain type of lymphoma and have visible disease on a CT scan with at least one lymph node larger than 1.5 cm.

I have a specific type of slow-growing lymphoma and have had at least one treatment.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive venetoclax, lenalidomide, and rituximab hyaluronidase in a dose-escalation study. Venetoclax is administered daily, lenalidomide starting from cycle 2, and rituximab in cycles 2, 4, 6, 8, 10, and 12.

12 months

Monthly visits for 12 cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up at 30 days and then for up to 5 years.

5 years

What Are the Treatments Tested in This Trial?

Interventions

• Lenalidomide
• Rituximab
• Rituximab and Hyaluronidase Human
• Venetoclax

Trial Overview The study tests a combination of three drugs: Venetoclax (which blocks proteins helping cancer cells survive), Lenalidomide (an immunotherapy that may alter the immune system to hinder tumor growth), and Rituximab/Hyaluronidase (antibodies aiming to boost the immune attack on cancer). The goal is to find safe doses for patients with relapsed/refractory low-grade lymphoma.

How Is the Trial Designed?

Group I: Treatment (venetoclax, lenalidomide, rituximab, hyaluronidase) Experimental Treatment 4 Interventions

Patient receive venetoclax PO QD on days 1-28. Beginning cycle 2, patients receive lenalidomide PO QD on days 1-21. Patients also receive rituximab IV on days 1, 8, 15, and 22 of cycle 2 and rituximab hyaluronidase (if no significant infusion reaction to rituximab) SC on day 1 of cycles 4, 6, 8, 10, and 12. Patients may receive rituximab IV (instead of rituximab hyaluronidase) on days 1, 8, 15, and 22 of cycles 4, 6, 8, 10, and 12 if the patient requires rituximab IV in the opinion of the treating physician. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

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?

Thomas Jefferson University

Lead Sponsor

Trials

475

Recruited

189,000+

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

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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 a phase I study involving 48 patients with relapsed or refractory multiple myeloma (RRMM), the combination of venetoclax with daratumumab and dexamethasone (VenDd) showed a remarkable overall response rate of 96%, indicating its strong efficacy, especially in patients with the t(11;14) translocation.

The combination of venetoclax with bortezomib, daratumumab, and dexamethasone (VenDVd) also demonstrated significant efficacy, with a 92% overall response rate, and an 18-month progression-free survival rate of 66.7%, suggesting that these combinations could provide durable responses in RRMM treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Study of Venetoclax Plus Daratumumab and Dexamethasone, With or Without Bortezomib, in Patients With Relapsed or Refractory Multiple Myeloma With and Without t(11;14). Bahlis, NJ., Baz, R., Harrison, SJ., et al.[2022]

In a review of 7 clinical trials involving 482 patients with relapsed/refractory multiple myeloma, venetoclax demonstrated a high overall response rate of 76%, indicating it is an effective treatment option.

The study found that while venetoclax is associated with some adverse events, the overall rate of severe adverse events (Grade 3 or higher) was 84%, suggesting that while it is effective, careful monitoring for side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of venetoclax in patients with relapsed/refractory multiple myeloma: a meta-analysis. Gao, X., Zeng, H., Zhao, X., et al.[2023]

Rituximab and hyaluronidase human is a newly approved subcutaneous formulation of rituximab for treating certain types of blood cancers, including follicular lymphoma and chronic lymphocytic leukemia.

This new formulation shows noninferior pharmacokinetics and similar treatment outcomes compared to traditional intravenous rituximab, potentially offering greater convenience for patients and more efficient use of healthcare resources.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Subcutaneous Rituximab in Follicular Lymphoma, Chronic Lymphocytic Leukemia, and Diffuse Large B-Cell Lymphoma. Yelvington, BJ.[2020]

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]

A Phase I study involving 24 healthy volunteers found that intravenous administration of rHuPH20 (up to 30,000 U) was well tolerated, with no serious adverse events reported, indicating a favorable safety profile.

The pharmacokinetics showed that rHuPH20 was rapidly cleared from the plasma, with plasma hyaluronan concentrations increasing in a dose-dependent manner and returning to baseline within one week, suggesting effective metabolism and clearance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase I Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Recombinant Human Hyaluronidase PH20 Administered Intravenously in Healthy Volunteers. Printz, MA., Dychter, SS., DeNoia, EP., et al.[2022]

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 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]

Subcutaneous rituximab, combined with recombinant human hyaluronidase, enhances the absorption of rituximab, allowing for effective treatment delivery.

There are clinical considerations regarding the potential for systemic toxicity from hyaluronidase and the possibility of increased absorption of other drugs administered after rituximab, which may impact patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical considerations of hyaluronidase as an adjunct to subcutaneous rituximab injection. de Lemos, ML., Dar Santos, A.[2019]

Citations

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

Adding venetoclax to lenalidomide and rituximab is safe ... Venetoclax can be added to lenalidomide and rituximab without the occurrence of any dose-limiting toxicity in patients with untreated MCL.

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. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6497517/

Venetoclax plus R- or G-CHOP in non-Hodgkin lymphoma The CAVALLI study explored the safety and efficacy of combining venetoclax with R-CHOP or G-CHOP chemotherapy in patients with NHL. Here, we report results of ...

5. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/20/NCT02055820/Prot_002.pdf

A Phase IB/II, Open-Label Study Evaluating the Safety and Details and most current data are provided in the ABT-199/Venetoclax ... with relapsed/refractory indolent non-Hodgkin lymphoma: results from the phase II.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5004354/

Safety and efficacy of lenalidomide in combination with ... A recently published Phase II study tested lenalidomide plus rituximab for treating relapsed/refractory indolent NHL. The results showed an ORR of 74%, with 44% ...