Zanubrutinib + Venetoclax for Chronic B-Cell Leukemia

Recruiting in Palo Alto (17 mi)

Overseen by John Allan, M.D.

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Weill Medical College of Cornell University

Must not be taking: Warfarin

Disqualifiers: Previous cancer therapy, Active infection, others

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

Bruton's tyrosine kinase inhibitors (BTKi), anti-CD20 antibodies, and the B cell lymphoma 2 inhibitor (BCL-2i) venetoclax are drug classes used to treat patients with chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL). Anti-CD20 therapy may not be required for all patients. 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 (minimal residual disease \[MRD\]) after being treated with a combination of two oral medications, zanubrutinib (a BTKi ) and venetoclax (a BCL-2i), instead of giving a combination of three drugs to all patients from the start of treatment. This strategy, if effective, will prevent overtreatment with anti-CD20 antibodies; reduce side effects of treatment while potentially increasing MRD negativity rates; and will possibly make the anti-CD20 antibody therapy more effective given the low tumor burden present when utilized. This study will test this hypothesis by treating subjects with 3 cycles of a zanubrutinib monotherapy lead-in, in order to debulk and mitigate tumor lysis risk, followed by 13 cycles of zanubrutinib and venetoclax combination therapy. Subjects who are both peripheral blood and bone marrow MRD negative at the completion of the 13 cycles of combination therapy will stop treatment and enter an observation phase every 3 months. Subjects that are MRD positive will continue combination therapy with zanubrutinib and venetoclax for an additional 6 cycles but also receive 6 cycles of obinutuzumab in order to augment response and increase MRD negative rates for the overall treated cohort.

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.

What data supports the effectiveness of the drug combination Zanubrutinib and Venetoclax for treating Chronic B-Cell Leukemia?

Research shows that Venetoclax, when used alone or with other drugs like rituximab, is effective in treating chronic lymphocytic leukemia (CLL), achieving high response rates and prolonging progression-free survival. Additionally, BTK inhibitors like Zanubrutinib have shown effectiveness in patients with CLL, especially those resistant to Venetoclax. ^{1 2 3 4 5}

Is the combination of Zanubrutinib and Venetoclax safe for treating chronic B-cell leukemia?

Venetoclax, when used for chronic lymphocytic leukemia, has shown an acceptable safety profile in various studies, with manageable side effects like neutropenia (low white blood cell count). While specific safety data for the combination with Zanubrutinib is not provided, Venetoclax alone or with other drugs has been generally safe in humans. ^{1 2 3 5 6}

What makes the drug combination of Zanubrutinib and Venetoclax unique for treating chronic B-cell leukemia?

The combination of Zanubrutinib and Venetoclax is unique because it combines two targeted therapies: Zanubrutinib, a BTK inhibitor, and Venetoclax, a BCL2 inhibitor, both of which are taken orally. This combination aims to enhance treatment effectiveness by targeting different pathways involved in cancer cell survival, offering a chemotherapy-free option for patients with chronic B-cell leukemia. ^{1 2 3 4 7}

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Obinutuzumab (Monoclonal Antibodies)
• Venetoclax (BCL-2 Inhibitor)
• Zanubrutinib (BTK Inhibitor)

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.

Participant Groups

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)

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Weill Cornell Medicine/NewYork-Presberteryian Hospital New York, NY

Who Is Running the Clinical Trial?

Weill Medical College of Cornell University Lead Sponsor

BeiGene Industry Sponsor

Genentech, Inc. Industry Sponsor

References

1. France pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Relapsed/Refractory Chronic Lymphocytic Leukemia. [2020] Venetoclax (Venclyxto®; Venclexta®) is a first-in-class, oral, selective B cell lymphoma-2 (BCL-2) inhibitor. The drug is approved in numerous countries, including those of the EU and in the USA, for the treatment of adults with relapsed or refractory (RR) chronic lymphocytic leukemia (CLL); the specific indication(s) for venetoclax may vary between individual countries. Venetoclax monotherapy or combination therapy with rituximab was an effective treatment, provided durable responses, and had a manageable safety profile in pivotal clinical trials in adults with RR CLL, including in patients with adverse prognostic factors. In combination with 6 cycles of rituximab, venetoclax (fixed 24 months' treatment) was more effective than bendamustine plus rituximab (6 cycles) in prolonging progression-free survival (PFS) and inducing undetectable minimal residual disease (uMRD) in peripheral blood (PB) and bone marrow (BM), with these benefits sustained during 36 months' follow-up. Hence, with its novel mechanism of action and convenient oral once-daily regimen, venetoclax monotherapy or fixed 24-month combination therapy with rituximab represents an important option for treating RR CLL, including in patients with del(17p) or TP53 mutation and those failing a B cell receptor (BCR) inhibitor and/or chemotherapy.

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

Venetoclax: A Review in Previously Untreated Chronic Lymphocytic Leukaemia. [2021] Venetoclax (Venclexta®; Venclyxto®) is a first-in-class, oral, selective inhibitor of B cell lymphoma 2 (BCL2). In several countries, including the USA and those of the EU, venetoclax is indicated in combination with obinutuzumab for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL). Approval was based on the results of the phase III CLL14 trial in patients with previously untreated CLL and co-existing conditions. In this study, fixed-duration (12 months) targeted treatment with venetoclax + obinutuzumab resulted in significantly longer progression-free survival (PFS; primary endpoint) relative to fixed-duration chemoimmunotherapy with chlorambucil + obinutuzumab. Venetoclax + obinutuzumab was also associated with significantly higher rates of undetectable minimal residual disease (MRD), complete response and overall response than chlorambucil + obinutuzumab. Improvements in clinical outcomes with venetoclax + obinutuzumab were maintained during long-term follow-up, when all patients had been off treatment for ≥ 2 years. No significant between-group difference was observed in overall survival (OS). Venetoclax had an acceptable tolerability profile. Notable adverse events such as grade 3 or 4 neutropenia can be managed with supportive therapy and venetoclax dose modifications. In conclusion, fixed-duration venetoclax + obinutuzumab represents an important chemotherapy-free first-line treatment option for patients with CLL, particularly those who are not fit enough to receive intensive chemoimmunotherapy.

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

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . [2018] Venetoclax (Venclexta™) is a potent, selective, orally available, small-molecule B-cell lymphoma 2 inhibitor that achieves response rates of about 80% and has an acceptable safety profile for patients with relapsed or refractory chronic lymphocytic leukemia (CLL). .

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

BTK inhibitor therapy is effective in patients with CLL resistant to venetoclax. [2021] Highly active BTK inhibitors (BTKis) and the BCL2 inhibitor venetoclax have transformed the therapeutic landscape for chronic lymphocytic leukemia (CLL). Results of prospective clinical trials demonstrate the efficacy of venetoclax to salvage patients with disease progression on BTKis, but data on BTKi therapy after disease progression on venetoclax are limited, especially regarding durability of benefit. We retrospectively evaluated the records of 23 consecutive patients with relapsed/refractory CLL who received a BTKi (ibrutinib, n = 21; zanubrutinib, n = 2) after stopping venetoclax because of progressive disease. Median progression-free survival (PFS) and median overall survival after BTKi initiation were 34 months (range,

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

Venetoclax: First Global Approval. [2018] Venetoclax (Venclexta™) is an oral selective inhibitor of the prosurvival protein BCL-2 and therefore restores the apoptotic ability of malignant cells. The drug arose from research by Abbott Laboratories (now AbbVie) during a collaboration with Genentech and is being co-developed by AbbVie and Genentech/Roche primarily for the treatment of haematological malignancies. Venetoclax is approved in the USA for use as monotherapy in patients with chronic lymphocytic leukaemia (CLL) with the 17p deletion (as detected by an approved FDA test) who have received at least one prior therapy, and is awaiting approval for similar indications in the EU and Canada. Venetoclax is also in phase I-III development as combination therapy for CLL, phase I/II development as monotherapy and/or combination therapy for non-Hodgkin lymphomas (including diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma) and acute myeloid leukaemia, and phase I development for multiple myeloma, systemic lupus erythematosus and breast cancer. This article summarizes the milestones in the development of venetoclax leading to this first approval for CLL.

6. England pubmed.ncbi.nlm.nih.gov

Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial. [2021] Therapy targeting Bruton's tyrosine kinase (BTK) with ibrutinib has transformed the treatment of chronic lymphocytic leukaemia. However, patients who are refractory to or relapse after ibrutinib therapy have poor outcomes. Venetoclax is a selective, orally bioavailable inhibitor of BCL-2 active in previously treated patients with relapsed or refractory chronic lymphocytic leukaemia. In this study, we assessed the activity and safety of venetoclax in patients with chronic lymphocytic leukaemia who are refractory to or relapse during or after ibrutinib therapy.

7. England pubmed.ncbi.nlm.nih.gov

Venetoclax, bendamustine, and rituximab in patients with relapsed or refractory NHL: a phase Ib dose-finding study. [2021] Venetoclax is a selective, potent inhibitor of the anti-apoptotic B-cell leukemia/lymphoma-2 protein approved for treatment of chronic lymphocytic leukemia. We conducted a dose-finding study of venetoclax in combination with bendamustine-rituximab (BR) in patients with relapsed/refractory non-Hodgkin's lymphoma (NHL).