M22-003 (EPCORE™ FL-2)

Adults ≥18 with untreated CD20+ classic FL, Ann-Arbor III/IV or II bulky, GELF treatment need, PET+ and measurable lesion(s), ECOG 0-2, adequate organ function, contraception and consent/compliance criteria met.

Subjects must meet all of the following criteria in order to be included in the study. Anything other than a positive response to the questions below will result in exclusion from study participation. Inclusion Criteria Consent 1. Subjects or their legally authorized representative (if permitted per local regulations) must voluntarily sign and date an informed consent, approved by an IEC/IRB, prior to the initiation of any screening or study-specific procedures. 2. Are willing and able to comply with procedures required in this protocol. Demographic and Laboratory Assessments 3. Adult individuals, at least 18 years old. 4. Subject must have adequate renal, liver, and hematologic function laboratory values meeting the following criteria (unless abnormalities are related to lymphoma): a. ANC ≥ 1.5 × 10^9/L; unless subject has a previously established diagnosis of benign ethnic neutropenia; growth factors permitted in case of bone marrow involvement by lymphoma, but subject must not have received growth factor within 14 days prior to screening lab collection. b. Hemoglobin ≥ 8 g/dL; RBC transfusions permitted, but subject must not have received blood transfusions within 7 days prior to screening labs. c. Platelet count ≥ 75 × 10^9/L, or ≥ 50 × 10^9/L if bone marrow infiltration by lymphoma or splenomegaly (platelet transfusions permitted, but subject must not have received platelet transfusions within 7 days prior to screening labs). d. INR and (a)PTT ≤ 1.5 × ULN, unless receiving anticoagulation. e. Serum AST and ALT ≤ 3.0 × ULN. f. Total Bilirubin ≤ 1.5 × ULN (≤ 5 × ULN for subjects with hepatic involvement of disease or of non-hepatic origin) or direct bilirubin < × 2 ULN (subjects with Gilbert's syndrome). g. Estimated CrCl (Cockcroft-Gault, modified as needed) ≥ 45 mL/min or eGFR (MDRD) ≥ 45 mL/min/1.73 m2. 5. Subject must be able to swallow capsules and must not have any disease significantly affecting drug absorption (e.g., resection of the stomach or small bowel, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction). 6. Subject must have available adequate fresh or paraffin-embedded tissue at Screening. 7. Subjects must not be incarcerated and must be freely willing and able to provide informed consent. Examples of subjects unable to freely provide informed consent may include some adults under legal protection measure (e.g., under guardianship/curatorship) or unable to express their consent and select adults under psychiatric care. Investigator's discretion should be applied. Disease/Condition Activity 8. Subject must have CD20+, histologically confirmed classic FL (previously Grade 1 to 3a FL) at most recent representative tumor biopsy based on the local pathology report, according to the 5th edition of WHO Classification of Haematolymphoid Tumours. 9. Subject must have Ann-Arbor Stage III or IV disease or Stage II with bulky disease (tumor diameter of ≥ 7 cm). 10. Subject must be in need of systemic treatment per investigator, as evidenced by meeting at least one GELF criteria (Appendix K). 11. Subject has one or more target lesions: a. A PET/CT scan demonstrating PET-positive lesion(s), and b. ≥ 1 measurable nodal lesion (long axis > 1.5 cm) or ≥ 1 measurable extra-nodal lesion (long axis > 1.0 cm) on CT scan or MRI. 12. ECOG performance status 0-2. 13. Subject is able to receive at least one of the standard of care CIT treatment regimens (Arm B) at the discretion of the Investigator, and R2 (Arm C). Contraception 14. Subjects of child-bearing potential must have a negative serum (beta-hCG) pregnancy test at the Screening Visit and a negative serum or urine pregnancy test at baseline (prior to initiating study treatment). The pregnancy test must be sensitive to at least 25 mIU/mL. 15. Female subjects of childbearing potential must practice at least 2 protocol-specified methods of birth control, that are effective from randomization and be willing to follow protocol-specified contraception based on their assigned arm (see Section 5.2). Female subjects of non-childbearing potential do not need to use birth control. 16. Female subject who is not pregnant or breastfeeding and is not considering becoming pregnant or donating eggs according to protocol contraception requirement (see Section 5.2). 17. Male subject who is sexually active with female partner(s) of childbearing potential, must agree to practice the protocol-specified contraception, particularly a latex or synthetic condom every time they have sexual intercourse with a partner of reproductive potential, even if they have undergone a successful vasectomy according to protocol contraception requirement (see Section 5.2). 18. Male subject who is not considering fathering a child or donating sperm according to protocol contraception requirement (see Section 5.2). Concomitant Medications 19. No contraindication to at least one form of anticoagulant therapy (such as aspirin, heparin, warfarin, or direct anticoagulant). 20. Subject must not have received any live vaccine within 4 weeks prior to the first dose of study treatment or expected need of live vaccination during study participation including at least 4 weeks after the last dose of study treatment. 21. Subject must not have been treated with any investigational drug within 30 days or 5 half-lives of the drug (whichever is longer) prior to randomization and must not be receiving treatment in another investigational clinical study. 22. Subject must not have been treated with a bispecific antibody targeting CD3 and CD20.

Exclude prior systemic FL therapy/transformation/CNS disease, major CV disease, active serious infection (HBV/HCV/HIV/TB/CMV), severe hypersensitivity/contraindications, active autoimmune-immunosuppression, pneumonitis/SCAR, and other high-risk comorbidity.

Exclusion Criteria Subject History 1. Subject has received prior systemic anti-lymphoma therapy for FL (including any definitive radiotherapy with curative intent). 2. Subject has prior history of aggressive B-cell lymphoma or current histologic transformation to DLBCL. 3. Subject has current suspected or documented evidence of primary CNS tumor or known CNS involvement at screening. 4. Subject has history of severe allergic or anaphylactic reactions or contraindication to any component or excipient of epcoritamab, lenalidomide, rituximab. 5. Known or suspected contraindication to the use of all locally available anti-cytokine therapies per local guidelines for management of CRS. 6. Subject had major surgery within 4 weeks prior to randomization. 7. Subject has clinically significant cardiovascular disease, such as: a. Myocardial infarction within 1 year or stroke within 6 months prior to randomization. b. Screening 12-lead ECG showing baseline QTcF > 470 msec (male) or > 480 msec (female). c. Within 3 months prior to randomization: unstable/uncontrolled disease related to cardiac function (e.g., unstable angina, NYHA Class III-IV CHF), uncontrolled arrhythmia, or other clinically significant ECG abnormalities in investigator opinion. d. Left ventricular ejection fraction < 45% by MUGA or transthoracic echocardiography at Screening. e. If any cardiovascular history: cardiology consult required within 60 days of randomization. 8. Subject has known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) requiring systemic therapy or antibiotics within 2 weeks prior to randomization. 9. Subject has an active HBV or HCV infection. Subjects positive for HBcAb, HBsAg, or HCV Ab must have negative PCR before enrollment; PCR positive subjects are excluded. 10. Subject has known history of HIV infection. 11. Subject has active TB or history of completed treatment for active TB within past 12 months. 12. Subject has active symptomatic CMV disease. 13. Subject has history of progressive multifocal leukoencephalopathy. 14. Subject has history of other prior malignancies, except: a. Malignancy treated with curative intent and no known active disease for ≥ 3 years before first dose. b. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease. c. Adequately treated carcinoma in situ without evidence of disease. d. Localized prostate cancer, post-radical prostatectomy or non-rising PSA < 0.1 ng/mL. 15. Subject has peripheral (sensory) neuropathy Grade > 1 except neuropathy directly related to lymphoma (e.g., nerve compression from tumor). 16. Subject has current autoimmune disease or allograft requiring immunosuppressive therapy other than prednisone ≤ 20 mg daily (or equivalent). 17. Subject has current seizure disorder requiring therapy. 18. Subject has history of clinically significant medical conditions or any other reason that investigator determines would interfere with participation, or would make subject unsuitable for study treatment. 19. Subject has history of pneumonitis requiring steroids, or current pneumonitis. 20. Subject has history of severe cutaneous adverse reaction (SCAR; including but not limited to SJS/TEN or DRESS).