Pirtobrutinib With Rituximab for the Treatment of Newly Diagnosed Marginal Zone Lymphoma

Inclusion Criteria:

Age ≥ 18 years
Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2
Histologically documented marginal zone lymphoma, including splenic, nodal, and extranodal sub-types at the enrolling institution

No prior systemic therapy for MZL except for the following:

Prior antibiotic therapy for helicobacter (H.) pylori, chlamydophila (C.) psittaci, and borrelia (B.) burgdorferi
Prior antiviral therapy for hepatitis C virus (HCV)
Note: Subjects are eligible if they had a prior splenectomy or other local surgical treatment or local radiation therapy without systemic therapy and now require their first ever systemic therapy. In the event of the receipt of radiation therapy, the minimum wash out period is 14 days
Patients with gastric mucosa-associated lymphoid tissue (MALT) lymphoma must be H. pylori negative or have failed a trial of H. pylori eradication
Patients with localized MALT lymphoma must be ineligible for, have refused or failed radiation therapy (washout period of 14 days)
Adequate coagulation, defined as activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT) and prothrombin (PT) or (international normalized ratio [INR] not greater than 1.5 x upper limit of normal [ULN])
Life expectancy of > 3 months, in the opinion of the investigator
Willingness of women of reproductive potential and their partners to observe highly effective birth control methods for the duration of treatment and for 1 month following the last dose of pirtobrutinib and 12 months following the last rituximab infusion
Patients must have an indication for treatment
Absolute neutrophil count (ANC) ≥ 750 cells/mm^3 ( ≥ 0.75 x 10^9/L) independent of granulocyte colony-stimulating factor [G-CSF] support, unless there is documented bone marrow involvement or splenomegaly with ensuing cytopenia in which case ANC of 500 cells/mm^3 (0.5 x 10^9/L) is permissible. Also, there should be no evidence of myelodysplasia or hypoplastic bone marrow

Platelet count ≥ 50,000 cells/mm^3 (≥ 50 x 10^9/L) independent of transfusion support unless there is documented bone marrow involvement in which case platelet count of 30,000 cells/mm^3 (0.3 x 10^9/L) is permissible. Patients must be responsive to transfusion support if given for thrombocytopenia and patients refractory to transfusion support are not eligible. Also, there should be no evidence of myelodysplasia or hypoplastic bone marrow

The platelet count threshold in the current study (≥ 50,000 cells/mm^3 or ≥ 50 x 10^9/L) is lower than normal threshold (≥ 75,000 cells/mm^3 or ≥ 75 x 10^9/L) as the majority of MZL patients have lower than normal platelets due to splenomegaly and or autoimmune phenomena (which are related to the underlying lymphoma) and hence the lower than normal platelet count threshold for study entry
Hemoglobin of ≥ 8 g/dL (≥ 80 g/L) independent of transfusion support unless there is documented bone marrow involvement or splenomegaly with ensuing cytopenia in which case hemoglobin of 7 g/dL (70 g/L) is permissible. Patients must be responsive to transfusion support if given for anemia and patients refractory to transfusion support are not eligible. Also, there should be no evidence of myelodysplasia or hypoplastic bone marrow
Total bilirubin ≤ 1.5 x upper limit of normal (ULN) or ≤ 3 x ULN with document liver involvement and/or Gilbert's disease transaminases (aspartate aminotransferase [AST] or alanine aminotransferase [ALT]) ≤ 3 x ULN or ≤ 5 x ULN with documented liver involvement
Calculated creatinine clearance ≥ 30 mL/min according to Cockcroft/Gault Formula
Ability to swallow oral tablets
Patients or their legal representatives must be able to read, understand, and provide informed consent to participate in the trial
Willing and capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol

Exclusion Criteria:

Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal (GI) absorption of the study drug
Major surgery within 4 weeks prior to enrollment
History of bleeding diathesis
History of stroke or intracranial hemorrhage within 6 months of enrollment

Significant cardiovascular disease defined as:

Unstable angina or acute coronary syndrome within the past 2 months prior to study enrollment
History of myocardial infarction within 3 months prior to study enrollment or
Documented left ventricular ejection fraction (LVEF) by any method of ≤ 40% in the 12 months prior to study enrollment
Grade 3 New York Heart Association (NYHA) functional classification system of heart failure, uncontrolled or symptomatic arrhythmias
Patients with central nervous system (CNS) involvement

Prolongation of the QT interval corrected for heart rate (Fridericia's Correction Formula [QTcF]) > 470 msec. 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
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

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 (anti-HBc) and negative HBsAg require hepatitis B polymerase chain reaction (PCR) evaluation before enrollment. Patients who are HBV deoxyribonucleic acid (DNA) PCR positive will be excluded. Patients with positive anti-HBc and negative HBV DNA should be on prophylactic nucleo(t)side analogue therapy to prevent reactivation with serial HBV DNA PCR monitoring
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
Known active cytomegalovirus (CMV) infection. Unknown or negative status are eligible
Evidence of other clinically significant uncontrolled condition(s) including but not limited to, 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 medical monitor may pose a risk for patient participation. Screening for chronic conditions is not required
Active uncontrolled auto-immune cytopenia (e.g., autoimmune hemolytic anemia [AIHA], idiopathic thrombocytopenic purpura [ITP]) for which new therapy was introduced or existing therapy was escalated within the 4 weeks prior to study enrollment to maintain adequate blood counts
Active second malignancy unless in remission and with life expectancy > 2 years
Pregnancy or plan to become pregnant during the study or within 1 month of the last dose of pirtobrutinib or 12 months following the last rituximab infusion
Lactation or plan to breastfeed during the study or within 1 week of the last dose of pirtobrutinib or 6 months following the last rituximab infusion
Patients requiring therapeutic anticoagulation with warfarin or another vitamin K antagonist
Receipt of live-virus vaccines within 28 days prior to the initiation of study treatment or need for live-virus vaccines at any time during study treatment
Have a known hypersensitivity to any of the excipients of Pirtobrutinib