Pirtobrutinib and Venetoclax for CLL or SLL Resistant to BTKi
This study is testing a combination of two medications, pirtobrutinib and venetoclax, for people with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) that hasn't responded well to previous treatments like ibrutinib, acalabrutinib, or zanubrutinib. Pirtobrutinib works by blocking a protein that helps cancer cells grow, and venetoclax targets another protein (BCL-2) essential for cancer cell survival. The goal is to see if this combination can eliminate more cancer cells, specifically aiming for undetectable minimal residual disease (uMRD), meaning very few cancer cells remain. You may be eligible if you have CLL or SLL, are at least 18 years old, and are currently taking one of the mentioned BTKi medications. The study is currently recruiting about 30 participants.
- Study design
- This is a Phase II interventional study. It involves about 30 participants and tests the combination of pirtobrutinib and venetoclax.
- What's involved
- You would take pirtobrutinib daily and venetoclax daily for up to 20 cycles, with each cycle lasting 28 days. You would also have blood tests, bone marrow aspirations and biopsies, and CT scans throughout the study.
- Compensation
- Not stated in the trial record.
- Follow-up
- After completing the study treatment, participants are followed up every 6 months.
AI-generated from the public study record. Only the study team can confirm whether you're eligible — confirm details with them before making decisions.
NCT06466122
Pirtobrutinib (LOXO-305) and Venetoclax for the Treatment of Patients With CLL or SLL Resistant to Covalent BTKi
Recruiting
PHASE2Ages 18+InterventionalTreatmentKerry RogersInvestigator-initiated
~30 participants
Updated 2026-02-19 on ClinicalTrials.gov
What's tested:Biospecimen CollectionBone Marrow AspirationBone Marrow BiopsyComputed TomographyPirtobrutinibVenetoclax
At a glance
Recruiting sites
1 of 1 listed site is recruiting right now
RecruitingSuspended, closed, or not yet open
What they're measuring
Rate of undetectable minimal residual disease (uMRD)
Measured over At cycle 21 day 1 (C21D1) [each cycle lasts 28 days]
Conditions
Where it's being run
1 sites across 1 statesOhio1
Study leadership
- Kerry A Rogers, MD · PRINCIPAL_INVESTIGATOR · Ohio State University Comprehensive Cancer Center
Who to contact
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Do you actually qualify for this trial?
Add a private profile and we'll compare every criterion below against your situation — and tell you which ones are met, uncertain, or excluding.
Eligibility criteria
Inclusion
Diagnosis of CLL or SLL according to the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 guidelines
Detectable CLL on flow cytometry of the blood or marrow at time of enrollment
Age ≥ 18 years old
Eastern Cooperative Oncology Group (ECOG) performance 0-2
Currently taking ibrutinib, acalabrutinib, or zanubrutinib at any daily dose and tolerating it for \> 4 weeks
Evidence of progressive disease by iwCLL 2018 criteria for progressive disease or doubling of absolute lymphocyte count (ALC) in ≤ 6 months while on BTK inhibitor provided ALC is \> 5 k/uL
Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) ≤ 3 x the upper limit of normal (ULN) or ≤ 5 x ULN with documented liver involvement
Bilirubin ≤ 1.5 x ULN or ≤ 3 x ULN with documented liver involvement and/or Gilbert's disease
Creatinine clearance (CrCl) ≥ 30 according to modified Cockcroft-Gault equation
Absolute neutrophil count (ANC) ≥ 0.75 k/uL
Without transfusion or growth factor administration in the 7 days prior to screening
Any values if cytopenias are due to bone marrow involvement with disease
Hemoglobin ≥ 8 g/dL
Without transfusion or growth factor administration in the 7 days prior to screening
Any values if cytopenias are due to bone marrow involvement with disease
Platelets ≥ 50 k/uL
Without transfusion or growth factor administration in the 7 days prior to screening
Any values if cytopenias are due to bone marrow involvement with disease
Prothrombin time (PT) and partial thromboplastin time (PTT) ≤ 1.5 x ULN
No known inherited qualitative platelet defect (e.g. delta granule storage pool deficiency)
Willing and able to complete study activities and treatment
Willing and capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol
Willingness of men and women of reproductive potential and their partners to observe conventional and highly effective or acceptable birth control methods for the duration of treatment and for 6 months following the last dose of pirtobrutinib or 30 days from the last dose of venetoclax
ELIGIBILITY FOR RE-TREATMENT WITH PIRTOBRUTINIB: Discontinued initial study treatment ≤ 12 months ago
ELIGIBILITY FOR RE-TREATMENT WITH PIRTOBRUTINIB: Meets iwCLL 2018 criteria for progressive disease
Exclusion
Inability to tolerate 2 Liters of oral or intravenous (IV) hydration
Prior venetoclax exposure \> 13 months or known resistance to venetoclax
Known hypersensitivity to any of the excipients of pirtobrutinib or venetoclax
Need for treatment with warfarin or other vitamin K antagonist during study treatment
History of bleeding diathesis
Patients who experienced a major bleeding event or grade ≥ 3 arrhythmia on prior treatment with a BTK inhibitor. Major bleeding is defined as bleeding having one or more of the following features: potentially life-threatening bleeding with signs or symptoms of hemodynamic compromise; bleeding associated with a decrease in the hemoglobin level of at least 2g per deciliter; or bleeding in a critical area or organ (e.g., retroperitoneal, intraarticular, pericardial, epidural, or intracranial bleeding or intramuscular bleeding with compartment syndrome)
History of stroke or intracranial hemorrhage within 6 months
Inability to take pills or oral medications
Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal (GI) absorption of either pirtobrutinib or venetoclax
Current known central nervous system involvement with CLL or SLL. Patients with previous treatment for central nervous system (CNS) involvement who are neurologically stable and without evidence of disease may be eligible if a compelling clinical rationale is provided by the investigator and with documented approval by the principal investigator
Treatment with the following:
Targeted agents, investigational agents, therapeutic monoclonal antibodies, or cytotoxic chemotherapy within 5 half-lives or 2 weeks, whichever is shorter
Treatment with immunoconjugated antibody treatment within 10 weeks
Receipt of broad field radiation ( ≥ 30% of the bone marrow or whole brain radiotherapy) within 14 days or palliative limited field radiation within 7 days prior to study enrollment
Note: Treatment with ibrutinib, acalabrutinib, or zanubrutinib is allowed. Treatment with topical chemotherapy agents for precancerous skin conditions or skin cancers is allowed
Unresolved adverse events from prior treatment not resolved to grade ≤ 1 with the exception of alopecia or grade 2 peripheral neuropathy
History of allogeneic or autologous stem cell transplant (SCT) or chimeric antigen receptor-modified T cell (CAR-T) therapy within 60 days. Patients with a history of allogeneic stem cell transplant must be stable off all immunosuppression for at least 2 months prior to study screening. Presence of any of the following, regardless of prior SCT and/or CAR-T therapy timing will be exclusionary:
Active graft versus host disease (GVHD)
Cytopenia from incomplete blood cell count recovery post-transplant
Need for anti-cytokine therapy for toxicity from CAR-T therapy and/or residual symptoms of neurotoxicity \> grade 1 from CAR-T therapy
Ongoing immunosuppressive therapy
Active second malignancy unless in remission and with life expectancy \> 2 years. Adjuvant endocrine therapy for breast or prostate cancer that is expected to be cured is allowed. Non-melanoma skin cancers are permitted if adequately treated
Psychiatric illness, or social situations that would limit compliance with study requirements
Active uncontrolled auto-immune cytopenia (e.g., autoimmune hemolytic anemia \[AIHA\], idiopathic thrombocytopenic purpura \[ITP\]) for which new therapy was introduced or existing therapy was escalated within the 4 weeks prior to study enrollment to maintain adequate blood counts
Evidence of other clinically significant uncontrolled condition(s) including but not limited to, uncontrolled systemic bacterial, viral, fungal or parasitic infection (except for fungal nail infection), or other clinically significant active disease process which in the opinion of the investigator may pose a risk for patient participation. Screening for chronic conditions is not required
Significant cardiovascular disease defined as:
Unstable angina or acute coronary syndrome within the past 2 months
History of myocardial infarction within 3 months
Documented left ventricular ejection fraction (LVEF) by any method of ≤ 40% in the 12 months
≥ grade 3 New York Heart Association (NYHA) functional classification system of heart failure
Uncontrolled or symptomatic arrhythmias
Prolongation of the QT interval corrected for heart rate (Fridericia's formula-corrected QT interval \[QTcF\]) \> 470 msec. QTcF is calculated using Fridericia's formula
Correction of suspected drug induced QTcF prolongation can be attempted at the investigator¡¦s discretion and only if clinically safe to do so with either discontinuation of the offending drug or switch to another drug not known to be associated with QTcF prolongation
Correction for underlying bundle branch block (BBB) allowed
Note: Patients with pacemakers are eligible if they have no history of fainting or clinically relevant arrhythmias while using the pacemaker
Known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection based on criteria below:
Hepatitis B virus (HBV): Patients with positive hepatitis B surface antigen (HBsAg) are excluded. Patients with positive hepatitis B core antibody (anti-HBc) and negative HBsAg require hepatitis B polymerase chain reaction (PCR) evaluation before inclusion. Patients who are hepatitis B PCR positive will be excluded
Hepatitis C virus (HCV): positive hepatitis C antibody. If positive hepatitis C antibody result, patient will need to have a negative result for hepatitis C ribonucleic acid (RNA) before inclusion. Patients who are hepatitis C RNA positive will be excluded. Patients previously treated for hepatitis C \> 6 months previously with a negative RNA test are eligible
Known HIV infection. For patients with unknown HIV status, HIV testing will be performed at screening and result should be negative for enrollment
Known active cytomegalovirus (CMV) infection. Unknown or negative status are eligible
Treatment with a strong CYP3A inhibitor or inducer and/or strong P-gp inhibitors within 3 days of starting or during study treatment. Treatment with a moderate or strong CYP3A inhibitor or inducer within 7 days prior to first dose of venetoclax or during cycle 2 or 3 of study treatment. Patients may not plan to consume grapefruit or grapefruit products, Seville oranges or products from Seville oranges, or star fruit
Pregnancy, lactation, or plan to breastfeed during the study or within 6 months of the last dose of either pirtobrutinib or venetoclax
Major surgery within 4 weeks prior to screening
Vaccination with live vaccine within 28 days of screening
Currently incarcerated
History of progressive multifocal leukoencephalopathy (PML) or human polyomavirus 2 (JC virus) infection
History of seizure disorder unless controlled without a seizure in the year prior to screening
ELIGIBILITY FOR RE-TREATMENT WITH PIRTOBRUTINIB: Has not developed any new medical conditions that would change the safety of treatment with pirtobrutinib
What this trial measures
- Rate of undetectable minimal residual disease (uMRD)At cycle 21 day 1 (C21D1) [each cycle lasts 28 days]
The rate of uMRD will be defined as the percentage of patients who have uMRD in both the peripheral blood and bone marrow at C21D1.