Pirtobrutinib + Venetoclax for Waldenström Macroglobulinemia

Recruiting at 3 trial locations

Overseen by Jorge J Castillo, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Dana-Farber Cancer Institute

Must not be taking: Warfarin, CYP3A4 inhibitors

Disqualifiers: CNS lymphoma, HIV, Hepatitis, others

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

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.

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.

What data supports the effectiveness of the drug combination Pirtobrutinib and Venetoclax for treating Waldenström Macroglobulinemia?

Research shows that Pirtobrutinib and Venetoclax are effective in treating chronic lymphocytic leukemia (CLL), with Pirtobrutinib showing a higher response rate compared to Venetoclax alone. Venetoclax has also been effective in combination therapies for other blood cancers, suggesting potential benefits for Waldenström Macroglobulinemia. ^{1 2 3 4 5}

How is the drug combination of Pirtobrutinib and Venetoclax unique for treating Waldenström Macroglobulinemia?

The combination of Pirtobrutinib and Venetoclax is unique because Pirtobrutinib is a highly selective, non-covalent (reversible) Bruton tyrosine kinase inhibitor (BTKi) designed to overcome limitations of other BTK inhibitors, while Venetoclax targets a specific protein to help kill cancer cells. This combination may offer a novel approach by potentially improving response rates and reducing severe side effects compared to other treatments. ^{1 2 5 6 7}

Research Team

Jorge J Castillo, MD

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

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

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.

My organs and bone marrow are functioning normally.

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

Trial Timeline

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

Treatment Details

Interventions

• Pirtobrutinib (Bruton Tyrosine Kinase (BTK) inhibitor)
• Venetoclax (BCL2 inhibitor)

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.

Participant Groups

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.

Who Is Running the Clinical Trial?

Dana-Farber Cancer Institute

Lead Sponsor

Trials

1,128

Recruited

382,000+

Dr. Benjamin L. Ebert

Dana-Farber Cancer Institute

Chief Executive Officer

MD from Harvard Medical School, PhD from Oxford University

Dr. Craig A. Bunnell

Dana-Farber Cancer Institute

Chief Medical Officer since 2012

MD from Harvard Medical School, MPH from Harvard School of Public Health, MBA from MIT Sloan School of Management

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

Findings from Research

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]

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, 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]

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 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]

References

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

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

2. Italy pubmed.ncbi.nlm.nih.gov

Pirtobrutinib versus venetoclax in covalent Bruton tyrosine kinase inhibitor-pretreated chronic lymphocytic leukemia: a matching-adjusted indirect comparison. [2023]

3. France pubmed.ncbi.nlm.nih.gov

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

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

Ibrutinib, obinutuzumab, and venetoclax in relapsed and untreated patients with mantle cell lymphoma: a phase 1/2 trial. [2021]

5. Austria pubmed.ncbi.nlm.nih.gov

Chronic lymphocytic leukemia at ASH 2017. [2020]

6. United States 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. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Venetoclax, bendamustine, and rituximab in patients with relapsed or refractory NHL: a phase Ib dose-finding study. [2021]