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)

72 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies how well pirtobrutinib and venetoclax work in treating patients with chronic lymphocytic leukemia or small lymphocytic lymphoma. This study also seeks to adopt a blood test which shows a small number of cancer cells in the body after cancer treatment called minimal residual disease as a guide to determine length of treatment. Drugs used in chemotherapy, such as pirtobrutinib and venetoclax, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Identifying minimal residual disease results after combination chemotherapy may help guide future treatment decisions for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma.

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.

What data supports the effectiveness of the drug combination Pirtobrutinib and Venetoclax for treating Chronic Lymphocytic Leukemia?

Research shows that Pirtobrutinib has a higher response rate compared to Venetoclax when used alone in patients who have been treated with other similar drugs before. Additionally, Venetoclax has been effective in combination with other drugs for treating relapsed or hard-to-treat Chronic Lymphocytic Leukemia, suggesting potential benefits when combined with Pirtobrutinib. ^{1 2 3 4 5}

Is the combination of Pirtobrutinib and Venetoclax safe for treating Chronic Lymphocytic Leukemia?

Both Pirtobrutinib and Venetoclax have been studied for safety in treating Chronic Lymphocytic Leukemia (CLL). Pirtobrutinib showed fewer severe side effects compared to Venetoclax in some analyses, while Venetoclax has been found to have a manageable safety profile in various studies, with some notable side effects like neutropenia (low white blood cell count) that can be managed with dose adjustments. ^{1 2 3 4 6}

What makes the drug combination of Pirtobrutinib and Venetoclax unique for treating chronic lymphocytic leukemia?

The combination of Pirtobrutinib and Venetoclax is unique because Pirtobrutinib is a non-covalent (reversible) Bruton tyrosine kinase inhibitor designed to overcome limitations of previous treatments, and when combined with Venetoclax, it offers a higher objective response rate and fewer severe side effects compared to Venetoclax alone in patients who have been pre-treated with other BTK inhibitors. ^{1 2 3 4 6}

Research Team

Yucai Wang

Principal Investigator

Mayo Clinic in Rochester

Eligibility Criteria

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

I have not received any treatment for CLL/SLL.

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

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

Treatment Details

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.

Participant Groups

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+

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]

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]

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]

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]

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]

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]

References

1. 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]

2. Austria pubmed.ncbi.nlm.nih.gov

Chronic lymphocytic leukemia at ASH 2017. [2020]

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

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . [2018]

5. England pubmed.ncbi.nlm.nih.gov

Combined ibrutinib and venetoclax for treatment of patients with ibrutinib-resistant or double-refractory chronic lymphocytic leukaemia. [2022]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Previously Untreated Chronic Lymphocytic Leukaemia. [2021]