Trial Title:
Pirtobrutinib (LOXO-305) and Venetoclax for the Treatment of Patients With CLL or SLL Resistant to Covalent BTKi
NCT ID:
NCT06466122
Condition:
Chronic Lymphocytic Leukemia
Small Lymphocytic Lymphoma
Conditions: Official terms:
Leukemia, Lymphocytic, Chronic, B-Cell
Venetoclax
Pirtobrutinib
Pyrazole
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Procedure
Intervention name:
Biospecimen Collection
Description:
Undergo blood sample collection
Arm group label:
Treatment (pirtobrutinib, venetoclax)
Other name:
Biological Sample Collection
Other name:
Biospecimen Collected
Other name:
Specimen Collection
Intervention type:
Procedure
Intervention name:
Bone Marrow Aspiration
Description:
Undergo bone marrow aspiration and biopsy
Arm group label:
Treatment (pirtobrutinib, venetoclax)
Intervention type:
Procedure
Intervention name:
Bone Marrow Biopsy
Description:
Undergo bone marrow aspiration and biopsy
Arm group label:
Treatment (pirtobrutinib, venetoclax)
Other name:
Biopsy of Bone Marrow
Other name:
Biopsy, Bone Marrow
Intervention type:
Procedure
Intervention name:
Computed Tomography
Description:
Undergo CT
Arm group label:
Treatment (pirtobrutinib, venetoclax)
Other name:
CAT
Other name:
CAT Scan
Other name:
Computed Axial Tomography
Other name:
Computerized Axial Tomography
Other name:
Computerized axial tomography (procedure)
Other name:
Computerized Tomography
Other name:
Computerized Tomography (CT) scan
Other name:
CT
Other name:
CT Scan
Other name:
tomography
Intervention type:
Drug
Intervention name:
Pirtobrutinib
Description:
Given PO
Arm group label:
Treatment (pirtobrutinib, venetoclax)
Other name:
5-Amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-((2S)-1,1,1-trifluoropropan-2-yl)-1h-pyrazole-4-carboxamide
Other name:
BTK Inhibitor LOXO-305
Other name:
Jaypirca
Other name:
LOXO 305
Other name:
LOXO-305
Other name:
LOXO305
Other name:
LY3527727
Intervention type:
Drug
Intervention name:
Venetoclax
Description:
Given PO
Arm group label:
Treatment (pirtobrutinib, venetoclax)
Other name:
ABT-0199
Other name:
ABT-199
Other name:
ABT199
Other name:
GDC-0199
Other name:
RG7601
Other name:
Venclexta
Other name:
Venclyxto
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). 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.
Detailed 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.
Criteria for eligibility:
Criteria:
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
- 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 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:
- 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
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Ohio State University Comprehensive Cancer Center
Address:
City:
Columbus
Zip:
43210
Country:
United States
Status:
Recruiting
Contact:
Last name:
Kerry A. Rogers, MD
Phone:
614-293-3196
Investigator:
Last name:
Kerry A. Rogers
Email:
Principal Investigator
Start date:
December 31, 2024
Completion date:
December 31, 2025
Lead sponsor:
Agency:
Kerry Rogers
Agency class:
Other
Source:
Ohio State University Comprehensive Cancer Center
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06466122
http://cancer.osu.edu
