Venetoclax + Ibrutinib for Chronic Lymphocytic Leukemia

Overseen By Maria Corfias

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Ohio State University Comprehensive Cancer Center

Must be taking: Ibrutinib

Must not be taking: Warfarin, Strong CYP3A inhibitors

Disqualifiers: Uncontrolled autoimmune, HIV, Hepatitis, 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: 3

Duration: 48-96 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of combining venetoclax and ibrutinib to treat individuals with chronic lymphocytic leukemia (CLL) who have developed genetic mutations after previous ibrutinib treatment. The researchers aim to determine if these drugs can inhibit cancer cell growth by blocking essential enzymes. Individuals currently taking ibrutinib and having CLL with specific genetic changes may be suitable candidates for this trial. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group, providing participants an opportunity to contribute to significant advancements in CLL treatment.

Do I need to stop my current medications to join the trial?

The trial requires that you continue taking ibrutinib, as it is part of the study treatment. However, you cannot take certain other medications, like strong CYP3A inhibitors or inducers, within 7 days before starting venetoclax. The protocol does not specify about other medications, so it's best to discuss with the trial team.

Is there any evidence suggesting that venetoclax and ibrutinib are likely to be safe for humans?

Research shows that the combination of venetoclax and ibrutinib is generally well-tolerated by people with chronic lymphocytic leukemia (CLL). Studies have found this treatment to be highly effective for patients. Although some side effects, such as low blood cell counts and diarrhea, have been noted, most patients manage the treatment without major issues.

The studies indicate that these side effects are often manageable. Both venetoclax and ibrutinib have been safely used in other CLL patients, suggesting that the treatment is safe for those considering participation in a trial with these medications. ^{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 targets cancer cells in a novel way. Unlike traditional chemotherapy, which attacks rapidly dividing cells indiscriminately, Venetoclax specifically inhibits a protein called BCL-2, which helps cancer cells survive. Ibrutinib, on the other hand, blocks the BTK enzyme, disrupting signals that promote cancer cell growth. This dual approach not only aims to be more effective in eliminating cancer cells but also holds promise for greater durability of response, potentially leading to longer remission periods for patients.

What evidence suggests that venetoclax and ibrutinib might be effective for chronic lymphocytic leukemia?

Research has shown that using venetoclax and ibrutinib together yields promising results for treating chronic lymphocytic leukemia (CLL). In this trial, participants will receive this combination. Studies have found it works well, particularly for patients with genetic changes such as TP53 abnormalities. It helps extend the time people live without disease progression. The treatment also results in stronger and longer-lasting improvements, significantly reducing cancer activity. Overall, the venetoclax-ibrutinib combination appears to be a strong option for managing CLL, especially after other treatments. ^{1 2 3 4 5}

Who Is on the Research Team?

Kerry Rogers, MD

Principal Investigator

Ohio State University Comprehensive Cancer Center

Are You a Good Fit for This Trial?

This trial is for people with chronic lymphocytic leukemia who have developed resistance to a drug called Ibrutinib. Participants must have certain blood cell counts, be able to perform daily activities with minimal assistance (ECOG ≤ 2), and show specific genetic mutations linked to the resistance. They should not have uncontrolled autoimmune reactions affecting their blood cells.

Inclusion Criteria

Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 ≤ ULN

Ability to understand and sign a written informed consent

My bone marrow works well on its own, or any issues are due to my CLL.

Exclusion Criteria

I may have had hepatitis but my current tests show no active virus.

I cannot continue taking ibrutinib for any reason.

I have uncontrolled autoimmune blood disorders.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive venetoclax and ibrutinib daily in 28-day cycles for up to 12 or 24 courses

48-96 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Every 3 months for 2 years, then every 6 months

What Are the Treatments Tested in This Trial?

Interventions

• Ibrutinib
• Venetoclax

Trial Overview The study is testing the combination of two drugs, Venetoclax and Ibrutinib, in patients whose leukemia has stopped responding to Ibrutinib alone. The goal is to see if this combo can block cancer growth by shutting down enzymes that cancer cells need.

How Is the Trial Designed?

Group I: Treatment (venetoclax, ibrutinib) Experimental Treatment 3 Interventions

Participants receive venetoclax PO daily on days 1-28 and ibrutinib PO QD on days 1-28. Treatment repeats every 28 days for up to 12 or 24 courses in the absence of disease progression or unacceptable toxicity. Participants with MRD negativity after 12 or 24 courses discontinue treatment, while participants with MRD positivity continue treatment with venetoclax in the absence of disease progression or unacceptable toxicity.

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?

Ohio State University Comprehensive Cancer Center

Lead Sponsor

Trials

350

Recruited

295,000+

Published Research Related to This Trial

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]

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 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]

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]

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]

Citations

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

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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 ...

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

The potential of venetoclax (ABT-199) in chronic lymphocytic ... (2015) Outcomes of patients with chronic lymphocytic leukemia after discontinuing ibrutinib. Blood 125: 2062–2067. [DOI] [PMC free article] [PubMed] [Google ...

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

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

5. 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.