What is the mechanism of action of this treatment?

BTK inhibitors, such as Pirtobrutinib, block Bruton's tyrosine kinase, disrupting the survival and proliferation of malignant B-cells in Waldenstrom Macroglobulinemia (WM). BCL2 inhibitors, like Venetoclax, target the BCL2 protein to promote apoptosis in cancer cells. These mechanisms are crucial for WM patients as they offer targeted treatment options that can reduce tumor burden and improve survival rates with potentially fewer side effects compared to traditional chemotherapy.

What side effects are associated with this type of intervention?

Common treatments for Waldenström Macroglobulinemia, such as BTK inhibitors (e.g., ibrutinib) and BCL2 inhibitors (e.g., venetoclax), have several known side effects. BTK inhibitors can cause diarrhea, peripheral edema, dry eye, arthralgia, upper respiratory tract infections, hypertension, atrial fibrillation, and major hemorrhage. BCL2 inhibitors are often associated with neutropenia and gastrointestinal events. Both drug classes are generally well-tolerated, but patients may experience varying degrees of these side effects.

What prior FDA approvals exist?

The FDA has approved several BTK inhibitors for the treatment of Waldenström Macroglobulinemia, including Ibrutinib, which was the first BTK inhibitor approved for WM. Ibrutinib works by blocking the Bruton's tyrosine kinase (BTK) pathway, which is crucial for the survival and proliferation of malignant B cells. Additionally, Venetoclax, a BCL2 inhibitor, has been approved for chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), which are related B-cell malignancies. Venetoclax targets the BCL2 protein to induce apoptosis in cancer cells. These approvals highlight the therapeutic potential of targeting BTK and BCL2 pathways in B-cell malignancies, including WM.

What other types of research exist?

Promising novel alternatives for Waldenstrom Macroglobulinemia patients in 2024 include: 1) Zanubrutinib, a next-generation BTK inhibitor with favorable efficacy and safety profiles. 2) Acalabrutinib, another BTK inhibitor showing promising results in clinical trials. 3) Selinexor, a selective inhibitor of nuclear export, which has shown activity in various hematologic malignancies. These alternatives offer new mechanisms of action and potential benefits for WM patients.

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Bruton Tyrosine Kinase (BTK) inhibitor

Pirtobrutinib + Venetoclax for Waldenström Macroglobulinemia

Phase 2

Recruiting

Led By Jorge Castillo, MD

Research Sponsored by Dana-Farber Cancer Institute

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

ECOG performance status ≤2

Men must agree to use a latex condom during sexual contact with a female of childbearing potential

Must not have

Concurrent administration of moderate or strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers and/or strong p-glycoprotein (P-gp) inhibitors

Female participants who are pregnant, breastfeeding, or planning to become pregnant or breastfeed

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 6 years

Awards & highlights

No Placebo-Only Group

Summary

This trial is testing the safety and effectiveness of two drugs, pirtobrutinib and venetoclax, in patients with Waldenström Macroglobulinemia (WM) who have already been treated but still have symptoms. Pirtobrutinib blocks a protein that helps cancer cells grow, while venetoclax blocks a protein that helps them survive. The goal is to see if this combination can better control the disease.

Who is the study for?

This trial is for adults over 18 with Waldenström Macroglobulinemia who've had at least one prior treatment. They must have symptoms needing treatment, measurable disease (IgM paraprotein), and normal organ/marrow function. Women of childbearing age and men must use contraception. Exclusions include major recent surgery, other clinical trials, certain heart conditions or infections, inability to swallow pills, drug abuse history, and known allergies to the drugs' components.

What is being tested?

The study tests the combination of pirtobrutinib (a BTK inhibitor) and venetoclax (a BCL2 inhibitor) for safety and effectiveness in treating Waldenström Macroglobulinemia. It aims to see if this drug duo can help patients who have already tried other treatments without success.

What are the potential side effects?

Potential side effects may include bleeding events or heart rhythm issues due to pirtobrutinib; also common are gastrointestinal symptoms like nausea or diarrhea from venetoclax. Other possible reactions could be fatigue, infection risk increase due to immune system suppression by both drugs.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I can take care of myself but might not be able to do heavy physical work.

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I agree to use a condom during sex if my partner can have children.

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My organs and bone marrow are functioning normally.

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My blood test shows high levels of IgM, more than twice the normal limit.

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I have been diagnosed with Waldenström Macroglobulinemia without MYD88 mutation.

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I am 18 years old or older.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I am not taking strong medication that affects liver enzymes or drug transporters.

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I am not pregnant, breastfeeding, nor planning to become pregnant or breastfeed.

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I have been diagnosed with lymphoma in my central nervous system.

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I have a serious heart condition.

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I have been treated with non-covalent BTK inhibitors before.

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I am currently on medication that suppresses my immune system.

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I am allergic to ingredients in pirtobrutinib or venetoclax.

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I have an active autoimmune blood condition that needed new or more treatment in the last 4 weeks.

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I cannot take medications by mouth due to a digestive condition.

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I can swallow pills and can attend all required clinic visits and tests.

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I had severe bleeding or heart rhythm problems with a previous BTK inhibitor treatment.

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I do not have any ongoing serious infections.

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I am currently taking warfarin.

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

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 6 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 6 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to 6 years for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Very Good Partial Response (VGPR) or Better Response Rate

Secondary study objectives

Best Response

Grade 3-5 Treatment-related Toxicity Rate

Median Duration of Response (DOR)

+8 more

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

1Treatment groups

Experimental Treatment

Group I: PIRTOBRUTINIB + VENETOCLAXExperimental Treatment2 Interventions

Participants will receive: * Standard of care bone marrow aspirate \& biopsy within 90 days of Cycle 1 Day 1. * Computed Tomography (CT) scan of chest, pelvis \& abdomen within 90 days of Cycle 1 Day 1. * Electrocardiogram at screening. * Cycle 1 * Electrocardiogram. * Day 1-28: Predetermined dose of Pirtobrutinib 1x daily. * Cycle 2 -Day 1-28: Predetermined dose Pirtobrutinib \& Venetoclax 1x daily. Tumor lysis syndrome (TLS) prophylaxis, predetermined dose Allopurinol at least 72 hrs prior to 1st administration of Venetoclax and dose escalation at Day 8 \& Day 15. * Cycles 3-24 * Day 1-28: Predetermined dose of Pirtobrutinib \& Venetoclax 1x daily. * Electrocardiogram: Cycles 3, 6, 9,12,15,18,21,24 * CT scan of chest, pelvis \& abdomen: Cycles 7, 13, End of Treatment if extramedullary disease at baseline unresolved in previous CT scan * Standard of care bone marrow aspirate and biopsy: Cycles 7, 13, End of Treatment * Follow up every 12 wks for 4 yrs.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Pirtobrutinib

2020

Completed Phase 1

~240

Venetoclax

2019

Completed Phase 3

~2240

0 / 20Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

BTK inhibitors, such as Pirtobrutinib, block Bruton's tyrosine kinase, disrupting the survival and proliferation of malignant B-cells in Waldenstrom Macroglobulinemia (WM). BCL2 inhibitors, like Venetoclax, target the BCL2 protein to promote apoptosis in cancer cells. These mechanisms are crucial for WM patients as they offer targeted treatment options that can reduce tumor burden and improve survival rates with potentially fewer side effects compared to traditional chemotherapy.