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

MC210806 Phase 2 Study of MRD Guided, FIxed DuRation TherApy for Previously Untreated Chronic Lymphocytic LeukEmia With Pirtobrutinib and Venetoclax (MIRACLE)

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma
• Intervention / Treatment: Drug: Venetoclax; Procedure: Positron Emission Tomography; Procedure: Computed Tomography; Procedure: Echocardiography; Procedure: Multigated Acquisition Scan; Procedure: Bone Marrow Aspiration; Procedure: Magnetic Resonance Imaging; Procedure: Biopsy; Procedure: Bone Marrow Biopsy; Procedure: Biospecimen Collection; Drug: Pirtobrutinib

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 tissue biopsy, 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.

• Study Type: Interventional
• Enrollment (Estimated): 72
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic in Rochester

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (pirtobrutinib and venetoclax); Patients receive pirtobrutinib and venetoclax PO on study. Patients also undergo CT, MRI, and PET scans during screening and on study. Patients also undergo bone marrow aspiration and bone marrow biopsy, and collection of blood, tissue, stool, and saliva samples on study.

Drug: Venetoclax; Given PO; Other Names: Venclexta; ABT-0199; ABT-199; ABT199; GDC-0199; RG7601; Venclyxto; Procedure: Positron Emission Tomography; Undergo PET scan; Other Names: Medical Imaging, Positron Emission Tomography; PET; PET Scan; Positron Emission Tomography Scan; Positron-Emission Tomography; proton magnetic resonance spectroscopic imaging; PT; Positron emission tomography (procedure); Procedure: Computed Tomography; Undergo CT scan; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Procedure: Echocardiography; Undergo ECHO; Other Names: EC; ECHO; Procedure: Multigated Acquisition Scan; Undergo MUGA; Other Names: Blood Pool Scan; Equilibrium Radionuclide Angiography; Gated Blood Pool Imaging; MUGA; RNVG; SYMA Scanning; Synchronized Multigated Acquisition Scanning; MUGA Scan; Multi-Gated Acquisition Scan; Radionuclide Ventriculogram Scan; Gated Heart Pool Scan; Radionuclide ventriculography; Procedure: Bone Marrow Aspiration; Undergo bone marrow aspiration; Procedure: Magnetic Resonance Imaging; Undergo MRI scan; Other Names: MRI; Magnetic Resonance; Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI Scan; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; Magnetic resonance imaging (procedure); Procedure: Biopsy; Undergo tissue biopsy; Other Names: Bx; Procedure: Bone Marrow Biopsy; Undergo bone marrow biopsy; Other Names: Biopsy of Bone Marrow; Biopsy, Bone Marrow; Procedure: Biospecimen Collection; Undergo collection of blood, tissue, stool, and saliva samples; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Drug: Pirtobrutinib; Given PO; Other Names: LOXO-305; LY3527727; 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; LOXO 305; LOXO305; Jaypirca

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Undetected minimal residual disease (uMRD)	Success of uMRD (< 1/10^4) will be measured by ClonoSEQ in both peripheral blood and bone marrow. The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true rate of uMRD by ClonoSEQ in both peripheral blood and bone marrow after cycle 15 will be calculated.	After cycle 15 (1 cycle = 28 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peripheral blood uMRD rate	The peripheral blood uMRD rate will be estimated by the number of patients who achieve uMRD in the peripheral blood by ClonoSEQ at any time during study divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true peripheral blood uMRD rate will be calculated.	Up to 3 years
Bone marrow uMRD rate	The bone marrow uMRD rate will be estimated by the number of patients who achieve uMRD in the bone marrow by ClonoSEQ at any time during study divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true bone marrow uMRD rate will be calculated.	Up to 3 years
Complete response rate	The complete response rate will be estimated by the number of patients with a complete response (including complete response with incomplete marrow recovery) by the iwCLL response criteria during study divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true complete response rate will be calculated.	Up to 3 years
Duration of response	The distribution of duration of response will be estimated using the method of Kaplan-Meier.	From when patient's objective status is first noted to be either a CR, CRi, PR, or nPR to the earliest date on which progressive disease is documented by the iwCLL criteria, assessed up to 3 years
Time to next treatment	The distribution of time to next treatment will be estimated using the method of Kaplan-Meier.	From registration to initiation of subsequent anti-CLL therapy, assessed up to 3 years
Overall response rate	The overall response rate will be estimated by the number of patients with a response [including complete response (CR), CR with incomplete marrow recovery (CRi), and partial response (PR) by the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) response criteria] during study.	Up to 3 years
Progression-free survival (PFS)	Defined as the time from registration to disease progression or death due to any cause.	Up to 3 years
Overall survival (OS)	Defined as the time from registration to death due to any cause.	Up to 5 years
Incidence of adverse events	Platelets and hemoglobin will be graded according to the Grading Scale for Hematologic Adverse Events in chronic lymphocytic leukemia studies. The maximum grade [per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0] for each type of adverse event will be recorded for each patient.	Up to 3 years

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Yucai Wang, MD, PhD, Mayo Clinic in Rochester

Publications and helpful links

Helpful Links

• Mayo Clinic Clinical Trials

Study record dates

Study Major Dates

• Study Start (Actual): January 31, 2023
• Primary Completion (Estimated): November 11, 2026
• Study Completion (Estimated): September 3, 2030

Study Registration Dates

• First Submitted: December 28, 2022
• First Submitted That Met QC Criteria: December 28, 2022
• First Posted (Actual): January 10, 2023

Study Record Updates

• Last Update Posted (Actual): February 12, 2026
• Last Update Submitted That Met QC Criteria: February 10, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Chronic Disease; Disease Attributes; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Pathological Conditions, Signs and Symptoms; Hemic and Lymphatic Diseases; Leukemia, Lymphocytic, Chronic, B-Cell; Investigative Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Surgical Procedures, Operative; Cytological Techniques; Cytodiagnosis; Diagnostic Techniques, Surgical; Chemistry Techniques, Analytical; Spectrum Analysis; Biopsy; Specimen Handling; Magnetic Resonance Spectroscopy; venetoclax; pirtobrutinib
• Other Study ID Numbers: MC210806 (Mayo Clinic in Rochester); NCI-2022-09676 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); 22-004216 (Other Identifier: Mayo Clinic Institutional Review Board)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No