Pirtobrutinib + Venetoclax for Chronic Lymphocytic Leukemia

Recruiting in Palo Alto (17 mi)

Overseen by Yucai Wang

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

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

Prior Safety Data

Breakthrough Therapy

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.

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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.

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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.

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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 am 18 years old or older.

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.

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 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

Participant Groups

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.

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

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Mayo Clinic in Rochester Rochester, MN

Who Is Running the Clinical Trial?

Mayo Clinic Lead Sponsor

National Cancer Institute (NCI) Collaborator

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] Venetoclax is a standard treatment for patients with CLL following covalent BTK inhibitor (cBTKi) therapy, despite relatively limited prospective data in this setting. Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi that was designed to overcome the pharmacologic limitations of cBTKi and re-establish BTK inhibition. An unanchored matching-adjusted indirect comparison (MAIC) was conducted to estimate the treatment effect of pirtobrutinib versus venetoclax monotherapy in patients with cBTKi pre-treated CLL. Data from patients with CLL who were venetoclax-naïve and pre-treated with cBTKi received pirtobrutinib (n=146) in the phase 1/2 BRUIN study were compared with the only identified trial of patients with CLL receiving venetoclax after a cBTKi (n=91), as administered as monotherapy until progression. Outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and treatment-emergent adverse events (TEAEs). Both unweighted and weighted analyses were conducted. PFS and OS of pirtobrutinib and venetoclax were comparable in both unweighted and weighted analyses (weighted hazard ratios for PFS: 1.01, 95% CI: 0.58-1.73, p=0.98 and OS: 0.64, 95% CI: 0.25-1.67, p=0.34). ORR was significantly higher for pirtobrutinib (80.2% vs 64.8%, p=0.01). Grade ≥3 TEAEs were lower in weighted analyses for pirtobrutinib vs venetoclax (all p.

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

Chronic lymphocytic leukemia at ASH 2017. [2020] At ASH (American Society of Hematology) 2017 three out of a plethora of trials showed remarkable and promising results. The combinations of venetoclax with rituximab and ibrutinib with venetoclax convinced with striking efficacy together with a manageable safety profile in relapsed/refractory setting as well as in first line therapy of high-risk disease. These two combinations are potential new standard treatment options in chronic lymphocytic leukemia.

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

Venetoclax: A Review in Relapsed/Refractory Chronic Lymphocytic Leukemia. [2020] Venetoclax (Venclyxto®; Venclexta®) is a first-in-class, oral, selective B cell lymphoma-2 (BCL-2) inhibitor. The drug is approved in numerous countries, including those of the EU and in the USA, for the treatment of adults with relapsed or refractory (RR) chronic lymphocytic leukemia (CLL); the specific indication(s) for venetoclax may vary between individual countries. Venetoclax monotherapy or combination therapy with rituximab was an effective treatment, provided durable responses, and had a manageable safety profile in pivotal clinical trials in adults with RR CLL, including in patients with adverse prognostic factors. In combination with 6 cycles of rituximab, venetoclax (fixed 24 months' treatment) was more effective than bendamustine plus rituximab (6 cycles) in prolonging progression-free survival (PFS) and inducing undetectable minimal residual disease (uMRD) in peripheral blood (PB) and bone marrow (BM), with these benefits sustained during 36 months' follow-up. Hence, with its novel mechanism of action and convenient oral once-daily regimen, venetoclax monotherapy or fixed 24-month combination therapy with rituximab represents an important option for treating RR CLL, including in patients with del(17p) or TP53 mutation and those failing a B cell receptor (BCR) inhibitor and/or chemotherapy.

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

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . [2018] Venetoclax (Venclexta™) is a potent, selective, orally available, small-molecule B-cell lymphoma 2 inhibitor that achieves response rates of about 80% and has an acceptable safety profile for patients with relapsed or refractory chronic lymphocytic leukemia (CLL). .

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] Patients with chronic lymphocytic leukaemia (CLL) disease progression on ibrutinib or after sequential ibrutinib and venetoclax-based treatments (double-refractory) have poor outcomes. In this retrospective study, we analysed outcomes with combined ibrutinib and venetoclax treatment in these groups of patients. The median treatment-free and overall survival for 22 patients with prior progression on ibrutinib (venetoclax-naïve) were 23.7 and 47.1 months respectively. In 11 patients with double-refractory CLL, the median treatment-free and overall survival were 11.2 and 27.0 months respectively. The combination of ibrutinib and venetoclax may help bridge the current gap in options for patients with disease refractory to the most commonly used novel agents.

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

Venetoclax: A Review in Previously Untreated Chronic Lymphocytic Leukaemia. [2021] Venetoclax (Venclexta®; Venclyxto®) is a first-in-class, oral, selective inhibitor of B cell lymphoma 2 (BCL2). In several countries, including the USA and those of the EU, venetoclax is indicated in combination with obinutuzumab for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL). Approval was based on the results of the phase III CLL14 trial in patients with previously untreated CLL and co-existing conditions. In this study, fixed-duration (12 months) targeted treatment with venetoclax + obinutuzumab resulted in significantly longer progression-free survival (PFS; primary endpoint) relative to fixed-duration chemoimmunotherapy with chlorambucil + obinutuzumab. Venetoclax + obinutuzumab was also associated with significantly higher rates of undetectable minimal residual disease (MRD), complete response and overall response than chlorambucil + obinutuzumab. Improvements in clinical outcomes with venetoclax + obinutuzumab were maintained during long-term follow-up, when all patients had been off treatment for ≥ 2 years. No significant between-group difference was observed in overall survival (OS). Venetoclax had an acceptable tolerability profile. Notable adverse events such as grade 3 or 4 neutropenia can be managed with supportive therapy and venetoclax dose modifications. In conclusion, fixed-duration venetoclax + obinutuzumab represents an important chemotherapy-free first-line treatment option for patients with CLL, particularly those who are not fit enough to receive intensive chemoimmunotherapy.