Venetoclax + Ibrutinib for Chronic Lymphocytic Leukemia

Overseen By Nitin Jain, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Warfarin, Strong CYP3A inhibitors

Disqualifiers: HIV, Hepatitis B, Hepatitis C, 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: Up to 27 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of combining two drugs, venetoclax and ibrutinib, to treat chronic or small lymphocytic leukemia, a type of blood cancer. Venetoclax blocks a protein that aids cancer cell survival, while ibrutinib inhibits enzymes that promote cancer cell growth. The trial seeks participants diagnosed with chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL), particularly those who have relapsed after other treatments or possess certain high-risk features. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group of people.

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

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot use warfarin or strong CYP3A inhibitors or inducers within 7 days of starting the study drugs.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that using ibrutinib and venetoclax together is generally safe and effective for treating chronic lymphocytic leukemia (CLL). Studies have found that these drugs work better together against CLL cells than when used separately.

While some patients might experience side effects, most can be managed. Common side effects include diarrhea, tiredness, and nausea, but serious side effects are less common. Overall, evidence suggests that this combination is a promising treatment option for CLL, with a safety profile considered acceptable based on current research. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using Venetoclax and Ibrutinib together for chronic lymphocytic leukemia (CLL) because this combination targets cancer cells in a unique way. Venetoclax works by blocking a protein called BCL-2 that helps cancer cells survive, while Ibrutinib inhibits a different pathway crucial for cancer cell growth. This dual-action approach might overcome resistance seen with other treatments, which usually focus on just one of these pathways. Additionally, this combination has the potential to reduce the time patients need to be on treatment, offering a more efficient and targeted option compared to traditional therapies.

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

Research has shown that using ibrutinib and venetoclax together may effectively treat chronic lymphocytic leukemia (CLL). This trial will evaluate the combination of these two drugs, particularly beneficial for patients with TP53 abnormalities, a genetic change linked to more aggressive cancer. These drugs block proteins and enzymes that help cancer cells survive and grow. While ibrutinib alone often leads to only partial improvement, adding venetoclax can enhance results. Studies suggest that this combination significantly increases the chances of controlling CLL. ^{2 3 5 6 7}

Who Is on the Research Team?

Nitin Jain, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for patients with chronic or small lymphocytic leukemia who are in good physical condition (ECOG <=2) and have properly functioning kidneys and liver. It includes those untreated with high-risk features, relapsed after prior therapy, or free from other malignancies for 2 years. Pregnant women, HIV-positive individuals, those with active infections or hepatitis B/C, recent recipients of certain therapies, and anyone on strong CYP3A inhibitors/inducers can't participate.

Inclusion Criteria

I have been diagnosed with CLL/SLL.

My condition did not improve after at least one treatment.

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3.0 x ULN, unless clearly due to disease involvement

Exclusion Criteria

I am HIV positive and understand there may be interactions with my medication.

I do not have an active hepatitis B infection, or I am vaccinated against it.

Consumed grapefruit, grapefruit products, Seville oranges, or star fruit within 7 days of starting study drugs

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ibrutinib orally once daily on days 1-28. Beginning on day 1 of cycle 4, participants also receive venetoclax orally once daily on days 1-28. Treatment repeats every 28 days for up to 27 cycles.

Up to 27 months

Monthly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion every 3-6 months.

Up to 8 years

Every 3-6 months (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Ibrutinib
• Venetoclax

Trial Overview The study tests the combination of venetoclax and ibrutinib to treat chronic/small lymphocytic leukemia. Venetoclax aims to block a protein that cancer cells need to survive while Ibrutinib targets enzymes important for cell growth. The goal is to see if this drug combo can control the disease better than current treatments.

How Is the Trial Designed?

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

Patients receive ibrutinib PO QD on days 1-28. Beginning on day 1 of cycle 4, patients also receive venetoclax PO QD on days 1-28. Treatment repeats every 28 days for up to 27 cycles in the absence of disease progression or unacceptable toxicity. Patients with residual disease or who are positive for MRD after cycle 27 may continue treatment with 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?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Published Research Related to This Trial

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]

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 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]

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 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]

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]

Citations

1. 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 ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4537801/

Pharmacological and protein profiling suggest venetoclax ... Though ibrutinib results in impressive clinical activity in chronic lymphocytic leukemia (CLL), most patients achieve only partial remission due to residual ...

3. 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 ...

4. 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 ...

5. 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 ...

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

Fixed-Duration Ibrutinib-Venetoclax in Patients with Chronic ... GLOW is a phase 3 trial evaluating the efficacy and safety of ibrutinib-venetoclax in older patients and/or those with comorbidities with ...