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Waldenstrom MacroglobulinemiaPhase 2NCT07231952

A Study of Pirtobrutinib, Venetoclax, and Rituximab in People With Waldenström's Macroglobulinemia (WM)/Lymphoplasmacytic Lymphoma (LPL)

A Phase 2 study testing Pirtobrutinib, Venetoclax and Rituximab in people with Waldenstrom Macroglobulinemia and Lymphoplasmacytic Lymphoma, run by Memorial Sloan Kettering Cancer Center at 9 sites in United States.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
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Trial summary

The purpose of this study is to find out if the combination of pirtobrutinib, venetoclax, and rituximab is an effective treatment for participants with Waldenström's macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Pirtobrutinib, Venetoclax and Rituximab
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
40 participants
Where
9 sitesUnited States
Study dates
11 Nov 2025to 11 Apr 2028
Phase
Phase 2
Are there results?
Not yet: the study is under way

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

  • Age greater than or equal to 18 years
  • Histologically confirmed treatment naive WM/LPL (participants with non-IgM LPL are NOT eligible for the study)
  • Patients must have measurable disease as defined by at least one lymph node ≥1.5 cm and/ or IgM levels > 0.5gm/dl quantified by using densitometry on serum protein electrophoresis (SPEP) or quantitative nephelometry.
  • Participants must have at least one of the established criteria to require therapy for WM, including anemia, thrombocytopenia, neuropathy related to WM, symptomatic hyperviscosity or serum viscosity levels greater than 4.0 centipoises, WM-associated glomerulonephritis or renal disease, bulky disease, or constitutional symptoms
  • ECOG performance status ≤2
  • Platelet count ≥ 25,000 mm3 without bleeding
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  • Hemoglobin ≥ 8 g/dL, unless due to disease involvement in which case ≥ 7 g/dL, independent of transfusions within 7 days of screening assessment
  • Absolute neutrophil count >1000 cells/mcL, independent of growth factor support within 7 days of screening assessment
  • Total bilirubin < 1.5 x upper normal institutional limits. In patients with Gilbert's disease total bilirubin up to 3x ULN will be allowed
  • AST(SGOT)/ALT(SGPT) < 3 x institutional upper limit of normal unless elevation is caused by liver involvement with WM in which case AST and ALT may be ≤ 5 x ULN. In the event of AST or ALT unable to result due to interference of the serum IgM with the liver function tests assay, patient can still be eligible per MSK PI discretion, dependent on other liver enzymes tests being within protocol parameters.
  • Creatinine within normal institutional limits OR Creatinine clearance >40 mL/min for patients with creatinine levels above institutional normal (by Cockcroft-Gault estimate or 12-24h creatinine clearance measurements)
  • Adequate coagulation, defined as activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT) and prothrombin (PT) or (international normalized ratio (INR) not greater than 1.5 x ULN
  • Ability to understand and the willingness to sign a written informed consent document.
  • Patient must be able to swallow pills
  • Patients with Hepatitis B surface antibody serum positivity due to prior immunization, as well as those with Hepatitis B core antibody positivity with negative PCR on antiviral therapy will be eligible.
  • Willingness of participants of reproductive potential and their partners to observe highly effective birth control methods for the duration of treatment and for 1 year following the last dose of study treatment

Who cannot join

  • Prior/Concomitant Therapy: Participants must not have had prior systemic therapy.
  • Medical Conditions
  • Major surgery within 4 weeks prior to start of treatment
  • History of bleeding diathesis
  • Patients who experienced a major bleeding event or grade ≥ 3 arrhythmia on prior treatment with a BTK inhibitor.
  • NOTE: Major bleeding is defined as bleeding having one or more of the following features: potentially life-threatening bleeding with signs or symptoms of hemodynamic compromise; bleeding associated with a decrease in the hemoglobin level of at least 2g per deciliter; or bleeding in a critical area or organ (e.g., retroperitoneal, intraarticular, pericardial, epidural, or intracranial bleeding or intramuscular bleeding with compartment syndrome)
Show all 40Show fewer
  • History of stroke or intracranial hemorrhage within 6 months of start of treatment
  • History of allogeneic or autologous stem cell transplant (SCT) or chimeric antigen receptor-modified T-cell (CAR-T) therapy within 60 days of start of treatment or presence of any of the following, regardless of prior SCT and/or CAR-T therapy timing:
  • active graft versus host disease (GVHD);
  • cytopenia from incomplete blood cell count recovery post-transplant;
  • need for anti-cytokine therapy for toxicity from CAR-T therapy; residual symptoms of neurotoxicity > Grade 1 from CAR-T therapy;
  • ongoing immunosuppressive therapy (> 20 mg prednisone or equivalent daily).
  • Significant cardiovascular disease defined as:
  • unstable angina or acute coronary syndrome within the past 2 months prior to start of treatment
  • history of myocardial infarction within 3 months prior to start of treatment or
  • documented LVEF by any method of ≤ 40% in the 12 months prior to start of treatment
  • ≥ Grade 3 NYHA functional classification system of heart failure
  • Uncontrolled or symptomatic arrhythmias
  • Prolongation of the QT interval corrected for heart rate (QTcF) > 470 msec. QTcF is calculated using Fridericia's Formula (QTcF): QTcF = QT/(RR0.33).
  • Correction of suspected drug-induced QTcF prolongation can be attempted at the investigator's discretion and only if clinically safe to do so with either discontinuation of the offending drug or switch to another drug not known to be associated with QTcF prolongation.
  • Correction for underlying bundle branch block (BBB) allowed. Note: Patients with pacemakers are eligible if they have no history of fainting or clinically relevant arrhythmias while using the pacemaker
  • Patients who have tested positive for Human Immunodeficiency Virus (HIV) are excluded due to risk of opportunistic infections with both HIV and BTK- inhibitors. For patients with unknown HIV status, HIV testing will be performed at Screening and result must be negative for enrollment.
  • Known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection based on criteria below:
  • Hepatitis B virus (HBV):
  • Patients with positive hepatitis B surface antigen (HBsAg) are excluded.
  • Patients with positive hepatitis B core antibody (anti-HBc) and negative HBsAg require a negative hepatitis B polymerase chain reaction (PCR) evaluation before start of treatment.
  • Patients who are HBV DNA PCR positive will be excluded.
  • Hepatitis C virus (HCV): positive hepatitis C antibody. If positive hepatitis C antibody result, patient will need to have a negative result for hepatitis C ribonucleic acid (RNA) before start of treatment. Patients who are hepatitis C RNA positive will be excluded.
  • Known active cytomegalovirus (CMV) infection. Unknown or negative status are eligible.
  • Pregnancy or plan to become pregnant during the study or within 1 month of the last dose of study treatment.
  • Lactation or plan to breastfeed during the study or within 1 week of the last dose of study treatment.
  • Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal (GI) absorption of the study drug.
  • Evidence of other clinically significant uncontrolled condition(s) including but not limited to, uncontrolled systemic bacterial, viral, fungal or parasitic infection (except for fungal nail infection), or other clinically significant active disease process which in the opinion of the investigator and medical monitor may pose a risk for patient participation. Screening for chronic conditions is not required.
  • Active uncontrolled auto-immune cytopenia (e.g., autoimmune hemolytic anemia [AIHA], idiopathic thrombocytopenic purpura [ITP]) for which new therapy was introduced or existing therapy was escalated within the 4 weeks prior to study enrollment to maintain adequate blood counts.
  • Active second malignancy unless in remission and with life expectancy > 2 years.
  • Patients requiring therapeutic anticoagulation with warfarin or another vitamin K antagonist.
  • Vaccination with live vaccine within 28 days prior to start of treatment
  • Other Exclusions
  • Have a known hypersensitivity to any of the excipients of Pirtobrutinib or to any intended study medications.
  • Participants who require ongoing use or received a moderate or strong CYP3A inducer, moderate or strong CYP3A inhibitor, P-gp inhibitor within 7 days prior to the first dose of study drug

Trial locations and contacts

9 sites in 1 country. Contact the study team or a site near you to ask about taking part.

M. Lia Palomba, MD contact

646-608-3711

Palombam@MSKCC.ORG

Jennifer Lue, MD contact

646-608-4160

luej@mskcc.org

9 sites in 1 country

United States9 sites, 9 recruiting

  • Memorial Sloan Kettering Basking Ridge

    Basking Ridge, New Jersey, 07920

    M. Lia Palomba, MD, 646-608-3711

    Recruiting

  • Dana Farber Cancer Institute (Data Collection and Specimen Analysis)

    Boston, Massachusetts, 02115

    Jorge Castillo, MD, 617-632-4218

    Recruiting

  • Beth Israel Deaconess Medical Center (Data Collection Only)

    Boston, Massachusetts, 02215

    Gottfried von Keudell, MD, 617-667-9920

    Recruiting

  • Memorial Sloan Kettering Suffolk - Commack

    Commack, New York, 11725

    M. Lia Palomba, MD, 646-608-3711

    Recruiting

  • Memorial Sloan Kettering Westchester

    Harrison, New York, 10604

    M. Lia Palomba, MD, 646-608-3711

    Recruiting

  • Memoral Sloan Kettering Monmouth

    Middletown, New Jersey, 07748

    M. Lia Palomba, MD, 646-608-3711

    Recruiting

  • Memorial Sloan Kettering Bergen

    Montvale, New Jersey, 07645

    M Lia Palomba, MD, 646-608-3711

    Recruiting

  • Memorial Sloan Kettering Cancer Center

    New York, New York, 10065

    M. Lia Palomba, MD, 646-608-3711

    Recruiting

  • Memorial Sloan Kettering Nassau

    Uniondale, New York, 11553

    M. Lia Palomba, MD, 646-608-3711

    Recruiting

Other trials in United States

About this study

Official title: A Phase II Study of Time-limited Combination of Pirtobrutinib, Venetoclax, and Rituximab in Treatment Naïve Patients With Waldenström's Macroglobulinemia (WM) / Lymphoplasmacytic Lymphoma (LPL) (PRoVen)

The purpose of this study is to find out if the combination of pirtobrutinib, venetoclax, and rituximab is an effective treatment for participants with Waldenström's macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL)

Being tested
Pirtobrutinib, Venetoclax, Rituximab
Keywords
Waldenstrom Macroglobulinemia, Lymphoplasmacytic Lymphoma, Memorial Sloan Kettering Cancer Center, 25-149
Medical subject headings
Waldenstrom Macroglobulinemia, Lymphoma, B-Cell, Marginal Zone

What participants receive

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

Study groups in NCT07231952
Study groupRoleWhat they receive
Participants with Waldenström's Macroglobulinemia (WM)/Lymphoplasmacytic Lymphoma (LPL)ExperimentalParticipants with treatment naive Waldenström's Macroglobulinemia (WM)/Lymphoplasmacytic Lymphoma (LPL)
Receives: Drug: Pirtobrutinib; Drug: Venetoclax; Drug: Rituximab

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 Rate or Better

    To evaluate the rate of very good partial response (VGPR) rate or better in previously untreated participants with WM / LPL who are treated upfront with this regimen.

    Measured: 1 year

Timeline

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

  1. First posted17 Nov 2025
  2. Study start11 Nov 2025
  3. Primary completion11 Apr 2028 (estimated)
  4. Study completion11 Apr 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
Single group
Masking
None (open label)
Enrolment
40 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT07231952
Sponsor's protocol ID
25-149
Status last verified
Nov 2026
First submitted
13 Nov 2025
Last updated
4 Nov 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: Memorial Sloan Kettering Cancer Center supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made beginning 12 months after publication and for up to 36 months post publication. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to: crdatashare@mskcc.org.

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Pirtobrutinib, Venetoclax and Rituximab in people with Waldenstrom Macroglobulinemia and Lymphoplasmacytic Lymphoma, run by Memorial Sloan Kettering Cancer Center at 9 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 16 inclusion and 40 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: looking for participants now, as of the sponsor's last update on 4 Nov 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 9 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?

This study is still under way. Results are not available in the source record yet.

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

Contact M. Lia Palomba, MD (646-608-3711, Palombam@MSKCC.ORG), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of participants with Very Good Partial Response Rate or Better (time frame: 1 year). 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 NCT07231952.

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 4 Nov 2026.

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