Obinutuzumab + Venetoclax + Lenalidomide for B-Cell Non-Hodgkin's Lymphoma

Recruiting at 1 trial location

Overseen By The Ohio State University Comprehensive Cancer Center

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Beth Christian

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: CNS involvement, HIV, Hepatitis, others

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

Compensation: Varies

Number of Visits: 1

Duration: Up to 12 months

22 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I study studies the side effects and best dose of venetoclax and lenalidomide when given together with obinutuzumab in treating patients with B-cell non-Hodgkin lymphoma that has returned after a period of improvement or not responding to treatment. Monoclonal antibodies, such as obinutuzumab, may interfere with the ability of cancer cells to grow and spread. Venetoclax may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as lenalidomide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving obinutuzumab, venetoclax, and lenalidomide may work better in treating patients with B-cell non-Hodgkin lymphoma.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop all current medications, but you cannot have taken venetoclax, lenalidomide, or certain other drugs recently. You also cannot use warfarin or certain other medications that interact with the trial drugs.

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

Research shows that Venetoclax combined with Obinutuzumab is effective in treating chronic lymphocytic leukemia (CLL), leading to longer progression-free survival and higher response rates compared to other treatments. Additionally, a study on mantle cell lymphoma found that a combination including Venetoclax and Obinutuzumab provided high response rates and was well tolerated. ^{1 2 3 4 5}

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

The combination of Obinutuzumab and Venetoclax has been studied in various trials for different types of lymphoma and leukemia, showing an acceptable safety profile. Common side effects include neutropenia (low white blood cell count), which can be managed with supportive care. No dose-limiting toxicities were observed, and serious side effects like infections were relatively low. ^{2 3 4 6 7}

What makes the combination of Obinutuzumab, Venetoclax, and Lenalidomide unique for treating B-Cell Non-Hodgkin's Lymphoma?

This treatment is unique because it combines three drugs that target cancer cells in different ways: Obinutuzumab is an antibody that helps the immune system attack cancer cells, Venetoclax blocks a protein that helps cancer cells survive, and Lenalidomide boosts the immune system to fight cancer. This combination aims to provide a more comprehensive approach to treating B-Cell Non-Hodgkin's Lymphoma compared to traditional chemotherapy. ^{4 5 7 8 9}

Research Team

Beth Christian, MD

Principal Investigator

Ohio State University Comprehensive Cancer Center

Eligibility Criteria

This trial is for adults with B-cell non-Hodgkin lymphoma that has come back or didn't respond to treatment. They must be in good physical condition, have not used certain drugs like venetoclax before, and have proper kidney function. Women who can get pregnant must follow strict pregnancy testing rules. People with severe allergies, recent major surgery, active infections, or other serious health issues cannot join.

Inclusion Criteria

This study has a separate group of participants called the "expansion cohort" who meet specific criteria for enrollment.

Absolute neutrophil count (ANC) >= 1000/mm^3

Eastern Cooperative Oncology Group (ECOG) performance status 0-2

Exclusion Criteria

You are allergic to both xanthine oxidase inhibitors and rasburicase.

Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction likely to interfere with the delivery, absorption, or metabolism of venetoclax or lenalidomide

Patients may take steroids for disease control up to 24 hours prior to study enrollment

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive lenalidomide orally on days 1-21, venetoclax orally on days 1-28, and obinutuzumab intravenously on days 1, 8, and 15 of course 1 and on day 1 of courses 2-6. Treatment repeats every 28 days for up to 12 courses.

Up to 12 months

Multiple visits per course

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

2 years

1 visit at 4 weeks, then every 3 months for 2 years, then every 6 months

Treatment Details

Interventions

• Lenalidomide
• Obinutuzumab
• Venetoclax

Trial Overview The study tests the combination of three drugs: Obinutuzumab (a monoclonal antibody), Venetoclax (blocks enzymes for cell growth), and Lenalidomide (chemotherapy). It aims to find the safest doses and see how well they work together against different types of B-cell non-Hodgkin lymphoma.

Participant Groups

Group I: Treatment (lenalidomide, venetoclax, obinutuzumab) Experimental Treatment 3 Interventions

Patients receive lenalidomide PO on days 1-21 and venetoclax PO on days 1-28. Patients also receive obinutuzumab IV on days 1, 8, and 15 of course 1, and day 1 of courses 2-6. Treatment repeats every 28 days for up to 12 courses 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?

Beth Christian

Lead Sponsor

Trials

3

Recruited

80+

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

Celgene

Industry Sponsor

Trials

649

Recruited

130,000+

Top Products

>- **Revlimid (lenalidomide)**: Multiple myeloma, myelodysplastic syndromes, and mantle cell lymphoma treatment. - **Pomalyst (pomalidomide)**: Relapsed/refractory multiple myeloma treatment. - **Otezla (apremilast)**: Psoriatic arthritis treatment. - **Thalomid (thalidomide)**: Erythema nodosum leprosum and multiple myeloma treatment.

Jay Backstrom

Celgene

Chief Medical Officer since 2016

MD

Mark Alles

Celgene

Chief Executive Officer since 2016

Bachelor's degree from Lock Haven University of Pennsylvania

Findings from Research

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]

The combination of venetoclax, ibrutinib, and obinutuzumab is well tolerated in patients with relapsed and untreated mantle cell lymphoma (MCL), with no dose-limiting toxicities reported and a maximum tolerated dose of 400 mg per day established for venetoclax.

High response rates were observed, with a complete response rate of 67% in relapsed patients and 86.6% in untreated patients, along with significant minimal residual disease clearance in 71.5% of relapsed and 100% of untreated patients after three cycles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib, obinutuzumab, and venetoclax in relapsed and untreated patients with mantle cell lymphoma: a phase 1/2 trial. Le Gouill, S., Morschhauser, F., Chiron, D., et al.[2021]

The study analyzed pharmacokinetics and exposure-response parameters of a 400 mg once-daily venetoclax regimen combined with obinutuzumab in 274 patients, confirming its suitability for first-line treatment of chronic lymphocytic leukemia (CLL).

No significant correlations were found between venetoclax exposure and progression-free survival or severe treatment-emergent adverse events, indicating that the treatment is both effective and safe at the studied dose.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and Exposure-Response Analysis of Venetoclax + Obinutuzumab in Chronic Lymphocytic Leukemia: Phase 1b Study and Phase 3 CLL14 Trial. Samineni, D., Gibiansky, L., Wang, B., et al.[2022]

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 phase 2 trial involving 70 patients with chronic lymphocytic leukaemia, both 12 cycles of venetoclax consolidation and minimal residual disease-guided consolidation showed similar effectiveness, with around 50% of patients achieving undetectable minimal residual disease in bone marrow after treatment.

While consolidation treatment did not lead to treatment-related deaths, it was associated with a higher incidence of adverse events, particularly infections, indicating that while it may extend treatment duration, it does not significantly improve disease response or reduce relapse risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax consolidation after fixed-duration venetoclax plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (HOVON 139/GiVe): primary endpoint analysis of a multicentre, open-label, randomised, parallel-group, phase 2 trial. Kersting, S., Dubois, J., Nasserinejad, K., et al.[2022]

The combination of venetoclax and obinutuzumab was found to be safe and well-tolerated in patients with relapsed/refractory or previously untreated chronic lymphocytic leukemia, with no dose-limiting toxicities observed during the study.

The treatment resulted in a high overall response rate of 95% in relapsed/refractory patients and 100% in previously untreated patients, with significant rates of undetectable minimal residual disease, indicating effective disease control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1b study of venetoclax-obinutuzumab in previously untreated and relapsed/refractory chronic lymphocytic leukemia. Flinn, IW., Gribben, JG., Dyer, MJS., et al.[2021]

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 3 trial involving 432 patients with untreated chronic lymphocytic leukaemia, the combination of venetoclax plus obinutuzumab resulted in significantly longer progression-free survival compared to chlorambucil plus obinutuzumab, with a hazard ratio of 0.31, indicating a strong treatment advantage.

After a median follow-up of 39.6 months post-treatment, patients receiving venetoclax plus obinutuzumab had not yet reached median progression-free survival, while those on chlorambucil plus obinutuzumab had a median of 35.6 months, highlighting the long-term efficacy of the venetoclax regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial. Al-Sawaf, O., Zhang, C., Tandon, M., et al.[2020]

References

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

Venetoclax: First Global Approval. [2018]

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

Ibrutinib, obinutuzumab, and venetoclax in relapsed and untreated patients with mantle cell lymphoma: a phase 1/2 trial. [2021]

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

Pharmacokinetics and Exposure-Response Analysis of Venetoclax + Obinutuzumab in Chronic Lymphocytic Leukemia: Phase 1b Study and Phase 3 CLL14 Trial. [2022]

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

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

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

Venetoclax consolidation after fixed-duration venetoclax plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (HOVON 139/GiVe): primary endpoint analysis of a multicentre, open-label, randomised, parallel-group, phase 2 trial. [2022]

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

Phase 1b study of venetoclax-obinutuzumab in previously untreated and relapsed/refractory chronic lymphocytic leukemia. [2021]

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

SAKK 35/15: a phase 1 trial of obinutuzumab in combination with venetoclax in patients with previously untreated follicular lymphoma. [2022]

8. France pubmed.ncbi.nlm.nih.gov

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

9. England pubmed.ncbi.nlm.nih.gov

Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial. [2020]