Pirtobrutinib + Venetoclax for Chronic Lymphocytic Leukemia

Overseen By The Ohio State University Comprehensive Cancer Center

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Kerry Rogers

Must be taking: Ibrutinib, Acalabrutinib, Zanubrutinib

Must not be taking: Warfarin, Vitamin K antagonists

Disqualifiers: Venetoclax resistance, Major bleeding, Stroke, 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: Unknown

Duration: 20 cycles (approximately 20 months)

30 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial allows participants to continue taking ibrutinib, acalabrutinib, or zanubrutinib. However, you cannot take warfarin or other vitamin K antagonists during the study. If you are on other medications, the protocol does not specify, so it's best to discuss with the study team.

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 Chronic Lymphocytic Leukemia, showing good response rates and manageable side effects. ^{1 2 3 4 5}

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

Pirtobrutinib and Venetoclax have been studied separately for safety in treating Chronic Lymphocytic Leukemia (CLL). Pirtobrutinib showed fewer severe side effects compared to Venetoclax in some analyses. Venetoclax has an acceptable safety profile, with manageable side effects like neutropenia (low white blood cell count) that can be addressed with supportive care and dose adjustments. ^{1 2 3 4 5}

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 used with Venetoclax, it shows a higher objective response rate and fewer severe side effects compared to Venetoclax alone in patients previously treated with other BTK inhibitors. ^{1 3 4 5 6}

What is the purpose of this trial?

This phase II trial tests how well pirtobrutinib (LOXO-305) and venetoclax works in treating patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) that remains despite treatment (resistant) with covalent bruton tyrosine kinase inhibitors (BTKi). Pirtobrutinib is in a class of medications called kinase inhibitors. It works by blocking the action of the a protein that signals cancer cells to multiply. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking BCL-2, a protein needed for cancer cell survival. Giving pirtobrutinib and venetoclax may kill more cancer cells in patients with CLL or SLL that is resistant to covalent BTKi.

Research Team

Kerry A. Rogers, MD

Principal Investigator

Ohio State University Comprehensive Cancer Center

Eligibility Criteria

This trial is for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who haven't responded to previous treatments with covalent BTK inhibitors. Participants should meet specific health criteria and not have conditions that would exclude them from the study.

Inclusion Criteria

I have been diagnosed with CLL or SLL following the 2018 iwCLL guidelines.

I have been on ibrutinib, acalabrutinib, or zanubrutinib for over 4 weeks without major issues.

I do not have any inherited blood platelet disorders.

Exclusion Criteria

I have an active autoimmune blood disorder that required new or more treatment recently.

I do not have a condition that affects how my stomach and intestines absorb medicine.

I do not have any uncontrolled infections or serious health conditions that could make participating risky.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pirtobrutinib orally once daily on days 1-28 of each cycle and venetoclax orally once daily on days 1-28 of cycles 2-20. Cycles repeat every 28 days for up to 20 cycles.

20 cycles (approximately 20 months)

Monthly visits for each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment completion every 6 months.

Up to 18 months

Biannual visits

Extension

Participants who experience disease progression within 12 months of stopping combination treatment may receive pirtobrutinib in the absence of disease progression or unacceptable toxicity.

Treatment Details

Interventions

• Pirtobrutinib (LOXO-305)
• Venetoclax

Trial Overview The trial is testing a combination of two drugs, pirtobrutinib (LOXO-305) and venetoclax, on patients with CLL or SLL resistant to other treatments. It includes procedures like bone marrow aspiration/biopsy, CT scans, and biospecimen collection to monitor effects.

Participant Groups

Group I: Treatment (pirtobrutinib, venetoclax) Experimental Treatment 6 Interventions

Patients receive pirtobrutinib PO QD on days 1-28 of each cycle and receive venetoclax PO QD on days 1-28 of cycles 2-20. Cycles repeat every 28 days for up to 20 cycles in the absence of disease progression or unacceptable toxicity. Patients who experience disease progression within 12 months of stopping combination treatment may receive pirtobrutinib PO QD in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection, bone marrow aspiration and biopsy and CT throughout the study.

Pirtobrutinib (LOXO-305) is already approved in United States for the following indications:

Approved in United States as LOXO-305 for:

• Relapsed or refractory mantle cell lymphoma (MCL) after at least 2 lines of systemic therapy, including prior covalent Bruton tyrosine kinase inhibitor (BTKi) therapy

Who Is Running the Clinical Trial?

Kerry Rogers

Lead Sponsor

Trials

3

Recruited

120+

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 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]

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 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]

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 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]

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

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

3. Austria pubmed.ncbi.nlm.nih.gov

Chronic lymphocytic leukemia at ASH 2017. [2020]

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

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

5. France pubmed.ncbi.nlm.nih.gov

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

6. England pubmed.ncbi.nlm.nih.gov

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