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

Trial Summary

What is the purpose of this trial?

The purpose of the study is to investigate whether the combination of venetoclax and ibrutinib (administered up to 840 mg per day) might be useful for the treatment of CLL or SLL that is not responding or no longer responding to treatment with ibrutinib alone. The study will evaluate whether this regimen can reduce the amount of cancerous cells in your body. If you agree, you will receive ibrutinib at a dose of up to 840 mg a day by mouth, as well as venetoclax. Although both of these agents are approved by the FDA for the treatment of CLL or SLL, the combination and the dosing schedule of ibrutinib are considered experimental.

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.

What data supports the effectiveness of the drug combination of ibrutinib and venetoclax for chronic lymphocytic leukemia?

Research shows that the combination of ibrutinib and venetoclax can improve outcomes for patients with chronic lymphocytic leukemia, especially in those who have not responded to other treatments. Studies indicate that this combination can lead to longer periods without disease progression and may become a new standard treatment option. ^{1 2 3 4 5}

Is the combination of Venetoclax and Ibrutinib generally safe for humans?

The combination of Venetoclax and Ibrutinib has shown a manageable safety profile in treating chronic lymphocytic leukemia, although there are some risks. Ibrutinib can cause bleeding and heart rhythm problems, while Venetoclax may lead to tumor lysis syndrome (a condition where cancer cells break down quickly, causing kidney damage). ^{1 2 4 5 6}

How is the drug combination of venetoclax and ibrutinib unique for treating chronic lymphocytic leukemia?

The combination of venetoclax and ibrutinib is unique because it targets CLL with two different mechanisms, potentially leading to deeper and longer-lasting responses compared to single-agent treatments. This combination is particularly promising for patients who have relapsed or have high-risk disease, offering a new option where other treatments may have failed. ^{1 4 5 7 8}

Research Team

Michael Choi, MD

Principal Investigator

University of California, San Diego

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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]

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]

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]

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]

References

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

Chronic Lymphocytic Leukemia Therapy Guided by Measurable Residual Disease. [2023]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Pharmacokinetic and Pharmacodynamic Considerations in the Treatment of Chronic Lymphocytic Leukemia: Ibrutinib, Idelalisib, and Venetoclax. [2021]

3. United States 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. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Combined ibrutinib and venetoclax for treatment of patients with ibrutinib-resistant or double-refractory chronic lymphocytic leukaemia. [2022]

5. Austria pubmed.ncbi.nlm.nih.gov

Chronic lymphocytic leukemia at ASH 2017. [2020]

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

The efficacy and safety of venetoclax therapy in elderly patients with relapsed, refractory chronic lymphocytic leukaemia. [2020]

7. England 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. [2021]

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

Combined ibrutinib and venetoclax treatment vs single agents in the TCL1 mouse model of chronic lymphocytic leukemia. [2022]