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Waldenstrom MacroglobulinemiaPhase 2NCT04273139

Ibrutinib + Venetoclax in Untreated WM

A Phase 2 study testing IBRUTINIB and Venetoclax in people with Waldenstrom Macroglobulinemia and MYD88 Gene Mutation, run by Dana-Farber Cancer Institute at 2 sites in United States.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
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Trial summary

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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
IBRUTINIB and Venetoclax
Could I receive a placebo?
No, everyone receives an active treatment
How many people
45 participants
Where
2 sitesUnited States
Study dates
9 Jul 2020to 1 Feb 2028
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Participants must meet the following criteria on screening examination to be eligible to participate. Screening evaluations including consent, physical exam, and laboratory assessments will be done within 30 days prior to Cycle 1 Day 1. Bone marrow biopsy \& aspirate, and CT C/A/P will be done within 90 days prior to Cycle 1 Day 1.
  • Clinicopathological diagnosis of Waldenström macroglobulinemia [28].
  • Known tumor expression of mutated MYD88 performed by a CLIA certified laboratory.
  • Symptomatic disease meeting criteria for treatment using consensus panel criteria from the Second International Workshop on Waldenström macroglobulinemia [29].
  • Participants with symptomatic hyperviscosity (e.g. nosebleeds, headaches, blurred vision) must undergo plasmapheresis prior to treatment initiation.
  • Age ≥ 18 years
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  • ECOG performance status ≤2 (see Appendix A)
  • Measurable disease, defined as presence of serum immunoglobin M (IgM) with a minimum IgM level of >2 times the upper limit of normal of each institution is required
  • At the time of screening, participants must have acceptable organ and marrow function as defined below:
  • Absolute neutrophil count ≥500/uL (no growth factor permitted)
  • Platelets ≥50,000/uL (no platelet transfusions permitted)
  • Hemoglobin ≥ 7 g/dL (transfusions permitted)
  • Total bilirubin < 1.5 x institutional ULN
  • AST(SGOT)/ALT(SGPT) ≤2.5 × institutional ULN
  • Estimated GFR ≥30 mL/min
  • Females of childbearing potential (FCBP) must use one reliable form of contraception or have complete abstinence from heterosexual intercourse during the following time periods related to this study: 1) while participating in the study; and 2) for at least 90 days after discontinuation from the study. FCBP must be referred to a qualified provider of contraceptive methods if needed. FCBP must have a negative serum pregnancy test at screening.
  • Men must agree to use a latex condom during treatment and for up to 90 days after the last dose of ibrutinib or venetoclax during sexual contact with a FCBP
  • Ability to understand and the willingness to sign a written informed consent document.

Who cannot join

  • Participants who exhibit any of the following conditions at screening will not be eligible for admission into the study:
  • Participants who have one or more prior systemic therapies for WM.
  • Participants who are receiving any other investigational agents.
  • Participants with known CNS lymphoma.
  • Participants with known history of Human Immunodeficiency Virus (HIV), chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring active treatment. Note: Participants with serologic evidence of prior vaccination to HBV (i.e., HBs Ag-, and anti-HBs+ and anti-HBC-) and positive anti-HBc from IVIG may participate.
  • Concurrent administration of medications or foods that are moderate or strong inhibitors or inducers of CYP3A within 7 days prior to first dose of study drug.
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  • Participants with chronic liver disease and hepatic impairment meeting Child-Pugh class C (Appendix B).
  • Concurrent administration of warfarin.
  • Concurrent systemic immunosuppressant therapy within 21 days of the first dose of study drug.
  • Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.
  • Recent infection requiring systemic treatment that was completed ≤ 14 days before the first dose of the study drug.
  • Known bleeding disorders (e.g., congenital von Willebrand's disease or hemophilia)
  • History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
  • Major surgery within 4 weeks of first dose of study drug.
  • Malabsorption syndrome or other condition that precludes enteral route of administration.
  • Female participants who are pregnant, breastfeeding, or planning to become pregnant while enrolled in this study or within 90 days of last dose of study drug.
  • Male participants who plan to father a child while enrolled in this study or within 90 days after the last dose of study drug
  • Participants with known history of alcohol or drug abuse.
  • Participants with inability to swallow pills.
  • On any active therapy for other malignancies with the exception of topical therapies for basal cell or squamous cell cancers of the skin.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Participants with a history of non-compliance to medical regimens.
  • Participants who are unwilling or unable to comply with the protocol.

Trial locations and contacts

2 sites in 1 country.

United States2 sites

  • Massachusetts General Hospital

    Boston, Massachusetts, 02214

  • Dana Farber Cancer Institute

    Boston, Massachusetts, 02215

Other trials in United States

About this study

Official title: Phase II Study on the Combination of Ibrutinib and Venetoclax in Treatment naïve Patients With Waldenström Macroglobulinemia

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
Read the detailed description
  • This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific disease. "Investigational" means that the drug is being studied.
  • The names of the study drugs involved in this study are:
  • Venetoclax
  • ibrutinib
  • The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits.
  • Participants will be on the research study for up to 2 years on combined venetoclax and ibrutinib and 4 years of follow-up .
  • It is expected that about 50 people will take part in this research study.
  • The U.S. Food and Drug Administration (FDA) has not approved venetoclax for your specific disease but it has been approved for other uses. -- Venetoclax is a targeted therapy that blocks BCL-2, a protein that is important for the survival of WM cells. Laboratory studies and early clinical data have shown that the investigational new agent, venetoclax, may kill cancer cells and may cause tumors to shrink.
  • The U.S. Food and Drug Administration (FDA) has approved ibrutinib as a treatment option for this disease. --Ibrutinib is a targeted therapy that blocks BTK. It has been FDA approved in chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), chronic graft vs. host disease (cGVHD), and Waldenstrom's macroglobulinemia (WM). It is also used in research studies in participants with recurrent B-cell lymphoma), diffuse large B-cell lymphoma (DLBCL), and prolymphocytic leukemia. In a study of ibrutinib in relapsed/refractory WM patients, response rates were high and the treatment was well tolerated.
  • The U.S. Food and Drug Administration (FDA) has not approved the combination of ibrutinib and venetoclax as a treatment for any disease.
  • The U.S. Food and Drug Administration (FDA) has not approved the MYD88 test. This test is investigational.
Being tested
IBRUTINIB, Venetoclax
Keywords
Waldenstrom Macroglobulinemia, ibrutinib, venetoclax
Medical subject headings
Waldenstrom Macroglobulinemia

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • IBRUTINIBDrug

    Also called Imbruvica

    Ibrutinib Cycle 1-24 will be administered at a predetermined dose, once daily for 28 days

  • VenetoclaxDrug

    Also called Venclexta

    Venetoclax Cycle 2-24 will be administered daily for 28 days. Predetermined dosage ramp up schedule during cycle 2.

Study groups in NCT04273139
Study groupRoleWhat they receive
Ibrutinib and VenetoclaxExperimentalThe 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.
Receives: Drug: IBRUTINIB; Drug: Venetoclax

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Number of Participants With Very Good Partial Response Within 24 Cycles of Therapy

    Proportion of patients with VGPR to therapy within 24 cycles of therapy initiation. (VGPR is >90% reduction in serum IgM from baseline)

    Measured: The primary objective of VGPR within 24 cycles of therapy was assessed starting at Cycle 3 Day 1 through the End of Treatment visit, range of 2 to 21 months after the initiation of therapy.

Secondary outcomes (12)

  1. Number of Participants With Complete Response (CR) After 6 Cycles

    Proportion of patients with a complete response after 6 cycles of therapy. A complete response (CR) is defined as having resolution of WM related symptoms, normalization of serum IgM levels with complete disappearance of IgM paraprotein by immunofixation, and resolution of any adenopathy or splenomegaly.

    Measured: 6 Cycles (28 day cycle)

  2. Number of Participants With Complete Response (CR) After 12 Cycles

    Proportion of patients with a complete response after 12 cycles of therapy. A complete response (CR) is defined as having resolution of WM related symptoms, normalization of serum IgM levels with complete disappearance of IgM paraprotein by immunofixation, and resolution of any adenopathy or splenomegaly.

    Measured: 12 Cycles (28 day cycle)

  3. Number of Participants With Complete Response (CR) After 24 Cycles

    Proportion of patients with a complete response after 24 cycles of therapy. A complete response (CR) is defined as having resolution of WM related symptoms, normalization of serum IgM levels with complete disappearance of IgM paraprotein by immunofixation, and resolution of any adenopathy or splenomegaly.

    Measured: Complete response to therapy was assessed starting at Cycle 3 Day 1 through the End of Treatment visit, range of 2 to 21 months after the initiation of therapy.

  4. Overall Response

    Proportion of patients with minor response (MR) , partial response (PR), very good partial response (VGPR), or complete response (CR) to therapy.

    Measured: 72 months

  5. Rate of VGPR at 30 Months

    Proportion of patients with a VGPR at 30 months from beginning therapy.

    Measured: 30 Months

  6. Median Time to Response

    Time from treatment initiation until achievement of a minor response (reduction in serum IgM >25%) or better.

    Measured: 24 months

  7. Median Time to Major Response

    Time from treatment initiation until partial response or better (>50% reduction in serum IgM)

    Measured: 24 months

  8. Progression Free Survival (PFS) at 24 Months

    Time from initiation of therapy until disease progression (>25% increase in serum IgM and 500 mg/dL absolute increase).

    Measured: 24 months

  9. Progression Free Survival (PFS) at 36 Months

    Time from initiation of therapy until disease progression (>25% increase in serum IgM and 500 mg/dL absolute increase).

    Measured: 36 Months

  10. Progression Free Survival (PFS) at 48 Months

    Time from initiation of therapy until disease progression (>25% increase in serum IgM and 500 mg/dL absolute increase).

    Measured: 48 Months

  11. Time to Next Treatment

    Time from initiation of IVEN protocol therapy until initiation of new line of therapy.

    Measured: 72 months

  12. Number of Participants With Treatment Related Adverse Events as Assessed (CTCAE) Version 5.0

    CTCAE version 5.0

    Measured: 6 Months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted17 Feb 2020
  2. Study start9 Jul 2020
  3. Primary completion6 Jun 2022
  4. Study completion1 Feb 2028 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Sequential
Masking
None (open label)
Enrolment
45 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04273139
Sponsor's protocol ID
19-651
Status last verified
Jul 2025
First submitted
14 Feb 2020
Last updated
11 May 2026
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to Sponsor Investigator or designee. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.

Publications

  • Castillo JJ, Branagan AR, Sermer D, Flynn CA, Meid K, Little M, Stockman K, White T, Canning A, Guerrera ML, Kofides A, Liu S, Liu X, Richardson K, Tsakmaklis N, Patterson CJ, Hunter ZR, Treon SP, Sarosiek S. Ibrutinib and venetoclax as primary therapy in symptomatic, treatment-naive Waldenstrom macroglobulinemia. Blood. 2024 Feb 15;143(7):582-591. doi: 10.1182/blood.2023022420.

    PubMed 37971194

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing IBRUTINIB and Venetoclax in people with Waldenstrom Macroglobulinemia and MYD88 Gene Mutation, run by Dana-Farber Cancer Institute at 2 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 18 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: under way, not looking for participants, as of the sponsor's last update on 11 May 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 23 Apr 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Participants With Very Good Partial Response Within 24 Cycles of Therapy (time frame: The primary objective of VGPR within 24 cycles of therapy was assessed starting at Cycle 3 Day 1 through the End of Treatment visit, range of 2 to 21 months after the initiation of therapy.). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04273139, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 May 2026.

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