Triple Combo Therapy for Chronic Lymphocytic Leukemia

Recruiting at 9 trial locations

Overseen By Anthony Mato, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: Immunotherapy, Hormone therapy, Warfarin

Disqualifiers: Active cancer, Uncontrolled illness, HIV, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 8 months

230 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of three drugs—zanubrutinib, obinutuzumab, and venetoclax—to evaluate their effectiveness in treating chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). The main goal is to determine if these drugs can lead to no evidence of disease after treatment. Individuals diagnosed with CLL or SLL who have not received systemic therapy may be suitable candidates for this study. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you must stop all current medications, but certain medications are restricted. You must stop taking strong or moderate inhibitors or inducers of CYP3A, CYP2C8, CYP2C9, and CYP2C19 within 7 days before the trial. You also cannot take warfarin, immunotherapy, hormone therapy (except contraceptives, hormone replacement, or megestrol acetate), or any therapies for lymphoma/leukemia outside of this study. Additionally, avoid grapefruit, Seville oranges, and star fruit within 3 days before the trial.

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

Research shows that the treatments in this trial—obinutuzumab, venetoclax, and zanubrutinib—have been safe in previous studies.

For obinutuzumab, research indicates a predictable and manageable safety profile when used for chronic lymphocytic leukemia (CLL), meaning side effects are expected and can be managed with current methods.

Venetoclax has also been well-researched and has shown good safety results in both real-world use and clinical trials. Serious side effects are rare, occurring in about 2% of patients without disease progression.

Zanubrutinib, another treatment in this trial, is generally well-tolerated and has a better safety profile than some similar treatments, with fewer heart-related issues reported compared to other drugs in the same category.

Overall, these treatments have been thoroughly studied and are considered to have manageable safety profiles. However, a small risk of side effects always exists. Anyone considering joining a clinical trial should discuss the potential risks and benefits with their healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the triple combo therapy of obinutuzumab, venetoclax, and zanubrutinib for treating Chronic Lymphocytic Leukemia (CLL) because it targets the disease in a unique way compared to standard treatments like chemoimmunotherapy or BTK inhibitors alone. This combination leverages the power of three different mechanisms: obinutuzumab is an antibody that helps the immune system attack cancer cells, venetoclax induces cancer cell death by targeting BCL-2 proteins, and zanubrutinib inhibits BTK, a protein that promotes cancer cell survival. This multi-pronged approach not only aims to improve effectiveness but also may reduce the likelihood of resistance developing. The potential to achieve deeper and longer-lasting remissions makes this treatment particularly promising.

What evidence suggests that this trial's treatments could be effective for chronic lymphocytic leukemia?

Research shows that the BOVEN treatment, which participants in this trial will receive, includes the drugs zanubrutinib, obinutuzumab, and venetoclax, and holds promise for treating chronic lymphocytic leukemia (CLL). In one study, 96% of patients had no detectable cancer in their blood, and 92% had no detectable cancer in their bone marrow, indicating the absence of cancer in these areas. This drug combination also helps patients live longer without disease progression. Overall, these findings suggest that the BOVEN treatment could be an effective option for CLL. ^{6 7 8 9 10}

Who Is on the Research Team?

Andrew Zelenetz, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

Adults diagnosed with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Leukemia (SLL), who haven't had systemic therapy for these conditions, can join. They should be in a stable health condition and willing to use effective contraception. People with other active cancers, serious infections, or certain heart/liver diseases cannot participate.

Inclusion Criteria

Signed, informed consent

I have been diagnosed with CLL, SLL, or MCL according to WHO standards.

My blood counts are within normal ranges, unless affected by my condition.

Exclusion Criteria

Other: Females who are currently pregnant or breastfeeding, Participation in a separate investigational therapeutic study unless authorized by the investigator

Co-morbidities: Any uncontrolled illness that in the opinion of the investigator would preclude administration of study therapy, Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection at study enrollment, or any major episode of infection requiring treatment with IV antibiotics or hospitalization within 4 weeks prior to Cycle 1, Day 1, Known bleeding diathesis, Prior major surgical procedure within 4 weeks of study, or anticipation of need for a major surgical procedure during the course of the study, Known CNS hemorrhage or stroke within 6 months of the study, History of progressive multifocal leukoencephalopathy (PML), History of HIV infection or active hepatitis B or hepatitis C infection

I haven't had any other cancers or treatments for them in the last 3 years, except for local treatments aimed at cure.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive zanubrutinib and obinutuzumab starting on Cycle 1, with venetoclax added from Cycle 3, over 28-day cycles

8 months

Multiple visits for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, including MRD response classification

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Obinutuzumab
• Venetoclax
• Zanubrutinib

Trial Overview The trial is testing the combination of three drugs: Zanubrutinib, Obinutuzumab, and Venetoclax in patients with CLL/SLL. The goal is to see if this drug combo can eliminate all detectable traces of the disease from the body.

How Is the Trial Designed?

Group I: BOVEN regimen Experimental Treatment 3 Interventions

Patients will be given zanubrutinib (160mg by mouth BID) and obinutuzumab (1000mg IVPB on Days 1\*, 8 and 15 of Cycle 1 and on Day 1 of Cycles 2 through 8) starting on Cycle 1 (28-day cycles). \* On Cycle 1, obinituzumab will be administered in "split dose" at 100mg IVPB on Day 1 and 900mg IVPB on Day 2 in patients at increased risk for IRR (ALC \>25,000 cells/ul or baseline lymph nodes \>5 cm diameter). Venetoclax will be added to the regimen starting on Cycle 3, and will be incorporated into the regimen using the 5-week ramp-up schedule to mitigate the risk of tumor lysis syndrome (beginning at 20mg and gradually increasing to 400mg), and venetoclax will be administered a ta fixed dose level of 400mg by mouth daily of 28-day cycles thereafter.

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

Approved in United States as Gazyva for:

• Chronic Lymphocytic Leukemia (CLL)
• Follicular Lymphoma

Approved in European Union as Gazyva for:

• Chronic Lymphocytic Leukemia (CLL)
• Follicular Lymphoma

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Roche-Genentech

Industry Sponsor

Trials

27

Recruited

3,800+

BeiGene USA, Inc.

Industry Sponsor

Trials

5

Recruited

490+

Massachusetts General Hospital

Collaborator

Trials

3,066

Recruited

13,430,000+

Published Research Related to This Trial

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 phase 1b study involving 12 patients with relapsed or refractory chronic lymphocytic leukemia (CLL), a fixed-duration regimen combining obinutuzumab, ibrutinib, and venetoclax resulted in a high overall response rate of 92%, with 42% of patients achieving complete remission.

The treatment regimen was found to be safe and tolerable, with no clinically significant tumor lysis syndrome reported, indicating that this combination therapy could effectively induce deep responses in CLL patients and warrants further investigation in larger trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1b study of obinutuzumab, ibrutinib, and venetoclax in relapsed and refractory chronic lymphocytic leukemia. Rogers, KA., Huang, Y., Ruppert, AS., et al.[2022]

The combination of rituximab and belimumab was found to be safe for patients with refractory lupus nephritis, showing no increase in adverse events compared to those receiving rituximab alone.

While the addition of belimumab did not improve clinical efficacy compared to rituximab and cyclophosphamide alone, it did lead to a greater reduction in certain B cell populations, suggesting a mechanism that enhances the negative selection of autoreactive B cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Randomized Trial of Rituximab Plus Cyclophosphamide Followed by Belimumab for the Treatment of Lupus Nephritis. Atisha-Fregoso, Y., Malkiel, S., Harris, KM., 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 phase III study involving 1,006 patients with active rheumatoid arthritis, treatment with ocrelizumab (both 200 mg and 500 mg doses) significantly improved symptoms and joint function compared to placebo, with ACR20 response rates of 56.9% and 54.5% at 24 weeks, respectively.

While both doses of ocrelizumab effectively reduced joint damage progression, the 500 mg dose was associated with a higher rate of serious infections compared to the 200 mg dose and placebo, indicating a need for careful monitoring of safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of ocrelizumab in patients with rheumatoid arthritis and an inadequate response to methotrexate: results of a forty-eight-week randomized, double-blind, placebo-controlled, parallel-group phase III trial. Rigby, W., Tony, HP., Oelke, K., et al.[2017]

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 retrospective study of 14 patients with chronic lymphocytic leukemia (CLL) treated with the venetoclax and obinutuzumab (VenG) regimen, 73% developed grade 3 or 4 neutropenia, indicating a high incidence of this side effect.

The study suggests that the high rate of neutropenia may be linked to patients having more comorbidities and high-risk disease features, highlighting the need for further research on supportive treatments to manage this side effect and allow for optimal dosing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation and associated risk factors for neutropenia with venetoclax and obinutuzumab in the treatment of chronic lymphocytic leukemia. Samuels, C., Abbott, D., Niemiec, S., et al.[2022]

In a long-term study involving 298 patients with systemic lupus erythematosus (SLE), intravenous belimumab combined with standard care showed sustained efficacy, with the percentage of patients achieving a significant response increasing from 32.8% in the first year to 75.6% by year 12.

Belimumab was well tolerated over a median treatment duration of approximately 9 years, with stable adverse event rates and maintained normal serum IgG levels, indicating its safety for long-term use in managing SLE.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Belimumab Plus Standard Therapy for Up to Thirteen Years in Patients With Systemic Lupus Erythematosus. Wallace, DJ., Ginzler, EM., Merrill, JT., et al.[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]

In a study of 31 patients with systemic lupus erythematosus (SLE) who had active nephritis or autoimmune cytopenias, the addition of anti-CD20 treatment (rituximab) led to complete B cell depletion and significant clinical improvements, including increased glomerular filtration rate (GFR) in 11 out of 17 nephritis patients.

The treatment was particularly effective for autoimmune thrombocytopenia, with significant increases in platelet counts observed within one month, and five out of ten patients achieving complete normalization of their platelet counts within six months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Longterm clinical and immunological effects of anti-CD20 treatment in patients with refractory systemic lupus erythematosus. Lindholm, C., Börjesson-Asp, K., Zendjanchi, K., et al.[2022]

Belimumab is the first biological drug approved for treating systemic lupus erythematosus (SLE) and has shown clinical effectiveness when used alongside standard immunosuppressants, based on a 7-year longitudinal study of patients.

The drug has demonstrated a positive impact on the quality of life for SLE patients, with ongoing trials expected to provide further insights into its benefits and potential areas for improvement in treatment protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Update on belimumab for the management of systemic lupus erythematosus. Lutalo, PM., D'Cruz, DP.[2018]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40944848/

Indirect Comparisons of the Efficacy and Safety ... Introduction: Compared with chemoimmunotherapy, both zanubrutinib monotherapy and venetoclax plus obinutuzumab prolong progression-free survival ...

2. onclive.com onclive.com/view/zanubrutinib-plus-obinutuzumab-venetoclax-associated-with-durable-umrd4-outcomes-in-treatment-naive-cll

Zanubrutinib Plus Obinutuzumab/Venetoclax Associated ... BOVen regimen significantly increases uMRD achievement in treatment-naive CLL patients, with 96% achieving uMRD in peripheral blood and 92% in ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.e19027

Efficacy of continuous zanubrutinib vs fixed-duration ... This unanchored MAIC investigated the relative efficacy of zanu vs VenO and suggested zanu had longer PFS and a trend for extended OS.

4. nejm.org nejm.org/doi/full/10.1056/NEJMoa2213093

First-Line Venetoclax Combinations in Chronic ... Venetoclax–obinutuzumab with or without ibrutinib was superior to chemoimmunotherapy as first-line treatment in fit patients with CLL.

5. clinicaltrials.gov clinicaltrials.gov/study/NCT05650723

NCT05650723 | Zanubrutinib and Venetoclax as Initial ... The investigators hypothesis is that it may be better to give anti-CD20 therapy (obinutuzumab) only to patients that still have detectable cancer in their blood ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/33605445/

Final analysis of the Phase IIIb GREEN study In this final analysis of the GREEN trial, the safety profile of G was consistent with current risk management strategies. Biomarker analyses ...

7. ashpublications.org ashpublications.org/bloodadvances/article/9/10/2431/536217/Long-term-outcomes-of-chemoimmunotherapy-with

Long-term outcomes of chemoimmunotherapy with ... In CLL11 and in a more recent study (CLL13), obinutuzumab achieved higher rates of undetectable minimal residual disease compared with rituximab when combined ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT01905943

A Safety and Efficacy Study of Obinutuzumab Alone or in ... This multicenter, open-label, single-arm study will evaluate the safety and efficacy of obinutuzumab alone or in combination with chemotherapy in ...

9. gazyva.com gazyva.com/first-line-cll/results-with-gazyva/clinical-trial-results.html

GAZYVA® (obinutuzumab) Efficacy Results | First-Line CLL More than 1 in 4 patients who took GAZYVA + chlorambucil chemotherapy vs rituximab product + chlorambucil went into complete remission* for a period of time.

10. sciencedirect.com sciencedirect.com/science/article/pii/S2473952925001788

Long-term outcomes of chemoimmunotherapy with ... These data suggest that CIT of CLL with obinutuzumab/chlorambucil could achieve long-lasting remissions over many years in patients with ...