Epcoritamab and Rituximab for First-line Follicular Lymphoma

Inclusion Criteria: * Histologically confirmed diagnosis of CD20+ FL (grade 1-3A) with review of the diagnostic pathology specimen at one of the participating institutions. Patients with current or prior histologic transformation are excluded. * No prior systemic therapy for FL. Prior treatment with radiation therapy or short course steroids is allowed. * Meets at least one criterion to begin treatment based on the modified GELF (Groupe d'Etude des Lymphomes Folliculaires) criteria: * Symptomatic adenopathy * Organ function impairment due to disease involvement, including cytopenias due to marrow involvement (WBC \<1.5x109/L; absolute neutrophil count \[ANC\] \<1.0x109/L, Hgb \<10g/dL; or platelets \<100x109/L) * Constitutional symptoms (defined as persistent fevers \>100.4 F, shaking chills, drenching night sweats, or loss of \>10% of body weight within a 6 month period) * Any nodal or extranodal tumor mass \>7 cm in maximum diameter * \>3 nodal sites of involvement \>3 cm * Local compressive symptoms or imminent risk thereof * Splenomegaly (craniocaudal diameter \> 16cm on CT imaging) * Clinically significant pleural or peritoneal effusion * Leukemic phase (\>5x109/L circulating malignant cells) * Rapid generalized disease progression * Renal infiltration * Bone lesions * Patients cannot be in need of urgent cytoreductive chemotherapy (in the opinion of the treating investigator). * Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. (Appendix A) * Age ≥18 years. * Adequate hematologic and organ function: 1. Absolute neutrophil count \> 1.0x109/L unless due to marrow involvement by lymphoma in which case ANC must be \>0.5x109/L 2. Platelets \> 75 x109/L, unless due to marrow involvement by lymphoma, in which case platelets must be \>50 x109/L 3. Estimated CrCl (Cockcroft Gault) ≥ 45ml/min 4. Total bilirubin \< 1.5 X ULN, unless Gilbert syndrome, in which case direct bilirubin must be \< 1.5 x ULN 5. AST/ALT \< 2.5 X ULN, unless documented liver involvement by lymphoma, in which case AST/ALT must be \<5 x ULN * Ability to understand and the willingness to sign a written informed consent document. * Willingness to provide a pre-treatment tumor sample by core needle or excisional surgical biopsy. A fresh biopsy is strongly encouraged, but an archival sample is acceptable if the following provisions are met: 1) availability of a tumor-containing formalin-fixed, paraffin-embedded (FFPE) tissue block, 2) if the tumor containing FFPE tissue block cannot be provided in total, sections from this block should be provided that are freshly cut and mounted on positively-charged glass slides. Preferably, 25 slides should be provided; if not possible, a minimum of 15 slides is required. Exceptions to this criterion may be made with approval of the Sponsor-Investigator. * Willingness to remain abstinent or to use two effective contraceptive methods that result in a failure rate of \<1% per year from screening until: (a) at least 3 months after pre-treatment with rituximab or 12 months after the last dose of epcoritamab, whichever is longer, if the patient is a male or (b) until at least 18 months after pre-treatment with rituximab or 12 months after the last dose of epcoritamab, whichever is longer, if patient is a female. Examples of contraceptive methods with a failure rate of \<1% per year include: * Tubal ligation, male sterilization, hormonal implants, established proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. * Alternatively, two methods (e.g., two barrier methods such as a condom and a cervical cap) may be combined to achieve a failure rate of \<1% per year. Barrier methods must always be supplemented with the use of a spermicide. Exclusion Criteria: * Patients who require systemic immunosuppressive therapy for an ongoing medical condition will be excluded. For corticosteroids, patients receiving a prednisone dose of \>10 mg daily (or equivalent) will not be eligible. A short course of steroids (up to 14 days) for symptom palliation is allowed, in which case patients should be off steroids prior to treatment start. * Patients with bulky cervical adenopathy that is compressing the upper airway or could result in significant airway compression during a tumor flare event. * Patients with stage I follicular lymphoma * Patients who are candidates for radiation therapy with curative intent (in the opinion of the treating investigator) * Patients, who have had a major surgery or significant traumatic injury within 4 weeks of start of study drug, patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia). * Active HBV (DNA PCR-positive) or hepatitis C (RNA PCR-positive infection). Subjects with evidence of prior HBV but who are PCR-negative are permitted in the trial but should receive prophylactic antiviral therapy. Subjects who received treatment for HCV that was intended to eradicate the virus may participate if hepatitis C RNA levels are undetectable. * Known history of seropositivity for human immunodeficiency virus (HIV). Note: HIV testing is required at screening only if required per local health authorities or institutional standards. * Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at trial enrolment or significant infections within 2 weeks prior to the first dose of epcoritamab. * Prior history of another malignancy (except for non-melanoma skin cancer or in situ cervical or breast cancer) unless disease free for at least 2 years. * Patients should not have received immunization with attenuated live vaccine within one week of study entry or during study period. * Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study or limit adherence to study requirements. * Patients with any one of the following currently on or in the previous 6 months will be excluded: myocardial infarction, congenital long QT syndrome, torsade de pointes, unstable angina, coronary/peripheral artery bypass graft, cardiac arrhythmia (CTCAE grade 3 or higher), clinically significant ECG abnormalities, or cerebrovascular accident. * Patients with New York Heart Association Class III or IV heart failure or known ejection fraction of \<45%. * Inability to comply with protocol mandated hospitalizations and restrictions. * Patients who are pregnant, breast-feeding, or intending to become pregnant during the study. * Prior solid organ or allogeneic stem cell transplantation. * History of known or suspected hemophagocytic lymphohistiocytosis (HLH). * History of autoimmune disease, including but not limited to myocarditis, pneumonitis, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. • Patients with a remote history of, or well controlled, autoimmune disease who meet above criteria may be eligible to enroll after consultation with the Sponsor-Investigator. * History of severe allergic or anaphylactic reactions to anti-CD20 mAb therapy or known allergy or intolerance to any component or excipient of epcoritamab. * Vaccination with live vaccines within 28 days prior to the first dose of epcoritamab. * Active CNS lymphoma * Neuropathy \> grade 2. (CTCAE) * Treatment with CAR-T therapy within 100 days prior to first dose of epcoritamab. * Treatment with an investigational drug within 4 weeks or 5 half-lives, whichever is longer, prior to the first dose of epcoritamab. * Chemotherapy and other non-investigational anti-neoplastic agents (except CD20 mAbs) within 4 weeks or 5 half-lives (whichever is shorter) prior to the first dose of epcoritamab. * No known active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. If a subject has signs/symptoms suggestive of SARS-CoV-2 infection or had recent known exposure to someone with SARS-CoV-2 infection, the subject must have a negative molecular (e.g., PCR) test, or 2 negative antigen test results at least 24 hours apart, to rule out SARS-CoV-2 infection. Subjects who do not meet SARS-CoV-2 infection eligibility criteria will be screen failed and may only rescreen after they meet the following SARS-CoV-2 infection viral clearance criteria: * No signs/symptoms suggestive of active SARS-CoV-2 infection * Negative molecular (e.g., PCR) result or 2 negative antigen test results at least 24 hours apart * Screening 12-lead ECG showing a baseline QTcF \>470 msec.