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About
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.
Full description
PRIMARY OBJECTIVE:
I. 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.
Enrollment
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Volunteers
Inclusion criteria
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
Hemoglobin ≥ 8 g/dL
Platelets ≥ 50 k/uL
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 criteria
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:
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 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:
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
Known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection based on criteria below:
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
Primary purpose
Allocation
Interventional model
Masking
30 participants in 1 patient group
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Central trial contact
The Ohio State University Comprehensive Cancer Center
Data sourced from clinicaltrials.gov
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