Pirtobrutinib + Venetoclax for Waldenström Macroglobulinemia

Recruiting at 3 trial locations

Overseen By Kirsten Meid

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Dana-Farber Cancer Institute

Must not be taking: Warfarin, CYP3A4 inhibitors

Disqualifiers: CNS lymphoma, HIV, Hepatitis, 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

Compensation: Varies

Number of Visits: 13

Duration: 24 months

42 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of two drugs, pirtobrutinib and venetoclax, to determine their safety and effectiveness in treating Waldenström Macroglobulinemia (WM), a rare blood cancer. The researchers aim to discover if this combination can manage WM symptoms better than current treatments. Individuals diagnosed with WM, who have experienced symptoms like fatigue or night sweats, and have tried at least one previous treatment, might be suitable for this trial. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot take certain drugs like warfarin, strong CYP3A4 inhibitors or inducers, and strong P-gp inhibitors while participating. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that using pirtobrutinib and venetoclax together appears promising for treating Waldenström Macroglobulinemia (WM). Earlier studies have found this combination safe for patients, with most side effects being mild and manageable.

Venetoclax, one of the drugs in this combination, has been studied independently for WM. It proved effective and safe, with patients tolerating it well over the long term. Common side effects included low blood cell counts, but these were generally treatable.

Pirtobrutinib is a newer drug, and studies suggest it is also well-tolerated. It works differently from other drugs, potentially resulting in fewer side effects for some people.

Overall, while all medicines can have side effects, research so far shows that pirtobrutinib and venetoclax together have been safe in studies. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Pirtobrutinib and Venetoclax for treating Waldenström Macroglobulinemia because it offers a novel approach to tackling this condition. Most treatments for Waldenström Macroglobulinemia, like BTK inhibitors and chemotherapy, work by targeting cancer cells broadly. However, Pirtobrutinib is a next-generation BTK inhibitor that more specifically targets the BTK pathway, potentially reducing side effects and overcoming resistance seen in other treatments. Venetoclax complements this by targeting BCL-2, a protein that helps cancer cells survive, adding a dual-targeted approach that could lead to more effective outcomes for patients. This combination is promising because it could offer a more precise and aggressive attack on cancer cells with fewer side effects.

What evidence suggests that pirtobrutinib combined with venetoclax could be an effective treatment for Waldenström Macroglobulinemia?

Research has shown that combining the drugs pirtobrutinib and venetoclax holds promise for treating Waldenström Macroglobulinemia (WM), a type of blood cancer. Earlier studies demonstrated that pirtobrutinib, which blocks a protein aiding cancer growth, worked well for WM patients unresponsive to other similar treatments. Venetoclax targets proteins that help cancer cells survive and has also proven effective in patients whose WM returned or was difficult to treat. In this trial, participants will receive both pirtobrutinib and venetoclax. Together, these drugs have led to a significant reduction in disease for over half of the patients with symptoms and previous treatments, achieving a very good partial response rate of 56%. ^{1 2 4 5 6}

Who Is on the Research Team?

Jorge J Castillo, MD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

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.

Inclusion Criteria

Women of childbearing potential must agree to use two reliable forms of contraception simultaneously or have complete abstinence from heterosexual intercourse

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

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

Exclusion Criteria

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

You have a history of HIV or active CMV infection.

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

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive Pirtobrutinib and Venetoclax for up to 2 years

24 months

Monthly visits for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 years

Every 12 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Pirtobrutinib
• Venetoclax

Trial Overview

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.

How Is the Trial Designed?

Group I: PIRTOBRUTINIB + VENETOCLAX Experimental Treatment 2 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.

Pirtobrutinib is already approved in United States for the following indications:

Approved in United States as Jaypirca for:

• Mantle Cell Lymphoma
• Chronic Lymphocytic Leukemia
• Small Lymphocytic Lymphoma

Who Is Running the Clinical Trial?

Dana-Farber Cancer Institute

Lead Sponsor

Trials

1,128

Recruited

382,000+

Eli Lilly and Company

Industry Sponsor

Trials

2,708

Recruited

3,720,000+

Dr. Daniel Skovronsky

Eli Lilly and Company

Chief Medical Officer since 2018

MD from Harvard Medical School

David A. Ricks

Eli Lilly and Company

Chief Executive Officer since 2017

BSc from Purdue University, MBA from Indiana University

Published Research Related to This Trial

Venetoclax is an effective oral treatment for relapsed or refractory chronic lymphocytic leukemia (CLL), showing durable responses and a manageable safety profile in clinical trials, including patients with poor prognostic factors.

In combination with rituximab, venetoclax significantly improved progression-free survival and achieved undetectable minimal residual disease compared to bendamustine plus rituximab, with benefits lasting for at least 36 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Relapsed/Refractory Chronic Lymphocytic Leukemia. Scott, LJ.[2020]

The combination of venetoclax with rituximab showed remarkable efficacy and a manageable safety profile in treating chronic lymphocytic leukemia (CLL), both in relapsed/refractory cases and as a first-line therapy for high-risk patients.

Similarly, the combination of ibrutinib with venetoclax also demonstrated striking efficacy, suggesting that these combinations could become new standard treatment options for CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic lymphocytic leukemia at ASH 2017. Wanner, D., Steurer, M.[2020]

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]

In the GLOW study, the combination of ibrutinib and venetoclax resulted in significantly higher rates of undetectable minimal residual disease (uMRD) in patients with chronic lymphocytic leukemia (CLL) compared to chlorambucil and obinutuzumab, with 40.6% and 43.4% achieving uMRD in bone marrow and peripheral blood, respectively, at 3 months after treatment.

Patients treated with ibrutinib and venetoclax maintained high progression-free survival (PFS) rates at 12 months, regardless of their MRD status, with rates of 96.3% for uMRD and 93.3% for detectable MRD, indicating that this treatment is effective even for those who do not achieve complete molecular remission.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of Minimal Residual Disease on Progression-Free Survival Outcomes After Fixed-Duration Ibrutinib-Venetoclax Versus Chlorambucil-Obinutuzumab in the GLOW Study. Munir, T., Moreno, C., Owen, C., et al.[2023]

The combination of venetoclax with bendamustine-rituximab (BR) was found to be safe and tolerable in a study of 60 patients with relapsed/refractory non-Hodgkin's lymphoma, with the recommended phase II dose established at 800 mg daily.

The overall response rate to the treatment was 65%, with a median duration of response of 38.3 months, indicating preliminary efficacy for this combination therapy in managing B-cell NHL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax, bendamustine, and rituximab in patients with relapsed or refractory NHL: a phase Ib dose-finding study. de Vos, S., Swinnen, LJ., Wang, D., et al.[2021]

Pirtobrutinib, a non-covalent BTK inhibitor, showed a significantly higher objective response rate (80.2%) compared to venetoclax (64.8%) in patients with chronic lymphocytic leukemia (CLL) who had previously been treated with covalent BTK inhibitors, based on a comparison of 146 patients receiving pirtobrutinib and 91 patients receiving venetoclax.

While progression-free survival (PFS) and overall survival (OS) rates were comparable between pirtobrutinib and venetoclax, pirtobrutinib was associated with fewer grade ≥3 treatment-emergent adverse events, indicating it may be a safer option for patients with relapsed CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pirtobrutinib versus venetoclax in covalent Bruton tyrosine kinase inhibitor-pretreated chronic lymphocytic leukemia: a matching-adjusted indirect comparison. Al-Sawaf, O., Jen, MH., Hess, LM., et al.[2023]

The combination of venetoclax, ibrutinib, and obinutuzumab is well tolerated in patients with relapsed and untreated mantle cell lymphoma (MCL), with no dose-limiting toxicities reported and a maximum tolerated dose of 400 mg per day established for venetoclax.

High response rates were observed, with a complete response rate of 67% in relapsed patients and 86.6% in untreated patients, along with significant minimal residual disease clearance in 71.5% of relapsed and 100% of untreated patients after three cycles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib, obinutuzumab, and venetoclax in relapsed and untreated patients with mantle cell lymphoma: a phase 1/2 trial. Le Gouill, S., Morschhauser, F., Chiron, D., et al.[2021]

Citations

1.

ashpublications.org

ashpublications.org/blood/article/144/Supplement%201/3011/532578/A-Phase-II-Study-of-Pirtobrutinib-and-Venetoclax

A Phase II Study of Pirtobrutinib and Venetoclax in Previously ...

Non-covalent BTK inhibitors have shown efficacy in WM patients progressing on covalent BTK inhibitors. However, BTK inhibitor therapy has an ...

2.

clinicaltrials.gov

clinicaltrials.gov/study/NCT05734495?term=PIRTOBRUTINIB&rank=1

NCT05734495 | Pirtobrutinib and Venetoclax in ...

This study is being done to examine the safety and effectiveness of pirtobrutinib combined with venetoclax as a possible treatment for participants with ...

3.

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).

4.

sciencedirect.com

sciencedirect.com/science/article/abs/pii/S000649712405763X

A Phase II Study of Pirtobrutinib and Venetoclax in ...

The combination of pirtobrutinib and venetoclax appears active in symptomatic, previously treated WM patients with a VGPR rate of 56%, exceeding the futility ...

5.

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 ...

6.

dana-farber.org

dana-farber.org/clinical-trials/22-611

A Phase II study evaluating venetoclax and pirtobrutinib in ...

This study is being done to examine the safety and effectiveness of pirtobrutinib combined with venetoclax as a possible treatment for participants with ...