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Chronic Lymphocytic LeukemiaPhase 2NCT06466122

Pirtobrutinib (LOXO-305) and Venetoclax for the Treatment of Patients With CLL or SLL Resistant to Covalent BTKi

A Phase 2 study testing Biospecimen Collection, Bone Marrow Aspiration and Bone Marrow Biopsy in people with Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma, run by Kerry Rogers at 1 site in United States.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
Search all trials

Trial summary

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). Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Biospecimen Collection, Bone Marrow Aspiration and Bone Marrow Biopsy
Type of treatment
Surgery or procedure
Could I receive a placebo?
No, everyone receives an active treatment
How many people
30 participants
Where
1 siteUnited States
Study dates
7 Nov 2024to 31 Dec 2026
Phase
Phase 2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
Show all 25Show fewer
  • 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

Who cannot join

  • 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)
Show all 48Show fewer
  • 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

Trial locations and contacts

1 site in 1 country. Contact the study team or a site near you to ask about taking part.

The Ohio State University Comprehensive Cancer Center contact

800-293-5066

OSUCCCClinicaltrials@osumc.edu

United States1 site, 1 recruiting

  • Ohio State University Comprehensive Cancer Center

    Columbus, Ohio, 43210

    Kerry A. Rogers, MD, 614-293-3196

    Kerry A. Rogers

    Recruiting

Other trials in United States

About this study

Official title: Phase 2 Study of Combination Pirtobrutinib (LOXO-305) and Venetoclax in CLL Patients With Resistance to Covalent BTKi

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.

Read the detailed description

PRIMARY OBJECTIVE:

  1. Determine if combination pirtobrutinib and venetoclax can induce undetectable minimal residual disease (uMRD) in CLL patients with resistance to ibrutinib, acalabrutinib, or zanubrutinib.

OUTLINE:

Patients receive pirtobrutinib orally (PO) once daily (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 computed tomography (CT) throughout the study.

After completion of study treatment, patients are followed up every 6 months.

Being tested
Biospecimen Collection, Bone Marrow Aspiration, Bone Marrow Biopsy, Computed Tomography, Pirtobrutinib
Medical subject headings
Leukemia, Lymphocytic, Chronic, B-Cell

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Biospecimen CollectionProcedure or surgery

    Also called Biological Sample Collection, Biospecimen Collected, Specimen Collection

    Undergo blood sample collection

  • Bone Marrow AspirationProcedure or surgery

    Undergo bone marrow aspiration and biopsy

  • Bone Marrow BiopsyProcedure or surgery

    Also called Biopsy of Bone Marrow, Biopsy, Bone Marrow

    Undergo bone marrow aspiration and biopsy

  • Computed TomographyProcedure or surgery

    Also called CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography

    Undergo CT

  • PirtobrutinibDrug

    Also called 5-Amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-((2S)-1,1,1-trifluoropropan-2-yl)-1h-pyrazole-4-carboxamide, BTK Inhibitor LOXO-305, Jaypirca, LOXO 305

    Given PO

  • VenetoclaxDrug

    Also called ABT-0199, ABT-199, ABT199, GDC-0199

    Given PO

Study groups in NCT06466122
Study groupRoleWhat they receive
Treatment (pirtobrutinib, venetoclax)ExperimentalPatients 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.
Receives: Procedure: Biospecimen Collection; Procedure: Bone Marrow Aspiration; Procedure: Bone Marrow Biopsy; Procedure: Computed Tomography; Drug: Pirtobrutinib; Drug: Venetoclax

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Rate of undetectable minimal residual disease (uMRD)

    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.

    Measured: At cycle 21 day 1 (C21D1) [each cycle lasts 28 days]

Secondary outcomes (7)

  1. Best overall response rate (ORR)

    Best ORR will be estimated with exact 95% confidence intervals.

    Measured: At cycle 21 day 1 (C21D1) [each cycle lasts 28 days]

  2. Overall Response Rate (ORR)

    ORR will be estimated with exact 95% confidence intervals.

    Measured: At cycle 21 day 1 (C21D1) [each cycle lasts 28 days]

  3. Progression-free survival (PFS) for all patients

    Clinical disease progression will be assessed by International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 criteria. PFS will be described using the method of Kaplan-Meier. Median and/or estimates at clinically meaningful time points for PFS will be reported with 95% confidence intervals.

    Measured: At start of treatment to progression or death up to 18 months after completion of study treatment

  4. PFS in patients who achieve uMRD and those who do not achieve uMRD with pirtobrutinib and venetoclax

    Clinical disease progression will be assessed by iwCLL 2018 criteria. PFS will be described using the method of Kaplan-Meier. Median and/or estimates at clinically meaningful time points for PFS will be reported with 95% confidence intervals.

    Measured: At end of treatment to progression or death up to 18 months after completion of study treatment

  5. Overall survival (OS) for all patients

    OS will be described using the method of Kaplan-Meier. Median and/or estimates at clinically meaningful time points for OS will be reported with 95% confidence intervals.

    Measured: At start of treatment to death up to 18 months after completion of study treatment

  6. OS for patients who achieve uMRD and those who do not achieve uMRD with pirtobrutinib and venetoclax

    OS will be described using the method of Kaplan-Meier. Median and/or estimates at clinically meaningful time points for OS will be reported with 95% confidence intervals.

    Measured: At end of treatment to death up to 18 months after completion of study treatment

  7. Incidence of adverse events (AEs)

    AEs will be summarized by type, severity and perceived attribution according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Hematologic AEs will be graded according to CLL specific criteria described in the iwCLL 2018 guidelines. The maximum grade for each type of AE will be recorded for each patient, and at a minimum, frequency tables will be reviewed to determine AE patterns. The number of patients who discontinue treatment due to AE will be summarized.

    Measured: Up to 28 days after last dose of study drugs

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted20 Jun 2024
  2. Study start7 Nov 2024
  3. Primary completion31 Dec 2026 (estimated)
  4. Study completion31 Dec 2026 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
30 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT06466122
Sponsor's protocol ID
OSU-22172
Other IDs
NCI-2024-04627
Status last verified
Feb 2026
First submitted
7 Jun 2024
Last updated
19 Feb 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Biospecimen Collection, Bone Marrow Aspiration and Bone Marrow Biopsy in people with Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma, run by Kerry Rogers at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 25 inclusion and 48 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 19 Feb 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact The Ohio State University Comprehensive Cancer Center (800-293-5066, OSUCCCClinicaltrials@osumc.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Rate of undetectable minimal residual disease (uMRD) (time frame: At cycle 21 day 1 (C21D1) [each cycle lasts 28 days]). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT06466122.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Feb 2026.

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