Ibrutinib + Venetoclax for Waldenstrom Macroglobulinemia

Not currently recruiting at 1 trial location

Overseen By Jorge J Castillo, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Dana-Farber Cancer Institute

Must not be taking: CYP3A inhibitors, Warfarin

Disqualifiers: Prior therapies, CNS lymphoma, HIV, 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: Unknown

Duration: 24 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two drugs, Ibrutinib (Imbruvica) and Venetoclax (Venclexta), to evaluate their safety and effectiveness in treating Waldenstrom's macroglobulinemia, a rare blood cancer. The focus is on patients whose cancer involves a specific change in the MYD88 gene. This trial may suit those diagnosed with Waldenstrom's macroglobulinemia who experience symptoms like nosebleeds, headaches, or blurred vision due to thickened blood. Participants will receive the treatment over several cycles, with close monitoring for safety and effectiveness. As a Phase 2 trial, the research measures how well the treatment works in an initial, smaller group of people.

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

The trial protocol does not specify if you need to stop taking your current medications, but you cannot take certain medications that affect liver enzymes (CYP3A) within 7 days before starting the study drugs. 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 the combination of Ibrutinib and Venetoclax is generally well-tolerated by patients. Earlier studies have shown promising results for people with Waldenstrom's macroglobulinemia (WM), a type of blood cancer. Reports indicate significant improvements in survival rates and disease control.

Side effects can occur, but most are manageable. Common side effects might include mild to moderate issues like diarrhea, tiredness, or nausea. Serious side effects are less common, but doctors closely monitor patients to manage any potential risks. Both drugs have been used for other conditions, which provides some confidence about their safety.

These findings come from studies where researchers closely monitor patients to ensure safety. If considering joining a trial, discussing potential risks and benefits with healthcare professionals is essential. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for Waldenstrom's macroglobulinemia?

Researchers are excited about using Ibrutinib and Venetoclax together for Waldenstrom Macroglobulinemia because this combination targets cancer cells in a unique way. While traditional treatments often focus on chemotherapy, Ibrutinib is a BTK inhibitor that disrupts signals essential for cancer cell survival, and Venetoclax is a BCL-2 inhibitor that helps trigger cancer cell death. This combination has the potential to be more effective by simultaneously blocking multiple pathways that cancer cells use to grow and survive.

What evidence suggests that this treatment might be an effective treatment for Waldenstrom's macroglobulinemia?

Research shows that combining ibrutinib and venetoclax effectively treats Waldenström macroglobulinemia (WM), particularly in patients who have not received prior treatment. Studies have found that these patients often experience significant and long-lasting improvements. In this trial, participants will receive the combination of ibrutinib and venetoclax, which has been linked to many lasting treatment successes. Additionally, venetoclax alone has shown promise for patients whose WM has returned or is resistant to other treatments. Overall, this combination appears highly effective for this type of cancer. ^{1 2 3 6 7}

Who Is on the Research Team?

Jorge J Castillo, MD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

Adults with Waldenstrom's macroglobulinemia (WM) and MYD88 gene mutation can join this trial. They must have measurable disease, be over 18, in stable health (ECOG ≤2), and have proper organ function. Women of childbearing age must use contraception or abstain from sex and not be pregnant or breastfeeding. Men must also agree to use condoms. People who've had prior WM treatments, uncontrolled illnesses, certain infections or liver diseases, or are non-compliant with medical regimens cannot participate.

Inclusion Criteria

I have undergone plasmapheresis for my symptomatic hyperviscosity before starting treatment.

I am a man and agree to use a condom for 90 days after my last dose of treatment.

I have been diagnosed with Waldenström macroglobulinemia.

Exclusion Criteria

I do not have any uncontrolled illnesses.

I have not had major surgery in the last 4 weeks.

I am currently taking warfarin.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Ibrutinib and Venetoclax for up to 2 years, with TLS prophylaxis prior to Venetoclax

24 months

Monthly visits for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

48 months

What Are the Treatments Tested in This Trial?

Interventions

• Ibrutinib
• Venetoclax

Trial Overview The trial is testing the combination of two drugs: Ibrutinib and Venetoclax for untreated WM patients with a specific gene mutation. It aims to see how safe this combo is and how well it works as a treatment option.

How Is the Trial Designed?

Group I: Ibrutinib and Venetoclax Experimental Treatment 2 Interventions

The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits. * Ibrutinib will be administered at a predetermined dose, once daily for 28 days * TLS Prophylaxis (Treatment to reduce risk of tumor lysis syndrome) prior to first dose of venetoclax (and for at least the first 2 weeks of treatment) * Venetoclax Cycle 2-24. PO daily, predetermined dosage ramp up during cycle 2.

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?

Dana-Farber Cancer Institute

Lead Sponsor

Trials

1,128

Recruited

382,000+

AbbVie

Industry Sponsor

Trials

1,079

Recruited

535,000+

Founded

2013

Headquarters

North Chicago, USA

Known For

Immunology treatments

Top Products

Humira (adalimumab), Skyrizi (risankizumab), Rinvoq (upadacitinib)

Dr. Roopal Thakkar

AbbVie

Chief Medical Officer since 2023

MD from Wayne State University School of Medicine

Robert A. Michael

AbbVie

Chief Executive Officer

Bachelor's degree in Finance from the University of Illinois

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

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]

After a median follow-up of 46 months in the GLOW study, patients with untreated chronic lymphocytic leukaemia who received ibrutinib-venetoclax had a significantly better progression-free survival rate (74.6%) compared to those treated with chlorambucil-obinutuzumab (24.8%), indicating the efficacy of the ibrutinib-venetoclax combination as a first-line treatment.

While there were treatment-related deaths in both groups, the overall mortality was lower in the ibrutinib-venetoclax group (15 deaths) compared to the chlorambucil-obinutuzumab group (30 deaths), suggesting a potentially safer profile for the ibrutinib-venetoclax regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fixed-duration ibrutinib-venetoclax versus chlorambucil-obinutuzumab in previously untreated chronic lymphocytic leukaemia (GLOW): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial. Niemann, CU., Munir, T., Moreno, C., et al.[2023]

Long-term treatment with the combination of venetoclax and ibrutinib in mantle cell lymphoma (MCL) patients led to significant changes in immune cell populations, particularly in CD4+ and CD8+ T cells and natural killer cells, indicating a potential for immune recovery.

Despite the restoration of normal immune subsets in patients who stopped treatment after achieving deep responses, certain myeloid gene expressions remained altered, suggesting that the combination therapy may have lasting effects on the immune system even after treatment cessation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune recovery in patients with mantle cell lymphoma receiving long-term ibrutinib and venetoclax combination therapy. Davis, JE., Handunnetti, SM., Ludford-Menting, M., et al.[2021]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10873534/

Ibrutinib and venetoclax as primary therapy in symptomatic ... The combination of ibrutinib and venetoclax induced deep and durable responses in treatment-naïve patients with Waldenström macroglobulinemia.

2. nature.com nature.com/articles/s41408-025-01271-3

Outcomes of patients with relapsed/refractory ... Venetoclax showed promising activity in a small phase II trial in relapsed/refractory Waldenström macroglobulinemia (WM).

3. cancernetwork.com cancernetwork.com/view/ibrutinib-venetoclax-combo-appears-effective-in-previously-untreated-waldenstr-m-macroglobulinemia

Ibrutinib-Venetoclax Combo Appears Effective in ... The use of ibrutinib (Imbruvica) in combination with venetoclax (Venclexta) was associated with a high number of durable treatment responses ...

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. clinicaltrials.gov clinicaltrials.gov/study/NCT05099471

Study Details | NCT05099471 | Efficacy of Venetoclax in ... First data in relapsed/refractory WM have documented high activity and low toxicity of Venetoclax also in WM, including patients with prior Ibrutinib treatment ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04273139

NCT04273139 | Ibrutinib + Venetoclax in Untreated WM This study evaluates the safety and efficacy of Ibrutinib combined with Venetoclax (IVEN) in the treatment of adults diagnosed with Waldenstrom's ...

7. ashpublications.org ashpublications.org/bloodadvances/article/9/19/4842/546239/Long-term-follow-up-of-venetoclax-monotherapy-in

Long-term follow-up of venetoclax monotherapy in previously ... The B-cell lymphoma 2 (BCL2) antagonist venetoclax is safe and effective for patients with relapsed Waldenström Macroglobulinemia (WM) and is ...