Venetoclax + Ibrutinib for Chronic Lymphocytic Leukemia

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Michael Choi

Must be taking: Ibrutinib

Must not be taking: Warfarin, CYP450 3A inhibitors

Disqualifiers: CNS lymphoma, Richter's, HIV, others

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

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

Compensation: Varies

Number of Visits: 2

Duration: 7 cycles (approximately 7 months)

24 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether combining two drugs, venetoclax and a higher dose of ibrutinib, can treat chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) that does not respond to ibrutinib alone. The goal is to determine if this combination can reduce cancer cells in the body. It targets individuals with CLL or SLL whose condition worsens despite ibrutinib treatment. Participants must be able to swallow pills and have good liver, kidney, and blood function. As a Phase 1 trial, the research focuses on understanding how the treatment works in people.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does mention that you cannot participate if you require treatment with a strong CYP450 3A inhibitor or anticoagulation with warfarin. It's best to discuss your current medications with the trial team.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research shows that combining venetoclax and ibrutinib offers a promising treatment for chronic lymphocytic leukemia (CLL). Both drugs have FDA approval for CLL, which supports their safety profile. Studies indicate that this combination is generally well-tolerated.

In earlier studies, patients taking both venetoclax and ibrutinib responded well, and the treatment proved mostly safe. Some experienced side effects, such as low blood cell counts or diarrhea, but these were manageable for most. While researchers continue to study this combination, early results suggest it is relatively safe for people with CLL. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Venetoclax and Ibrutinib for treating chronic lymphocytic leukemia (CLL) because it offers a unique approach compared to standard treatments. Most current therapies for CLL focus on either targeting specific proteins on cancer cells or boosting the immune system. However, this combination treatment works in a novel way by simultaneously inhibiting two critical pathways that cancer cells use for survival: the BCL-2 protein with Venetoclax and the Bruton’s tyrosine kinase (BTK) with Ibrutinib. This dual action has the potential to be more effective, particularly for patients whose disease has progressed on Ibrutinib alone. Researchers are hopeful that this combination will lead to quicker and more robust responses in patients.

What evidence suggests that the combination of venetoclax and high-dose ibrutinib could be effective for chronic lymphocytic leukemia?

Research has shown that combining venetoclax and ibrutinib holds promise for treating chronic lymphocytic leukemia (CLL). This trial will specifically test venetoclax with high-dose ibrutinib for patients whose disease progresses on single-agent ibrutinib. This combination appears particularly effective for patients with certain genetic differences, though results can vary. One study found that patients taking both ibrutinib and venetoclax had better outcomes than those on other treatments. Another study found that many patients remained cancer-free for years when using these drugs together. Overall, evidence suggests that this combination can significantly reduce cancer cells in people with CLL. ^{1 6 7 8 9}

Who Is on the Research Team?

Michael Choi, MD

Principal Investigator

University of California, San Diego

Are You a Good Fit for This Trial?

This trial is for individuals with CLL or SLL that's not improving on Ibrutinib alone. Participants must have been on Ibrutinib, be able to become pregnant and agree not to during the study, and have good blood, liver, and kidney function. Exclusions include significant heart disease history, active hepatitis B/C, severe liver impairment, CNS leukemia/lymphoma, certain prior cancers or surgeries.

Inclusion Criteria

I have been diagnosed with B cell CLL or SLL and my disease can be measured.

I agree not to become pregnant during the study.

My blood, liver, and kidney functions are all within normal ranges.

Exclusion Criteria

I have been diagnosed with CNS lymphoma or leukemia.

I have an active hepatitis B or C infection.

I have not had a heart attack or significant heart disease in the last 6 months.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive venetoclax with high-dose ibrutinib, with venetoclax dose ramp-up over 5 weeks

7 cycles (approximately 7 months)

Cycle 1, Day 1 visit for dose assignment and initiation

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years or more

What Are the Treatments Tested in This Trial?

Interventions

• Ibrutinib
• Venetoclax

Trial Overview The study tests a combination of Venetoclax with high-dose Ibrutinib (up to 840 mg daily) in patients whose CLL/SLL isn't responding to just Ibrutinib. The goal is to see if this combo can better reduce cancer cells. Both drugs are FDA-approved separately but used together at these doses is experimental.

How Is the Trial Designed?

Group I: venetoclax with high-dose ibrutinib Experimental Treatment 2 Interventions

venetoclax with high-dose ibrutinib for the treatment of patients with chronic lymphocytic leukemia with progressive disease on single agent ibrutinib.

Ibrutinib is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Imbruvica for:

• Chronic lymphocytic leukemia
• Mantle cell lymphoma
• Waldenström's macroglobulinemia
• Marginal zone lymphoma
• Graft-versus-host disease

Approved in United States as Imbruvica for:

• Chronic lymphocytic leukemia/small lymphocytic lymphoma
• Mantle cell lymphoma
• Waldenström's macroglobulinemia
• Marginal zone lymphoma
• Graft-versus-host disease

Approved in Canada as Imbruvica for:

• Chronic lymphocytic leukemia
• Mantle cell lymphoma
• Waldenström's macroglobulinemia
• Marginal zone lymphoma

Approved in Japan as Imbruvica for:

• Chronic lymphocytic leukemia
• Mantle cell lymphoma
• Waldenström's macroglobulinemia

Who Is Running the Clinical Trial?

Michael Choi

Lead Sponsor

Trials

3

Recruited

30+

Pharmacyclics LLC.

Industry Sponsor

Trials

114

Recruited

13,800+

Dr. Maky Zanganeh

Pharmacyclics LLC.

Chief Executive Officer

Degree from Louis Pasteur University in Strasbourg, France; MBA from Schiller International University in France

Dr. Ellie Im

Pharmacyclics LLC.

Chief Medical Officer

MD from an unspecified institution

Published Research Related to This Trial

In a phase 3 trial with 523 patients, the combination of ibrutinib and venetoclax significantly improved progression-free survival compared to the traditional FCR treatment, with only 12 patients experiencing disease progression or death in the ibrutinib-venetoclax group versus 75 in the FCR group.

The study also found that 65.9% of patients on ibrutinib-venetoclax achieved undetectable measurable residual disease (MRD) in bone marrow after 5 years, indicating effective disease control, although there was a higher incidence of serious cardiac adverse events in this group compared to FCR.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic Lymphocytic Leukemia Therapy Guided by Measurable Residual Disease. Munir, T., Cairns, DA., Bloor, A., et al.[2023]

The HOVON 141/VISION trial is investigating the combination treatment of ibrutinib and venetoclax in patients with relapsed or refractory chronic lymphocytic leukaemia (RR-CLL), focusing on the possibility of stopping ibrutinib in patients who achieve undetectable minimal residual disease (uMRD) after 12 cycles of treatment.

The primary goal of the study is to assess progression-free survival 12 months after randomization, providing insights into the long-term efficacy and safety of discontinuing ibrutinib in patients who have reached deep remission.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Protocol description of the HOVON 141/VISION trial: a prospective, multicentre, randomised phase II trial of ibrutinib plus venetoclax in patients with creatinine clearance ≥30 mL/min who have relapsed or refractory chronic lymphocytic leukaemia (RR-CLL) with or without TP53 aberrations. Levin, MD., Kater, AP., Mattsson, M., et al.[2021]

The combination of venetoclax with rituximab showed remarkable efficacy and a manageable safety profile in treating chronic lymphocytic leukemia (CLL), both in relapsed/refractory cases and as a first-line therapy for high-risk patients.

Similarly, the combination of ibrutinib with venetoclax also demonstrated striking efficacy, suggesting that these combinations could become new standard treatment options for CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic lymphocytic leukemia at ASH 2017. Wanner, D., Steurer, M.[2020]

In a murine model of chronic lymphocytic leukemia (CLL), the combination of ibrutinib and venetoclax showed greater efficacy than either drug alone, leading to deeper responses and longer-lasting effects due to reduced cell proliferation and increased apoptosis.

The combination treatment also positively altered the T-cell compartment, increasing naive T-cells and decreasing effector memory T-cells, although resistance to treatment eventually developed, linked to downregulation of BIM expression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined ibrutinib and venetoclax treatment vs single agents in the TCL1 mouse model of chronic lymphocytic leukemia. Kater, AP., Slinger, E., Cretenet, G., et al.[2022]

In the GLOW study, the combination of ibrutinib and venetoclax resulted in significantly higher rates of undetectable minimal residual disease (uMRD) in patients with chronic lymphocytic leukemia (CLL) compared to chlorambucil and obinutuzumab, with 40.6% and 43.4% achieving uMRD in bone marrow and peripheral blood, respectively, at 3 months after treatment.

Patients treated with ibrutinib and venetoclax maintained high progression-free survival (PFS) rates at 12 months, regardless of their MRD status, with rates of 96.3% for uMRD and 93.3% for detectable MRD, indicating that this treatment is effective even for those who do not achieve complete molecular remission.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of Minimal Residual Disease on Progression-Free Survival Outcomes After Fixed-Duration Ibrutinib-Venetoclax Versus Chlorambucil-Obinutuzumab in the GLOW Study. Munir, T., Moreno, C., Owen, C., et al.[2023]

In a retrospective study of 22 patients with chronic lymphocytic leukaemia (CLL) who progressed on ibrutinib, the combination of ibrutinib and venetoclax resulted in a median overall survival of 47.1 months, indicating potential efficacy in this challenging patient group.

For 11 patients with double-refractory CLL, the same combination therapy led to a median overall survival of 27.0 months, suggesting that this treatment may provide a valuable option for patients who have limited alternatives after failing standard therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined ibrutinib and venetoclax for treatment of patients with ibrutinib-resistant or double-refractory chronic lymphocytic leukaemia. Hampel, PJ., Rabe, KG., Call, TG., et al.[2022]

Ibrutinib, idelalisib, and venetoclax are novel oral therapies for chronic lymphocytic leukemia that provide unique clinical benefits compared to traditional treatments, but they also come with specific safety concerns and logistical challenges.

Each of these agents has distinct adverse effects: ibrutinib can cause bleeding and atrial fibrillation, idelalisib may lead to hepatotoxicity, and venetoclax carries a risk of tumor lysis syndrome, necessitating careful monitoring and potential dose adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic and Pharmacodynamic Considerations in the Treatment of Chronic Lymphocytic Leukemia: Ibrutinib, Idelalisib, and Venetoclax. Waldron, M., Winter, A., Hill, BT.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11899398/

Real-World Effectiveness of Frontline Treatments Among ... We describe the effectiveness of front-line CLL treatments in adult patients with CLL in real-world settings.

2. ashpublications.org ashpublications.org/bloodneoplasia/article/1/3/100034/517258/Ibrutinib-and-venetoclax-in-combination-for

Ibrutinib and venetoclax in combination for chronic ... The ibrutinib-venetoclax combination demonstrated promising effectiveness in patients with TP53 abnormalities, although outcomes remain less ...

3. jnj.com jnj.com/media-center/press-releases/significant-efficacy-benefit-of-imbruvica-ibrutinib-plus-venetoclax-versus-acalabrutinib-plus-venetoclax-in-frontline-treatment-of-patients-with-chronic-lymphocytic-leukaemia-suggested-by-indirect-treatment-comparison

Significant efficacy benefit of IMBRUVICA® (ibrutinib) plus ... Cross-study findings indicate significant clinical benefit of frontline fixed-duration ibrutinib plus venetoclax with improved likelihood of ...

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.e19035

Safety and efficacy of venetoclax and ibrutinib in relapsed ... Safety and efficacy of venetoclax and ibrutinib in relapsed/refractory chronic lymphocytic leukemia: A systematic review and meta-analysis.

5. onclive.com onclive.com/view/fixed-duration-ibrutinib-plus-venetoclax-demonstrates-long-term-efficacy-in-untreated-cll-sll

Fixed-Duration Ibrutinib Plus Venetoclax Demonstrates ... Fixed-duration ibrutinib and venetoclax showed durable PFS and OS in treatment-naive CLL/SLL patients, with 5.5-year rates of 66% and 97%, ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT02141282

Study Details | NCT02141282 | A Phase 2 Open-Label ... This was an open-label, non-randomized, multicenter, Phase 2 study evaluating the efficacy and safety of ABT-199 in 127 participants with relapsed or refractory ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5026291/

The potential of venetoclax (ABT-199) in chronic lymphocytic ... This review summarizes the role of BCL2 in CLL pathogenesis, the development path targeting its inhibition prior to VEN, and the preclinical and clinical data ...

8. sciencedirect.com sciencedirect.com/science/article/pii/S2950328024000347

Ibrutinib and venetoclax in combination for chronic ... The combination of ibrutinib and venetoclax has emerged as a promising therapeutic strategy for patients with chronic lymphocytic leukemia (CLL).

9. evidence.nejm.org evidence.nejm.org/doi/full/10.1056/EVIDoa2200006

Fixed-Duration Ibrutinib-Venetoclax in Patients with Chronic ... Ibrutinib-venetoclax, an all-oral, once-daily, fixed-duration combination, demonstrated superior PFS and deeper and better sustained responses.