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

4 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 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.

What data supports the effectiveness of the drug combination Venetoclax, Lenalidomide, and Rituximab for Non-Hodgkin's Lymphoma?

Venetoclax, when used with rituximab, has shown effectiveness in treating chronic lymphocytic leukemia (CLL), providing durable responses and prolonging progression-free survival. Additionally, venetoclax has demonstrated activity in multiple myeloma, suggesting potential benefits when combined with other agents. ^{1 2 3 4 5}

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

Venetoclax, when used alone or with Rituximab, has shown a manageable safety profile in patients with chronic lymphocytic leukemia. Rituximab, including its subcutaneous form with hyaluronidase, has comparable adverse events to its intravenous form, suggesting it is generally safe for use in humans. ^{1 4 6 7 8}

What makes the drug combination of Venetoclax, Lenalidomide, and Rituximab unique for treating Non-Hodgkin's Lymphoma?

This drug combination is unique because Venetoclax is a first-in-class oral BCL-2 inhibitor that, when combined with Rituximab, has shown a synergistic effect, enhancing progression-free survival in other conditions like chronic lymphocytic leukemia. This suggests potential benefits in Non-Hodgkin's Lymphoma, especially when combined with Lenalidomide, which modulates the immune system. ^{1 2 3 4 9}

What is the purpose of this trial?

This phase I trial studies the side effects and best dose of venetoclax when given together with lenalidomide and rituximab hyaluronidase in treating patients with follicular lymphoma and marginal zone lymphoma that has come back after treatment (relapsed) or has not responded to treatment (refractory). Venetoclax may stop the growth of cancer cells by blocking the action of a protein called Bcl-2, that helps cancer cells survive. Immunotherapy with lenalidomide, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Immunotherapy with monoclonal antibodies, such as rituximab and rituximab hyaluronidase, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. The purpose of this research is to determine if the combination of three drugs, venetoclax, lenalidomide, and rituximab hyaluronidase are safe to administer in patients whose low-grade lymphoma (follicular or marginal zone) has come back after initial therapy or was not responsive to initial therapy.

Research Team

Ubaldo R Martinez-Outschoorn, MD

Principal Investigator

Thomas Jefferson University

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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 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]

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 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]

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]

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]

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]

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. France pubmed.ncbi.nlm.nih.gov

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

2. United States 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). [2022]

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

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

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

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

5. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of venetoclax in patients with relapsed/refractory multiple myeloma: a meta-analysis. [2023]

6. United States 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. [2022]

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

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

8. England pubmed.ncbi.nlm.nih.gov

Clinical considerations of hyaluronidase as an adjunct to subcutaneous rituximab injection. [2019]

9. 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]