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Trial Title: Pirtobrutinib and Venetoclax With MRD Detection for Previously Untreated Chronic Lymphocytic Leukemia

NCT ID: NCT05677919

Condition: Chronic Lymphocytic Leukemia
Small Lymphocytic Lymphoma

Conditions: Official terms:
Leukemia
Leukemia, Lymphoid
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 collection of blood, tissue, stool, and saliva samples
Arm group label: Treatment (pirtobrutinib and 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
Arm group label: Treatment (pirtobrutinib and venetoclax)

Intervention type: Procedure
Intervention name: Bone Marrow Biopsy
Description: Undergo bone marrow biopsy
Arm group label: Treatment (pirtobrutinib and venetoclax)

Other name: Biopsy of Bone Marrow

Other name: Biopsy, Bone Marrow

Intervention type: Procedure
Intervention name: Computed Tomography
Description: Undergo CT scan
Arm group label: Treatment (pirtobrutinib and venetoclax)

Other name: CAT

Other name: CAT Scan

Other name: Computed Axial Tomography

Other name: Computerized Axial Tomography

Other name: Computerized Tomography

Other name: CT

Other name: CT Scan

Other name: tomography

Other name: Computerized axial tomography (procedure)

Intervention type: Procedure
Intervention name: Magnetic Resonance Imaging
Description: Undergo MRI scan
Arm group label: Treatment (pirtobrutinib and venetoclax)

Other name: Magnetic Resonance

Other name: Magnetic Resonance Imaging Scan

Other name: Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance

Other name: MR

Other name: MR Imaging

Other name: MRI

Other name: MRI Scan

Other name: NMR Imaging

Other name: NMRI

Other name: Nuclear Magnetic Resonance Imaging

Other name: Magnetic resonance imaging (procedure)

Intervention type: Drug
Intervention name: Pirtobrutinib
Description: Given PO
Arm group label: Treatment (pirtobrutinib and 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: LOXO 305

Other name: LOXO-305

Other name: LOXO305

Other name: LY3527727

Other name: Jaypirca

Intervention type: Procedure
Intervention name: Positron Emission Tomography
Description: Undergo PET scan
Arm group label: Treatment (pirtobrutinib and venetoclax)

Other name: Medical Imaging, Positron Emission Tomography

Other name: PET

Other name: PET Scan

Other name: Positron Emission Tomography Scan

Other name: Positron-Emission Tomography

Other name: proton magnetic resonance spectroscopic imaging

Other name: PT

Other name: Positron emission tomography (procedure)

Intervention type: Drug
Intervention name: Venetoclax
Description: Given PO
Arm group label: Treatment (pirtobrutinib and 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

Intervention type: Procedure
Intervention name: Echocardiography
Description: Undergo ECHO
Arm group label: Treatment (pirtobrutinib and venetoclax)

Other name: EC

Other name: ECHO

Intervention type: Procedure
Intervention name: Multigated Acquisition Scan
Description: Undergo MUGA
Arm group label: Treatment (pirtobrutinib and venetoclax)

Other name: Blood Pool Scan

Other name: Equilibrium Radionuclide Angiography

Other name: Gated Blood Pool Imaging

Other name: Gated Heart Pool Scan

Other name: MUGA

Other name: MUGA Scan

Other name: Multi-Gated Acquisition Scan

Other name: Radionuclide Ventriculogram Scan

Other name: Radionuclide ventriculography

Other name: RNVG

Other name: SYMA Scanning

Other name: Synchronized Multigated Acquisition Scanning

Summary: 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.

Detailed description: PRIMARY OBJECTIVE: I. To assess the rate of undetectable minimal residual disease (MRD) (uMRD, by ClonoSEQ) in both peripheral blood and bone marrow after 15 cycles of treatment. SECONDARY OBJECTIVES: I. To assess best peripheral blood uMRD rate and best bone marrow uMRD rate by ClonoSEQ. II. To assess progression-free survival (PFS). III. To assess overall response rate (ORR) and complete response (CR) rate. IV. To assess duration of response (DOR), time to next treatment (TTNT), and overall survival (OS). V. To assess toxicities associated with pirtobrutinib and venetoclax. CORRELATIVE RESEARCH OBJECTIVE: I. To analyze the dynamics of MRD (by ClonoSEQ) and its association with response to treatment and clinical outcomes. OUTLINE: Patients receive pirtobrutinib orally (PO) daily (QD) on days 1-28 of each cycle and venetoclax PO QD starting in cycle 4 on days 1-28 of each cycle. Treatment repeats every 28 days for up to 27 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT), magnetic resonance imaging (MRI), and/or positron emission tomography (PET)/CT scans during screening and on study. Patients also undergo bone marrow aspiration and biopsy and collection of blood samples throughout the study and collection of stool and saliva on study. Patients may undergo echocardiography (ECHO) or multigated acquisition (MUGA) scan during screening. After completion of study treatment, patients follow up at 30 days and every 6 months for up to 3 years for clinical follow-up and then every 6 months for up to 5 years after registration for survival follow-up.

Criteria for eligibility:
Criteria:
Inclusion Criteria: - PRE-REGISTRATION - INCLUSION CRITERIA - Age >= 18 years. - Confirmed diagnosis of CLL according to the International Workshop on (iw)CLL 2018 criteria or biopsy proven small lymphocytic lymphoma (SLL) according to the World Health Organization (WHO) criteria. - NOTE: The diagnosis of CLL requires the presence of > 5 × 10^9/L B lymphocytes in the peripheral blood. Typically, CLL cells express CD19, CD5, and CD23, with variable expression of CD20 (typically dim), and show kappa or lambda light chain restriction. - NOTE: A diagnosis of mantle cell lymphoma must be excluded by demonstrating a negative cyclin D1 expression and/or a negative t(11;14) translocation. - No prior CLL/SLL-directed therapy such as chemotherapy, immunotherapy, targeted therapy with small molecule inhibitors, radiation therapy, or cellular therapy. - NOTE: Nutraceutical treatments with no established benefit in CLL (such as epigallocatechin gallate or EGCG, found in green tea or other herbal treatments or supplemental vitamins) will not be considered prior CLL/SLL-directed therapy. - NOTE: Prior corticosteroid therapy for an indication other than CLL/SLL will not be considered prior CLL/SLL-directed therapy. - NOTE: A short course of corticosteroid (e.g., =< 1 week of intravenous or =< 2 weeks of oral corticosteroid) given for acute SLL-related symptoms or impending severe organ dysfunction is allowed. - Provide written informed consent. - REGISTRATION - INCLUSION CRITERIA - Patients with SLL must have a measurable B-cell clone (of CLL immunophenotype) in either peripheral blood or bone marrow (e.g., by flow cytometry) at baseline. - Meeting at least one of the following indications for treatment: - Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia (Hb < 11 g/dL) and/or thrombocytopenia (platelet counts < 100 × 10^9/L). - Massive (i.e., >= 6 cm below the left costal margin) or progressive or symptomatic splenomegaly. - Massive nodes (i.e., >= 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy. - Progressive lymphocytosis with an increase of >= 50% over a 2-month period, or lymphocyte doubling time (LDT) < 6 months. LDT can be obtained by linear regression extrapolation of absolute lymphocyte counts obtained at intervals of 2 weeks over an observation period of 2 to 3 months; patients with initial blood lymphocyte counts < 30 × 10^9/L may require a longer observation period to determine the LDT. Factors contributing to lymphocytosis other than CLL (e.g., infections, steroid administration) should be excluded. - Autoimmune complications including anemia or thrombocytopenia poorly responsive to corticosteroids. - Symptomatic or functional extranodal involvement (e.g., skin, kidney, lung, spine). - Disease-related symptoms as defined by any of the following: - Unintentional weight loss >= 10% within the previous 6 months. - Significant fatigue (i.e., cannot work or unable to perform usual activities). - Fevers >= 100.4°F or 38.0°C for 2 or more weeks without evidence of infection. - Night sweats for >= 1 month without evidence of infection. - Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0, 1 or 2 - Absolute neutrophil count (ANC) >= 0.75 × 10^9/L (750/mm^3) (obtained =< 14 days prior to registration) - Platelet count >= 50 × 10^9/L (obtained =< 14 days prior to registration) - Hemoglobin >= 8 g/dL (obtained =< 14 days prior to registration) - Activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT) and prothrombin (PT) or international normalized ratio (INR) =< 1.5 × upper normal limit (ULN) (obtained =< 14 days prior to registration) - Total bilirubin =< 1.5 × ULN (or =< 3 × ULN if there is evidence of parenchymal liver involvement with CLL/SLL); patients with hemolysis or Gilbert's disease may enroll if indirect bilirubin is =< 3 × ULN and direct bilirubin is =< 1.5 × ULN (obtained =< 14 days prior to registration) - Alanine aminotransferase (ALT) and aspartate transaminase (AST) =< 3 × ULN (or =< 5 × ULN if there is evidence of parenchymal liver involvement with CLL/SLL) (obtained =< 14 days prior to registration) - Calculated creatinine clearance >=40 ml/min using the Cockcroft-Gault formula. - Negative serum pregnancy test done =< 7 days prior to registration, for persons of childbearing potential only. - NOTE: Persons of reproductive potential is defined as following: menarche and who are not postmenopausal (and 2 years of non-therapy-induced amenorrhea) or surgically sterile. - Male and females of reproductive potential must agree to use a highly effective (preferred) or an acceptable form of birth control during study treatment and for 6 months following the last dose of pirtobrutinib. - Males must be willing to not donate sperm during the study and for 6 months after the last dose of any study drug. - Willingness to provide mandatory research blood, bone marrow, saliva, and stool specimens for correlative research. - Willing to return to enrolling institution for follow-up (during treatment and Clinical Follow-up). Exclusion Criteria: - REGISTRATION - EXCLUSION CRITERIA - Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown: - Pregnant persons. - Nursing persons (lactating persons are eligible provided that they agree not to breast feed while receiving treatment on the study or within 6 months of the last dose of study treatment). - Male or females of reproductive potential who are unwilling to employ adequate contraception during treatment and for 6 months after pirtobrutinib. - Evidence of Richter transformation. - Central nervous system (CNS) involvement of CLL/SLL (e.g., any parenchymal, leptomeningeal, cerebrospinal fluid [CSF], cranial or spinal nerve root involvement). - Active uncontrolled autoimmune complications (e.g., active autoimmune hemolytic anemia or clinically significant immune thrombocytopenia). - Receiving any other investigational agent which would be considered as a treatment for the CLL/SLL (with the exception of corticosteroid). - Any of the following medication requirement or recent use: - Requirement of a strong cytochrome P450 (CYP) 3A inhibitor or inducer during the study. - Use of a strong or moderate CYP3A inhibitor or inducer =< 7 days prior to registration. - Requirement of a strong P-glycoprotein 1 (PgP) inhibitor during the study. - Anticoagulation with a vitamin K antagonist =< 7 days prior to registration or anticipated use during the study. - Vaccination with live vaccine =< 28 days prior to registration. - NOTE: Because of their effect on CYP3A4, use of any of the following =< 3 days of study therapy start or planned use during study participation is prohibited: - Grapefruit or grapefruit products. - Seville oranges or products from Seville oranges. - Star fruit. - Malabsorption syndrome or other condition that precludes enteral route of administration. - History of a bleeding diathesis (e.g., hemophilia, von Willebrand disease, etc.). - Patients who have tested positive for Human Immunodeficiency Virus (HIV) are excluded due to potential drug-drug interactions between anti-retroviral medications and pirtobrutinib and risk of opportunistic infections with both HIV and irreversible BTK inhibitors. For patients with unknown HIV status, HIV testing will be performed at Screening and result should be negative for enrollment. - Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens. - Uncontrolled intercurrent illness including, but not limited to: - Ongoing or active infection. - Known active cytomegalovirus (CMV) infection is ineligible; unknown or negative status are eligible. - 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. Patients who are hepatitis B PCR positive will be excluded. - Hepatitis C virus (HCV): If hepatitis C antibody result is positive, patient will need to have a negative result for hepatitis C ribonucleic acid (RNA). Patients who are hepatitis C RNA positive will be excluded. - New York Heart Association (NYHA) Class III or IV or symptomatic congestive heart failure. - Documented left ventricular ejection fraction (LVEF) by any method of =< 40% =< 12 months prior to registration. - Unstable angina or acute coronary syndrome =<3 months prior to registration. - History of myocardial infarction =< 6 months prior to registration. - Uncontrolled or symptomatic cardiac arrhythmia. - NOTE: Patients with pacemakers are eligible if they have no history of fainting or clinically relevant arrhythmias while using the pacemaker - Prolongation of the QT interval corrected for heart rate (Fridericia's correction formula [QTcF]) > 470 msec on at least 2/3 consecutive electrocardiograms (ECGs), and mean QTcF > 470 msec on all 3 ECGs, during screening. - NOTE: QTcF is calculated using Fridericia's Formula (QTcF). - NOTE: Correction for a widened QRS complex such as pacing, underlying bundle branch block (BBB), etc. is allowed e.g., "Adjusted QTcF" = measured QTcF - (measured QRS - 90 ms). - NOTE: 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. - History of cerebral vascular accident =< 6 months prior to registration. - Ongoing inflammatory bowel disease (such as ulcerative colitis) requiring active treatment. - Oxygen dependent baseline lung disease (such as interstitial lung disease or chronic obstructive pulmonary disease [COPD]). - Psychiatric illness/social situations that would limit compliance with study requirements. - Major surgery =< 4 weeks prior to registration. - Other active primary malignancy (other than localized non-melanotic skin cancer or carcinoma in situ of the cervix) requiring treatment or limiting expected survival to =< 2 years. - NOTE: If there is a history of prior malignancy, the patient must not require ongoing therapy such as radiation, chemotherapy, or immunotherapy for their cancer. Patients on hormonal therapy for adequately treated nonmetastatic breast or prostate cancer are permitted if they meet other eligibility criteria. - Have a known hypersensitivity to any of the excipients of pirtobrutinib.

Gender: All

Minimum age: 18 Years

Maximum age: N/A

Healthy volunteers: No

Locations:

Facility:
Name: Mayo Clinic in Rochester

Address:
City: Rochester
Zip: 55905
Country: United States

Status: Recruiting

Contact:
Last name: Clinical Trials Referral Office

Phone: 855-776-0015
Email: mayocliniccancerstudies@mayo.edu

Investigator:
Last name: Yucai Wang, M.D., Ph.D.
Email: Principal Investigator

Investigator:
Last name: Sameer A. Parikh, M.B.B.S.
Email: Principal Investigator

Start date: January 31, 2023

Completion date: August 31, 2027

Lead sponsor:
Agency: Mayo Clinic
Agency class: Other

Source: Mayo Clinic

Record processing date: ClinicalTrials.gov processed this data on November 12, 2024

Source: ClinicalTrials.gov page: https://clinicaltrials.gov/ct2/show/NCT05677919
https://www.mayo.edu/research/clinical-trials

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