Ibrutinib + Venetoclax for Waldenstrom Macroglobulinemia

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

45 Participants Needed

Trial Summary

What is the purpose of this trial?

This study evaluates the safety and efficacy of Ibrutinib combined with Venetoclax (IVEN) in the treatment of adults diagnosed with Waldenstrom's macroglobulinemia (WM) cancer with a specific MYD88 gene mutation. This research study involves an experimental drug combination of targeted therapies. The names of the study drugs involved in this study are: * Venetoclax * ibrutinib

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.

What data supports the effectiveness of the drug combination of Ibrutinib and Venetoclax for Waldenstrom Macroglobulinemia?

In a study of patients with Waldenstrom Macroglobulinemia, 42% achieved a very good partial response (VGPR) with the combination of Ibrutinib and Venetoclax, and the 24-month progression-free survival rate was 76%. This suggests the drug combination can be effective, although there were some serious side effects like heart rhythm problems. ^{1 2 3 4 5}

How is the drug combination of Ibrutinib and Venetoclax unique for treating Waldenstrom Macroglobulinemia?

The combination of Ibrutinib and Venetoclax is unique for treating Waldenstrom Macroglobulinemia because it targets both BTK and BCL2 proteins, which are involved in cancer cell survival, and has shown high rates of very good partial responses in patients who have not received prior treatment. This approach is novel as it addresses resistance mechanisms seen with Ibrutinib alone, offering a potentially more effective treatment option. ^{1 2 4 6 7}

Research Team

Jorge J Castillo, MD

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

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]

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]

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]

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]

References

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

Ibrutinib and venetoclax as primary therapy in symptomatic treatment naïve Waldenström macroglobulinemia. [2023]

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

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

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

Immune recovery in patients with mantle cell lymphoma receiving long-term ibrutinib and venetoclax combination therapy. [2021]

4. England 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. [2023]

5. Germany pubmed.ncbi.nlm.nih.gov

Ibrutinib combined with venetoclax for the treatment of relapsed/refractory diffuse large B cell lymphoma. [2021]

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

Waldenstrom macroglobulinemia cells devoid of BTKC481S or CXCR4WHIM-like mutations acquire resistance to ibrutinib through upregulation of Bcl-2 and AKT resulting in vulnerability towards venetoclax or MK2206 treatment. [2021]

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]