Pirtobrutinib + Venetoclax for Chronic Lymphocytic Leukemia

Overseen By Clinical Trials Referral Office

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Mayo Clinic

Must not be taking: CYP3A inhibitors, CYP3A inducers, PgP inhibitors, Vitamin K antagonists

Disqualifiers: Richter transformation, CNS involvement, HIV, 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: 7

Duration: 27 cycles (approximately 2 years)

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate the effectiveness of combining two drugs, pirtobrutinib (Jaypirca) and venetoclax, in treating chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Researchers will use a special blood test to detect minimal residual disease, identifying tiny amounts of cancer cells remaining after treatment, to help determine the treatment duration. This study may suit individuals diagnosed with CLL or SLL who have not yet received treatment specifically targeting these conditions. As a Phase 2 trial, the research focuses on assessing 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 use certain medications like strong CYP3A inhibitors or inducers, strong P-glycoprotein inhibitors, or vitamin K antagonists during the study. You should discuss your current medications with the study 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 combining pirtobrutinib and venetoclax is generally safe for patients with chronic lymphocytic leukemia (CLL). Earlier studies found no major drug interactions when patients took these drugs together, supporting their safety as a combination. Although each drug is safer when used alone, they still work well together without causing major issues.

Most patients in studies experienced only mild side effects, such as tiredness or nausea, and serious problems were rare. Since this trial is in phase 2, the treatment has already demonstrated some safety in earlier tests. However, anyone considering joining a clinical trial should consult their doctor about possible risks to make an informed decision. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about pirtobrutinib combined with venetoclax for treating Chronic Lymphocytic Leukemia because it targets cancer cells in a new way. Unlike standard treatments that might use chemotherapy or other kinase inhibitors, pirtobrutinib is a next-generation Bruton's tyrosine kinase (BTK) inhibitor, designed to be more effective against resistant cancer cells. Venetoclax, on the other hand, works by targeting and disrupting the BCL-2 protein, which helps the cancer cells survive. Together, these drugs aim to attack the leukemia cells from two different angles, potentially offering a more comprehensive approach to treatment.

What evidence suggests that pirtobrutinib and venetoclax could be effective for chronic lymphocytic leukemia?

Research shows that combining the drugs pirtobrutinib and venetoclax, which participants in this trial will receive, may help treat chronic lymphocytic leukemia (CLL). Studies suggest this combination could be effective, especially for patients who have tried other treatments without success. Early results indicate that these drugs can stop cancer cells from growing by either killing them or halting their division. This treatment seems particularly helpful for patients whose cancer has returned or didn't respond to previous treatments. Although more information is needed, the initial findings are promising for those considering this option. ^{5 6 7 8 9}

Who Is on the Research Team?

Yucai Wang

Principal Investigator

Mayo Clinic in Rochester

Are You a Good Fit for This Trial?

This trial is for adults with chronic lymphocytic leukemia or small lymphocytic lymphoma who haven't had previous treatments. Participants must be in good physical condition, have certain blood cell counts within a specific range, and agree to use birth control. People can't join if they've had recent heart issues, are pregnant/nursing, have HIV, or need certain medications that could interfere with the study drugs.

Inclusion Criteria

I am able to care for myself and perform daily activities.

Various hematological and biochemical parameters within specified ranges

Willingness to provide mandatory research blood, bone marrow, saliva, and stool specimens for correlative research

Exclusion Criteria

I do not have any uncontrolled illnesses or serious heart, infection, or mental health issues.

Receiving any other investigational agent for CLL/SLL treatment

I do not have another cancer that needs treatment or shortens my life expectancy to 2 years or less.

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 orally on a daily basis. Treatment repeats every 28 days for up to 27 cycles.

27 cycles (approximately 2 years)

Monthly visits for each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up includes clinical assessments and survival monitoring.

Up to 5 years

Every 6 months

What Are the Treatments Tested in This Trial?

Interventions

• Pirtobrutinib
• Venetoclax

Trial Overview The trial tests pirtobrutinib and venetoclax's effectiveness on patients with chronic lymphocytic leukemia/small lymphocytic lymphoma. It also uses minimal residual disease detection to guide treatment duration. The goal is to see how these drugs stop cancer cells from growing by killing them or preventing division.

How Is the Trial Designed?

Group I: Treatment (pirtobrutinib and venetoclax) Experimental Treatment 11 Interventions

Patients receive pirtobrutinib and venetoclax PO on study. Patients also undergo CT, MRI, and PET scans during screening and on study. Patients also undergo bone marrow aspiration and bone marrow biopsy, and collection of blood, tissue, stool, and saliva samples on study.

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?

Mayo Clinic

Lead Sponsor

Trials

3,427

Recruited

3,221,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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]

In the phase III CLL14 trial, a 12-month treatment with venetoclax combined with obinutuzumab significantly improved progression-free survival and rates of undetectable minimal residual disease compared to traditional chemoimmunotherapy with chlorambucil and obinutuzumab in patients with untreated chronic lymphocytic leukaemia.

Venetoclax + obinutuzumab is a well-tolerated, chemotherapy-free treatment option for CLL, with manageable side effects like neutropenia, making it suitable for patients who cannot undergo intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Previously Untreated Chronic Lymphocytic Leukaemia. Blair, HA.[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 a retrospective study of 22 patients with chronic lymphocytic leukaemia (CLL) who progressed on ibrutinib, the combination of ibrutinib and venetoclax resulted in a median overall survival of 47.1 months, indicating potential efficacy in this challenging patient group.

For 11 patients with double-refractory CLL, the same combination therapy led to a median overall survival of 27.0 months, suggesting that this treatment may provide a valuable option for patients who have limited alternatives after failing standard therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined ibrutinib and venetoclax for treatment of patients with ibrutinib-resistant or double-refractory chronic lymphocytic leukaemia. Hampel, PJ., Rabe, KG., Call, TG., et al.[2022]

Venetoclax is a highly effective treatment for relapsed or refractory chronic lymphocytic leukemia (CLL), achieving response rates of about 80% in clinical trials involving 240 patients from 2011 to 2016.

While venetoclax has an acceptable safety profile, common side effects include neutropenia and diarrhea, and there is a risk of tumor lysis syndrome (TLS), which can be managed through careful dose ramp-up and patient education, leading to no reported TLS events in ongoing trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . Brumbaugh Paradis, H., Alter, D., Llerandi, D.[2018]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39344587/

Efficacy and Effectiveness Outcomes of Treatments for ... This study highlights the limited clinical data on efficacy outcomes for double-exposed CLL/SLL patients. Pirtobrutinib, lisocabtagene maraleucel, and a ...

2. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/3269/504047/Fixed-Duration-Pirtobrutinib-Combined-with

Fixed-Duration Pirtobrutinib Combined with Venetoclax ... Here, we report the safety and efficacy of fixed-duration pirtobrutinib combined with venetoclax ± rituximab in pts with R/R CLL. Methods: Pts ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.e19019

Efficacy outcomes of treatments for double exposed ... Conclusions: This study underscores the scarcity of clinical data addressing efficacy outcomes in double-exposed CLL/SLL patients. Treatments ...

4. haematologica.org haematologica.org/article/view/haematol.2023.284150

Pirtobrutinib <i>versus</i> venetoclax in covalent Bruton ... These results suggest that pirtobrutinib may also be considered as an effective and well-tolerated treatment for patients with relapsed CLL following cBTKi.

5. healthtree.org healthtree.org/cll/community/articles/sponsorstudy-pirtobrutinib-venetoclax-cll-phase-1

Two-Year Pirtobrutinib + Venetoclax for R/R CLL New study explores 2-year combo of pirtobrutinib + venetoclax ± rituximab for relapsed/refractory CLL. Promising early results.

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38031799/

Pirtobrutinib versus venetoclax in covalent Bruton tyrosine ... Data from patients with CLL who were venetoclax-naïve and pretreated with cBTKi received pirtobrutinib (N=146) in the phase I/II BRUIN study ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S1040842824001719

Safety profile of first-line targeted therapies in elderly and/ ... The therapies appear to be safer when used as monotherapy rather than in combination with immunological agents in naïve CLL patients with advanced age and/or ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT05677919

NCT05677919 | Pirtobrutinib and Venetoclax With MRD ... This phase II trial studies how well pirtobrutinib and venetoclax work in treating patients with chronic lymphocytic leukemia or small lymphocytic lymphoma.

9. clinicaltrials.gov clinicaltrials.gov/study/NCT06466122

NCT06466122 | Pirtobrutinib (LOXO-305) and Venetoclax ... This phase II trial tests how well pirtobrutinib (LOXO-305) and venetoclax works in treating patients with chronic lymphocytic leukemia (CLL) or small ...