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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of combining two drugs, pirtobrutinib and venetoclax, to treat chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) that resists certain current treatments. Pirtobrutinib stops cancer cells from multiplying, while venetoclax blocks proteins essential for cancer cell survival. The trial targets individuals with CLL or SLL who experience disease progression despite taking specific daily medications. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group of participants.

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.

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

Research shows that pirtobrutinib and venetoclax are being tested together to treat chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). Previous studies have shown promise, especially for patients whose cancers did not respond to other treatments. While both drugs have been used separately before, using them together is a new approach.

Studies have found that both pirtobrutinib and venetoclax are generally well-tolerated. However, using them together can cause side effects. Some patients have experienced low blood cell counts, increasing the risk of infections, or digestive issues like nausea. Monitoring these side effects is important.

This trial is in phase 2, indicating some initial safety information is available, but researchers are still learning about the long-term safety of this drug combination in more patients. Those considering joining this trial should discuss the possible risks and benefits with a healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about pirtobrutinib and venetoclax for Chronic Lymphocytic Leukemia (CLL) because they bring new mechanisms to the table. Pirtobrutinib is a next-generation BTK inhibitor, which targets a specific protein involved in cancer cell survival, offering a more precise attack on the cancer compared to older treatments. Venetoclax works by targeting and blocking the BCL-2 protein, which helps cancer cells avoid death, making it a powerful partner in this combination. Unlike traditional chemotherapy, which can be harsh and non-specific, this combination aims to be more targeted, potentially leading to fewer side effects and improved outcomes for patients.

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

Research has shown that using pirtobrutinib and venetoclax together may benefit patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who haven't responded to other treatments. In this trial, participants will receive both pirtobrutinib and venetoclax. Pirtobrutinib blocks a protein that aids cancer cell growth, while venetoclax targets a protein essential for cancer cell survival. This combination aims to kill more cancer cells. Specifically, studies have found that pirtobrutinib can improve outcomes for patients when other treatments have failed. This approach offers hope for those who have not succeeded with previous therapies. ^{2 6 7 8 9}

Who Is on the Research Team?

Kerry A. Rogers, MD

Principal Investigator

Ohio State University Comprehensive Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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.

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

Citations

1. 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.

2. mayo.edu mayo.edu/research/clinical-trials/diseases-conditions/chronic-lymphocytic-leukemia

Chronic Lymphocytic Leukemia Clinical Trials This phase II trial studies how well pirtobrutinib and venetoclax work in treating patients with chronic lymphocytic leukemia or small lymphocytic lymphoma.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11440144/

Efficacy and Effectiveness Outcomes of Treatments for ... Following the discontinuation of covalent BTKi and venetoclax, the outcomes in CLL patients are extremely poor, with less than 6 months median time to ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT05317936

Study Details | NCT05317936 | Pirtobrutinib (LOXO-305) ... Primary Objective: I. To estimate the therapeutic efficacy of pirtobrutinib consolidation in patients who have detectable CLL in peripheral blood after ...

5. ajmc.com ajmc.com/view/study-finds-pirtobrutinib-associated-with-improved-outcomes-vs-venetoclax-in-relapsed-cll

Study Finds Pirtobrutinib Associated With Improved ... Pirtobrutinib led to improved outcomes compared with venetoclax in patients with relapsed chronic lymphocytic leukemia (CLL) following covalent

6. 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 ...

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. mayo.edu mayo.edu/research/clinical-trials/diseases-conditions/chronic-lymphocytic-

Chronic Lymphocytic Clinical Trials This phase II trial studies how well pirtobrutinib and venetoclax work in treating patients with chronic lymphocytic leukemia or small lymphocytic lymphoma.

9. cdek.pharmacy.purdue.edu cdek.pharmacy.purdue.edu/trial/NCT05317936/

Trial | NCT05317936 To learn if the combination of LOXO-305 (pirtobrutinib) and venetoclax can help to control previously treated chronic lymphocytic leukemia/small lymphocytic ...