Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma
Conditions
Brief 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 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.
Interventions
PROCEDUREBiospecimen Collection
Undergo collection of blood, tissue, stool, and saliva samples
PROCEDUREBone Marrow Aspiration
Undergo bone marrow aspiration
PROCEDUREBone Marrow Biopsy
Undergo bone marrow biopsy
PROCEDUREComputed Tomography
Undergo CT scan
PROCEDUREMagnetic Resonance Imaging
Undergo MRI scan
DRUGPirtobrutinib
Given PO
PROCEDUREPositron Emission Tomography
Undergo PET scan
DRUGVenetoclax
Given PO
PROCEDUREEchocardiography
Undergo ECHO
PROCEDUREMultigated Acquisition Scan
Undergo MUGA
PROCEDUREBiopsy
Undergo tissue biopsy
Sponsors
Mayo Clinic
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 -
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Undetected minimal residual disease (uMRD) | After cycle 15 (1 cycle = 28 days) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Peripheral blood uMRD rate | Up to 3 years | 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. |
| Bone marrow uMRD rate | Up to 3 years | 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. |
| Overall response rate | Up to 3 years | 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. |
| Complete response rate | Up to 3 years | 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. |
| Duration of response | 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 | The distribution of duration of response will be estimated using the method of Kaplan-Meier. |
| Time to next treatment | From registration to initiation of subsequent anti-CLL therapy, assessed up to 3 years | The distribution of time to next treatment will be estimated using the method of Kaplan-Meier. |
| Progression-free survival (PFS) | Up to 3 years | Defined as the time from registration to disease progression or death due to any cause. |
| Overall survival (OS) | Up to 5 years | Defined as the time from registration to death due to any cause. |
| Incidence of adverse events | Up to 3 years | 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. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORYucai Wang, MD, PhD
Mayo Clinic in Rochester
Outcome results
None listed