Venetoclax and Pirtobrutinib for the Treatment of Previously Treated Waldenstrom Macroglobulinemia

Inclusion Criteria

• Clinicopathological diagnosis of Waldenstrom macroglobulinemia
• MYD88 mutated disease confirmed by Clinical Laboratory Improvement Act (CLIA) certified laboratory
• At least 1 prior line of treatment * Prior covalent BTK inhibitor is allowed even if prior progression documented on this agent * Prior venetoclax is allowed unless participant had documented progression while on this agent
• Patients are required to have the following washout periods prior to planned cycle 1 day 1 (C1D1). In addition, prior treatment-related AEs must have recovered to grade ≤ 1 with the exception of alopecia and grade 2 peripheral neuropathy. * Targeted agents, investigational agents, therapeutic monoclonal antibodies or cytotoxic chemotherapy: 5 half-lives or 2 weeks, whichever is shorter. * Immunoconjugated antibody treatment within 10 weeks prior to randomization. * Broad field radiation (≥ 30% of the bone marrow or whole brain radiotherapy) must be completed 14 days prior to study enrollment. * Palliative limited field radiation must be completed 7 days prior to study enrollment
• Symptomatic disease meeting criteria for treatment using consensus panel criteria from the Second International Workshop on WM. At least one of the following: * Constitutional symptoms ** Recurrent fever ** Night sweats ** Fatigue ** Weight loss * Progressive or symptomatic lymphadenopathy or splenomegaly * Hemoglobin =< 10 g/dL * Platelet count =< 100 k/uL * Hyperviscosity syndrome * Symptomatic peripheral neuropathy * Systemic amyloidosis * Renal insufficiency * Symptomatic cryoglobulinemia
• Age 18 years or older
• Measurable disease, defined as presence of immunoglobulin M (IgM) paraprotein with a minimum serum IgM level of > 2 times the upper limit normal
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
• Women of childbearing potential: Females of childbearing potential (FCBP) must agree to use two highly effective forms of contraception simultaneously or have or will have complete abstinence from heterosexual intercourse during the following time periods related to this study: 1) while participating in the study; and 2) for at least 1 month after discontinuation from the study. FCBP must be referred to a qualified provider of contraceptive methods if needed
• Absolute neutrophil count >= 750/ uL the patient may enroll below this threshold if there is documented bone marrow involvement considered to impair hematopoiesis
• Platelets >= 50,000/ uL not requiring transfusion support; the patient may enroll below this threshold if there is documented bone marrow involvement considered to impair hematopoiesis
• Hemoglobin >= 8 g/dL not requiring transfusion support or growth factors; the patient may enroll below this threshold if there is documented bone marrow involvement considered to impair hematopoiesis or hemolysis
• Total bilirubin =< 1.5 X upper limit of normal (ULN), or =< 3 x ULN with documented liver involvement, hemolysis, or Gilbert’s disease
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional upper limit of normal, or =< 5 X ULN with documented liver involvement
• Creatinine clearance >= 30 ml/min using Cockcroft/Gault formula
• Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• Able to adhere to the study visit schedule and other protocol requirements
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

• Prior exposure to non-covalent BTK inhibitors
• Participants who experienced a major bleeding event or grade > 3 arrhythmia on prior treatment with a BTK inhibitor. NOTE: 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)
• Participants who are receiving any other investigational agents
• Female participants who are pregnant, breastfeeding, or planning to become pregnant or breastfeed while enrolled in this study or within 1 month of last dose of study drug
• Participants with known central nervous system (CNS) lymphoma
• Participants with known history of human immunodeficiency virus (HIV) and known active cytomegalovirus (CMV) infection
• 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 (antiHBc) and negative HBsAg require hepatitis B polymerase chain reaction (PCR) evaluation before enrollment. 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 enrollment. Patients who are hepatitis C RNA positive will be excluded
• Concurrent administration of warfarin
• Concurrent administration of moderate or strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers and/or strong p-glycoprotein (P-gp) inhibitors
• Concurrent systemic immunosuppressant therapy. System steroids at doses =< 20 mg prednisone per day are permitted
• Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug
• Active 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 and the Sponsor makes it undesirable for the patient to participate in the trial. Screening for chronic conditions is not required
• Major surgery within 4 weeks of first dose of study drug
• Malabsorption syndrome or other condition that precludes enteral route of administration
• Participants with known history of alcohol or drug abuse
• Participants with inability to swallow pills and inability to comply with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of the study participation
• Active uncontrolled auto-immune cytopenia (e.g., autoimmune hemolytic anemia [AIHA], idiopathic thrombocytopenic purpura [ITP]) where new therapy introduced or concomitant therapy escalated within the 4 weeks prior to study enrollment is required to maintain adequate blood counts
• Prolongation of the QT interval corrected for heart rate (Fridericia’s formula–corrected QT interval [QTcF]) > 470 msec during screening. QTcF is calculated using Fridericia’s Formula (QTcF): * 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
• Significant cardiovascular disease defined as: * Unstable angina, or * History of myocardial infarction within 6 months prior to planned start of pirtobrutinib, or * Previously documented left ventricular ejection fraction (LVEF) by any method of =< 45% in the 12 months prior to planned start of pirtobrutinib; assessment of LVEF via echocardiogram or multigated acquisition (MUGA) scan during screening should be performed in selected patients as medically indicated, or * Any class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or * Uncontrolled or symptomatic arrhythmias
• History of stroke or intracranial hemorrhage within 6 months of starting therapy
• Prior or ongoing clinically significant illness, medical condition, surgical history, physical finding, electrocardiogram (EKG) finding, or laboratory abnormality that, in the investigator's opinion, could affect the safety of the patient; alter the absorption, distribution, metabolism or excretion of the study drug; or impair the assessment of study results
• Participants with a known hypersensitivity to any of the excipients of pirtobrutinib or venetoclax
• Participants with a history of non-compliance to medical regimens