Zanubrutinib + Venetoclax for Chronic B-Cell Leukemia

Overseen By Tejasvi Kaur Sahni

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Weill Medical College of Cornell University

Must not be taking: Warfarin

Disqualifiers: Previous cancer therapy, Active infection, 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

50 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial researches a treatment plan for individuals with chronic lymphocytic leukemia or small lymphocytic leukemia (types of blood cancer). The study tests the effectiveness of starting with two oral medications, zanubrutinib (Brukinsa) and venetoclax (Venclexta), without initially using an additional drug, obinutuzumab. If cancer remains detectable after the initial treatment, obinutuzumab is added to assess its impact on outcomes. This approach aims to minimize unnecessary side effects by avoiding overtreatment. The trial suits those diagnosed with CLL/SLL who have not received prior systemic anti-cancer therapy and meet treatment indications according to specific guidelines. As a Phase 2 trial, it measures the treatment's effectiveness in an initial, smaller group, allowing participants to contribute to important research.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot participate if you require chronic immunosuppressive therapy or warfarin, or if you've had certain treatments or conditions recently. It's best to discuss your specific medications with the trial team.

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

Research has shown that the combination of zanubrutinib and venetoclax is generally well-tolerated by patients with chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL). Previous studies identified bruising, diarrhea, and low blood counts, including platelets and neutrophils, as the most common side effects. These blood cells assist with clotting and fighting infections. Although these side effects might seem concerning, they are common in cancer treatments and usually manageable.

For those requiring a more intensive approach, adding obinutuzumab has been tested. Some studies suggest that using these three drugs can be effective, but combining medications, especially with a drug like obinutuzumab that affects the immune system, can lead to more significant side effects. Therefore, the trial under consideration carefully evaluates when to add this third drug.

In conclusion, both treatment combinations have shown promising safety results. However, like any treatment, potential side effects exist. Participants are closely monitored to manage any issues that arise. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using zanubrutinib and venetoclax for treating chronic B-cell leukemia because these drugs work in a unique way compared to current options. Most treatments for this condition, like chemoimmunotherapy, can be harsh and less targeted. Zanubrutinib is a next-generation Bruton’s tyrosine kinase (BTK) inhibitor, and venetoclax targets B-cell lymphoma 2 (BCL-2) proteins, both of which play roles in cancer cell survival. This combo aims to more precisely disrupt cancer cells' growth pathways, potentially offering a more effective and less toxic treatment. Plus, the addition of obinutuzumab in cases where more aggressive treatment is needed can enhance immune response against the cancer cells.

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

Research has shown that combining zanubrutinib and venetoclax is highly effective in treating chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL), with studies finding that about 97.4% of patients respond well to this treatment. In this trial, all participants will initially receive zanubrutinib and venetoclax. Patients who do not achieve complete remission and remain MRD positive will enter the triple therapy arm, adding obinutuzumab to improve results. This three-drug approach significantly increases the number of patients whose cancer cells are reduced to very low levels, known as undetectable minimal residual disease (uMRD). These combination therapies aim to reduce side effects while effectively fighting the disease. ^{1 2 6 7 8}

Who Is on the Research Team?

John Allan, M.D.

Principal Investigator

Weill Medical College of Cornell University

Are You a Good Fit for This Trial?

This trial is for adults with confirmed chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL) who need treatment but haven't had any cancer therapy before. They must be able to follow pregnancy prevention measures if applicable. Exclusions include recent heart issues, severe infections, certain blood disorders, previous malignancies (except some skin cancers), and known allergies to the study drugs.

Inclusion Criteria

I have been diagnosed with CLL/SLL.

I need treatment for my condition.

Participants of childbearing potential must be willing to comply with pregnancy prevention interventions

Exclusion Criteria

I am on long-term medication to suppress my immune system or have been within the last 6 months.

Participant is positive for human immunodeficiency virus (HIV)

I have or might have had PML in the past.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Therapy

Participants receive 3 cycles of zanubrutinib monotherapy to debulk and mitigate tumor lysis risk

3 months

Combination Therapy

Participants receive 13 cycles of zanubrutinib and venetoclax combination therapy, with MRD assessments at cycle 16

13 months

Observation

Participants who achieve MRD negativity enter an observation phase with study visits every 3 months

Long-term

Triple Therapy

Participants who remain MRD positive receive 6 cycles of obinutuzumab in addition to zanubrutinib and venetoclax

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

36 months

What Are the Treatments Tested in This Trial?

Interventions

• Obinutuzumab
• Venetoclax
• Zanubrutinib

Trial Overview The trial tests a new approach using Zanubrutinib and Venetoclax pills as initial therapy for CLL, adding Obinutuzumab injections only if minimal residual disease is detected after treatment. The goal is to reduce unnecessary medication use while trying to increase the rate of no detectable cancer.

How Is the Trial Designed?

Group I: Triple Therapy (Zanubrutinib, Venetoclax, and Obinutuzumab) Experimental Treatment 3 Interventions

Participants that meet definition of MRD positivity at C16D1 will enter the triple therapy arm (zanubrutinib, venetoclax, and obinutuzumab). These participants will continue combination therapy with zanubrutinib and venetoclax, but will also receive 6 cycles of obinutuzumab starting at C17D1. In this subgroup, peripheral blood and bone marrow MRD assessments will occur after an additional 6 cycles of the triplet combination therapy (C23D1) at which point all participants will stop study treatment regardless of MRD status.

Group II: Double Therapy (Zanubrutinib plus Venetoclax) Experimental Treatment 2 Interventions

All participants will receive an initial 3 cycles of zanubrutinib monotherapy. This lead-in period will then be followed by 12 cycles of zanubrutinib and venetoclax combination therapy. All participants will complete 12 cycles of zanubrutinib and venetoclax combination therapy or 15 cycles of total treatment. Peripheral blood and bone marrow MRD assessments will occur at C16D1. Participants will continue on double combination treatment for an additional 1 month while results of MRD testing are obtained. In total, all participants will be on treatment for at least 16 full cycles. Participants that meet definition of MRD negativity will stop therapy at C17D1 and enter an observation phase with study visits every 3 months. Participants that remain MRD positive at C16D1 will enter the triple therapy (zanubrutinib, venetoclax, and obinutuzumab) arm.

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

Approved in United States as Venclexta for:

• Chronic lymphocytic leukemia (CLL)
• Small lymphocytic lymphoma (SLL)
• Acute myeloid leukemia (AML)

Approved in European Union as Venclyxto for:

• Chronic lymphocytic leukemia (CLL)
• Small lymphocytic lymphoma (SLL)
• Acute myeloid leukemia (AML)

Who Is Running the Clinical Trial?

Weill Medical College of Cornell University

Lead Sponsor

Trials

1,103

Recruited

1,157,000+

BeiGene

Industry Sponsor

Trials

216

Recruited

32,500+

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

Published Research Related to This Trial

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]

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 23 patients with relapsed/refractory chronic lymphocytic leukemia (CLL), BTK inhibitors (ibrutinib and zanubrutinib) were found to provide durable disease control after patients progressed on venetoclax, with a median progression-free survival of 34 months.

Patients who had a prior remission duration of 24 months or longer and those who achieved complete remission on venetoclax experienced significantly longer progression-free survival after starting BTK inhibitors, highlighting the importance of previous treatment response in predicting outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BTK inhibitor therapy is effective in patients with CLL resistant to venetoclax. Lin, VS., Lew, TE., Handunnetti, SM., et al.[2021]

In a study involving 127 patients with relapsed or refractory chronic lymphocytic leukaemia who had previously been treated with ibrutinib, 65% showed an overall response to venetoclax, indicating its effectiveness as a treatment option for those who did not respond to ibrutinib.

Venetoclax was found to have a favorable safety profile, with no treatment-related deaths reported, although common side effects included neutropenia and thrombocytopenia, which were observed in a significant number of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial. Jones, JA., Mato, AR., Wierda, WG., 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]

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 with bendamustine-rituximab (BR) was found to be safe and tolerable in a study of 60 patients with relapsed/refractory non-Hodgkin's lymphoma, with the recommended phase II dose established at 800 mg daily.

The overall response rate to the treatment was 65%, with a median duration of response of 38.3 months, indicating preliminary efficacy for this combination therapy in managing B-cell NHL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax, bendamustine, and rituximab in patients with relapsed or refractory NHL: a phase Ib dose-finding study. de Vos, S., Swinnen, LJ., Wang, D., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05650723

NCT05650723 | Zanubrutinib and Venetoclax as Initial ... All subjects will complete 12 cycles of zanubrutinib and venetoclax combination therapy or 15 cycles of total treatment. Peripheral blood and bone marrow MRD ...

2. cancernetwork.com cancernetwork.com/view/zanubrutinib-venetoclax-demonstrates-robust-efficacy-in-cll-sll

Zanubrutinib/Venetoclax Demonstrates Robust Efficacy in ... After a median follow-up of 31.2 months, the objective response rate was 97.4% among patients with CLL/SLL.

3. onclive.com onclive.com/view/fixed-duration-zanubrutinib-venetoclax-shows-efficacy-in-r-r-chronic-lymphocytic-leukemia

Fixed-Duration Zanubrutinib/Venetoclax Shows Efficacy in ... In a phase 2 study, the combination of zanubrutinib and venetoclax achieved a 95% ORR in relapsed/refractory CLL, with a 17% CR rate and a 78% ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40448577/

Zanubrutinib and Venetoclax for Patients With Treatment- ... Zanubrutinib + venetoclax demonstrated impressive efficacy and a favorable safety profile in patients with TN CLL/SLL, regardless of the presence of TP53- ...

5. onclive.com onclive.com/view/zanubrutinib-venetoclax-yields-deep-responses-in-treatment-naive-cll-regardless-of-del17p-tp53-mutational-status

Zanubrutinib/Venetoclax Yields Deep Responses in ... Zanubrutinib and venetoclax combination shows high efficacy in CLL/SLL, with a 97.4% overall response rate and favorable safety profile. · The ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11253904/

An update on the efficacy of Venetoclax for chronic ... In preclinical studies, venetoclax (ABT-199/GDC-0199) was able to potently inhibit the growth of BCL2 dependent tumors, while sparing the deleterious effect on ...

7. cllsociety.org cllsociety.org/2025/08/zanubrutinib-and-venetoclax-for-relapsed-refractory-cll/

Zanubrutinib and Venetoclax for Relapsed / Refractory CLL The most common side effects were bruising (57%), diarrhea (42%), low platelet counts (38%), and low neutrophil counts (35%). Two patients ...

8. mayo.edu mayo.edu/research/clinical-trials/diseases-conditions/chronic-lymphocytic-leukemia

Chronic Lymphocytic Leukemia Clinical Trials This phase II trial studies how well pirtobrutinib and venetoclax work in treating patients with chronic lymphocytic leukemia or small lymphocytic lymphoma.