50 Participants Needed

Zanubrutinib + Venetoclax for Chronic B-Cell Leukemia

BH
TK
Overseen ByTejasvi Kaur Sahni
Age: 18+
Sex: Any
Trial Phase: Phase 2
Sponsor: Weill Medical College of Cornell University
No Placebo GroupAll trial participants will receive the active study treatment (no placebo)
Prior Safety DataThis treatment has passed at least one previous human trial
Breakthrough TherapyThis drug has been fast-tracked for approval by the FDA given its high promise

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.12345

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.12356

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.12347

Research Team

JA

John Allan, M.D.

Principal Investigator

Weill Medical College of Cornell University

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.
See 17 more

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
  • Venetoclax
  • Zanubrutinib
Trial OverviewThe 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
2Treatment groups
Experimental Treatment
Group I: Triple Therapy (Zanubrutinib, Venetoclax, and Obinutuzumab)Experimental Treatment3 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 Treatment2 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

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 profile image

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway profile image

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

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.
Venetoclax: A Review in Relapsed/Refractory Chronic Lymphocytic Leukemia.Scott, LJ.[2020]
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.
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.
Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia .Brumbaugh Paradis, H., Alter, D., Llerandi, D.[2018]

References

Venetoclax: A Review in Relapsed/Refractory Chronic Lymphocytic Leukemia. [2020]
Venetoclax: A Review in Previously Untreated Chronic Lymphocytic Leukaemia. [2021]
Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . [2018]
BTK inhibitor therapy is effective in patients with CLL resistant to venetoclax. [2021]
Venetoclax: First Global Approval. [2018]
Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial. [2021]
Venetoclax, bendamustine, and rituximab in patients with relapsed or refractory NHL: a phase Ib dose-finding study. [2021]