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

Inclusion Criteria:

• PRE-REGISTRATION - INCLUSION CRITERIA

• Age >= 18 years.

• Confirmed diagnosis of CLL according to the International Workshop on (iw)CLL 2018criteria or biopsy proven small lymphocytic lymphoma (SLL) according to the WorldHealth Organization (WHO) criteria.

• NOTE: The diagnosis of CLL requires the presence of > 5 × 10^9/L B lymphocytesin the peripheral blood. Typically, CLL cells express CD19, CD5, and CD23, withvariable expression of CD20 (typically dim), and show kappa or lambda lightchain restriction.

• NOTE: A diagnosis of mantle cell lymphoma must be excluded by demonstrating anegative cyclin D1 expression and/or a negative t(11;14) translocation.

• No prior CLL/SLL-directed therapy such as chemotherapy, immunotherapy, targetedtherapy with small molecule inhibitors, radiation therapy, or cellular therapy.

• NOTE: Nutraceutical treatments with no established benefit in CLL (such asepigallocatechin gallate or EGCG, found in green tea or other herbal treatmentsor supplemental vitamins) will not be considered prior CLL/SLL-directedtherapy.

• NOTE: Prior corticosteroid therapy for an indication other than CLL/SLL willnot be considered prior CLL/SLL-directed therapy.

• NOTE: A short course of corticosteroid (e.g., =< 1 week of intravenous or =< 2weeks of oral corticosteroid) given for acute SLL-related symptoms or impendingsevere organ dysfunction is allowed.

• Provide written informed consent.

• REGISTRATION - INCLUSION CRITERIA

• Patients with SLL must have a measurable B-cell clone (of CLL immunophenotype) ineither 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, orworsening 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 orsymptomatic splenomegaly.

• Massive nodes (i.e., >= 10 cm in longest diameter) or progressive orsymptomatic lymphadenopathy.

• Progressive lymphocytosis with an increase of >= 50% over a 2-month period, orlymphocyte doubling time (LDT) < 6 months. LDT can be obtained by linearregression extrapolation of absolute lymphocyte counts obtained at intervals of 2 weeks over an observation period of 2 to 3 months; patients with initialblood lymphocyte counts < 30 × 10^9/L may require a longer observation periodto 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 responsiveto 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 daysprior 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 normallimit (ULN) (obtained =< 14 days prior to registration)

• Total bilirubin =< 1.5 × ULN (or =< 3 × ULN if there is evidence of parenchymalliver involvement with CLL/SLL); patients with hemolysis or Gilbert's disease mayenroll 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 ofchildbearing potential only.

• NOTE: Persons of reproductive potential is defined as following: menarche andwho are not postmenopausal (and 2 years of non-therapy-induced amenorrhea) orsurgically 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 6months following the last dose of pirtobrutinib.

• Males must be willing to not donate sperm during the study and for 6 months afterthe last dose of any study drug.

• Willingness to provide mandatory research blood, bone marrow, saliva, and stoolspecimens for correlative research.

• Willing to return to enrolling institution for follow-up (during treatment andClinical Follow-up).

Exclusion Criteria:

• REGISTRATION - EXCLUSION CRITERIA

• Any of the following because this study involves an investigational agent whosegenotoxic, mutagenic and teratogenic effects on the developing fetus and newborn areunknown:

• Pregnant persons.

• Nursing persons (lactating persons are eligible provided that they agree not tobreast feed while receiving treatment on the study or within 6 months of thelast dose of study treatment).

• Male or females of reproductive potential who are unwilling to employ adequatecontraception 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 rootinvolvement).

• Active uncontrolled autoimmune complications (e.g., active autoimmune hemolyticanemia or clinically significant immune thrombocytopenia).

• Receiving any other investigational agent which would be considered as a treatmentfor 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 duringthe study.

• Use of a strong or moderate CYP3A inhibitor or inducer =< 7 days prior toregistration.

• Requirement of a strong P-glycoprotein 1 (PgP) inhibitor during the study.

• Anticoagulation with a vitamin K antagonist =< 7 days prior to registration oranticipated 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 =< 3days of study therapy start or planned use during study participation isprohibited:

• Grapefruit or grapefruit products.

• Seville oranges or products from Seville oranges.

• Star fruit.

• Malabsorption syndrome or other condition that precludes enteral route ofadministration.

• History of a bleeding diathesis (e.g., hemophilia, von Willebrand disease, etc.).

• Patients who have tested positive for Human Immunodeficiency Virus (HIV) areexcluded due to potential drug-drug interactions between anti-retroviral medicationsand pirtobrutinib and risk of opportunistic infections with both HIV andirreversible BTK inhibitors. For patients with unknown HIV status, HIV testing willbe performed at Screening and result should be negative for enrollment.

• Co-morbid systemic illnesses or other severe concurrent disease which, in thejudgment of the investigator, would make the patient inappropriate for entry intothis study or interfere significantly with the proper assessment of safety andtoxicity of the prescribed regimens.

• Uncontrolled intercurrent illness including, but not limited to:

• Ongoing or active infection.

• Known active cytomegalovirus (CMV) infection is ineligible; unknown ornegative status are eligible.

• Hepatitis B virus (HBV): Patients with positive hepatitis B surfaceantigen (HBsAg) are excluded. Patients with positive hepatitis B coreantibody (anti-HBc) and negative HBsAg require hepatitis B polymerasechain reaction (PCR) evaluation. Patients who are hepatitis B PCR positivewill be excluded.

• Hepatitis C virus (HCV): If hepatitis C antibody result is positive,patient will need to have a negative result for hepatitis C ribonucleicacid (RNA). Patients who are hepatitis C RNA positive will be excluded.

• New York Heart Association (NYHA) Class III or IV or symptomatic congestiveheart 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 offainting or clinically relevant arrhythmias while using the pacemaker

• Prolongation of the QT interval corrected for heart rate (Fridericia'scorrection formula [QTcF]) > 470 msec on at least 2/3 consecutiveelectrocardiograms (ECGs), and mean QTcF > 470 msec on all 3 ECGs, duringscreening.

• NOTE: QTcF is calculated using Fridericia's Formula (QTcF).

• NOTE: Correction for a widened QRS complex such as pacing, underlyingbundle 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 beattempted at the investigator's discretion and only if clinically safe todo so with either discontinuation of the offending drug or switch toanother 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) requiringactive treatment.

• Oxygen dependent baseline lung disease (such as interstitial lung disease orchronic obstructive pulmonary disease [COPD]).

• Psychiatric illness/social situations that would limit compliance with studyrequirements.

• Major surgery =< 4 weeks prior to registration.

• Other active primary malignancy (other than localized non-melanotic skin cancer orcarcinoma in situ of the cervix) requiring treatment or limiting expected survivalto =< 2 years.

• NOTE: If there is a history of prior malignancy, the patient must not requireongoing therapy such as radiation, chemotherapy, or immunotherapy for theircancer. Patients on hormonal therapy for adequately treated nonmetastaticbreast or prostate cancer are permitted if they meet other eligibilitycriteria.

• Have a known hypersensitivity to any of the excipients of pirtobrutinib.