Epcoritamab, Zanubrutinib, and Rituximab (EZR) for R/R FL Relapsed or Refractory Follicular Lymphoma

Inclusion Criteria:

• Histologically confirmed diagnosis of CD20+ FL (grade 1-3A) (at time of trial entry)with review of the diagnostic pathology specimen at one of the participatinginstitutions. Patients with current histologic transformation are excluded.

• Receipt of at least one prior line of therapy for FL (with prior treatment includingboth a CD20 monoclonal antibody and an alkylating agent).

• Measurable disease, defined as ≥1 measurable nodal lesion (long axis >1.5 cm orshort axis >1.0 cm) or ≥1 measurable extra-nodal lesion (long axis >1.0 cm) on PET,CT, or magnetic resonance imaging (MRI). Disease should be FDG-avid based on PET.

• Meets at least one criterion to begin treatment based on the modified GELF (Grouped'Etude des Lymphomes Folliculaires) criteria:

• Symptomatic adenopathy

• Organ function impairment due to disease involvement, including cytopenias dueto 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

• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. (Appendix A)

• Age ≥18 years.

• Adequate hematologic and organ function:

• Absolute neutrophil count > 1.0x109/L unless due to marrow involvement bylymphoma in which case ANC must be >0.5x109/L

• Platelets > 75 x109/L, unless due to marrow involvement by lymphoma, in whichcase platelets must be >50 x109/L

• Estimated CrCl (based on Cockcroft Gault or MDRD) ≥ 45ml/min or ≥45ml/min/1.73m2

• Total bilirubin < 1.5 X ULN, unless Gilbert syndrome, in which case directbilirubin must be < 1.5 x ULN

• AST/ALT < 2.5 X ULN, unless documented liver involvement by lymphoma, in whichcase AST/ALT must be <5 x ULN

• Ability to understand and the willingness to sign a written informed consentdocument.

• Willingness to provide a pre-treatment tumor sample by core needle or excisionalsurgical biopsy. A fresh biopsy is strongly encouraged, but an archival sample isacceptable if it is collected within 90 days and without intervening treatment andthe following provisions are met: 1) availability of a tumor-containingformalin-fixed, paraffin-embedded (FFPE) tissue block, 2) if the tumor containingFFPE tissue block cannot be provided in total, sections from this block should beprovided 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 isrequired. Exceptions to this criterion may be made with approval of theSponsor-Investigator.

• Willingness to remain abstinent1 or to use two effective contraceptive methods thatresult in a failure rate of <1% per year from screening until: (a) at least 3 monthsafter pre- treatment with rituximab, 12 months after the last dose of epcoritamab,or 3 months after the last dose of zanubrutinib, whichever is longer, if the patientis a male or (b) until at least 18 months after pre-treatment with rituximab, 12months after the last dose of epcoritamab, or 3 months after the last dose ofzanubrutinib, whichever is longer, if patient is a female. Examples of contraceptivemethods with a failure rate of <1% per year include:

• Tubal ligation, male sterilization, hormonal implants, established proper useof hormonal contraceptives that inhibit ovulation, hormone-releasingintrauterine devices, and copper intrauterine devices.

• Alternatively, two methods (e.g., two barrier methods such as a condom and acervical 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.

• True abstinence is acceptable when this is in line with the preferred and usuallifestyle of the subject. In contrast, periodic abstinence (eg, calendar,ovulation, symptothermal, post-ovulation methods) and withdrawal are notacceptable methods of contraception.

Exclusion Criteria:

• Patients who require systemic immunosuppressive therapy for an ongoing medicalcondition will be excluded. For corticosteroids, patients receiving a prednisonedose of >10 mg daily (or equivalent) will not be eligible. A short course ofsteroids (up to 14 days) for lymphoma-related symptom palliation or for prophylaxis (i.e., IV contrast allergy) is allowed, in which case patients should be offsteroids prior to treatment start.

• Patients with bulky cervical adenopathy that is compressing the upper airway orcould result in significant airway compression during a tumor flare event.

• Patients, who have had a major surgery or significant traumatic injury within 4weeks of start of study drug, patients who have not recovered from the side effectsof any major surgery (defined as requiring general anesthesia).

• Presence of HCV antibody. Patients with presence of HCV antibody are eligible if HCVRNA is undetectable (NOTE: the limit of detection for HCV RNA must have asensitivity of < 15 IU/mL). Subjects who received treatment for HCV that wasintended to eradicate the virus and who have an undetectable HCV RNA may participatewithout serial HCV RNA screening. Other patients may participate if they are willingto undergo every 3- month monitoring for HCV reactivation.

• Presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb). Patients with positive hepatitis B serologies with undetectable HBV DNA (NOTE: the limit of detection for HBV DNA must have a sensitivity of < 20 IU/mL) arepermitted in the trial but should receive prophylactic antiviral therapy (i.e.entecavir) and undergo every 3 month HBV DNA monitoring.

• Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) requiring antimicrobial therapy at trialenrolment or significant infections within 2 weeks prior to the first dose ofepcoritamab.

• Subject has a known active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. If a subject has signs/symptoms suggestive of SARS-CoV-2 infectionor has had recent known exposure to someone with SARS-CoV-2 infection, the subjectmust have a negative molecular (e.g., PCR) test, or 2 negative antigen test resultsat least 24 hours apart, to rule out SARS-CoV-2 infection. Subjects who do not meetSARS- CoV-2 infection eligibility criteria must be screen failed and may onlyrescreen after they meet the following SARS-CoV-2 infection viral clearancecriteria:

• No signs/symptoms suggestive of active SARS-CoV-2 infection

• Negative molecular (e.g., PCR) result or 2 negative antigen test results atleast 24 hours apart

• Prior history of another malignancy (except for non-melanoma skin cancer, in situcervical or breast cancer, or Gleason 6 prostate cancer managed with observation)unless disease free for at least 2 years.

• Patients should not have received immunization with attenuated live vaccine withinone week of study entry or during study period. Vaccination with live vaccineswithin 28 days of the first dose of study treatment is prohibited.

• Patients who have any severe and/or uncontrolled medical conditions or otherconditions that could affect their participation in the study or limit adherence tostudy requirements.

• Patients with any one of the following currently on or in the previous 6 months willbe excluded: myocardial infarction, congenital long QT syndrome, torsade de pointes,unstable angina, coronary/peripheral artery bypass graft, cardiac arrhythmia (CTCAEgrade 3 or higher), or cerebrovascular accident. History of Mobitz II second-degreeor third-degree heart block without a permanent pacemaker in place. Uncontrolledhypertension as indicated by ≥ 2 consecutive blood pressure measurements showingsystolic blood pressure > 170 mm Hg and diastolic blood pressure > 105 mm Hg atscreening.

• Patients with 1) New York Heart Association Class III or IV heart failure or knownejection fraction of <45%, 2) MI within 6 months prior to screening, 3) unstableangina within 3 months before screening, or 4) history of clinically significantarrhythmias within 6 months of screening (eg sustained Vtach, Vfib, torsades depointes).

• Inability to comply with protocol mandated restrictions.

• Patients who are pregnant, breast-feeding, or intending to become pregnant duringthe study.

• Prior solid organ or allogeneic stem cell transplantation.

• History of known or suspected hemophagocytic lymphohistiocytosis (HLH).

• History of clinically significant autoimmune disease, including but not limited tomyocarditis, pneumonitis, myasthenia gravis, myositis, autoimmune hepatitis,systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease,vascular thrombosis associated with antiphospholipid syndrome, Wegener'sgranulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis,vasculitis, or glomerulonephritis.

• Patients with a remote history of, or well controlled, autoimmune disease who meetabove criteria may be eligible to enroll after consultation with theSponsor-Investigator.

• Inability to tolerate anti-CD20 mAb therapy or known allergy or intolerance to anycomponent or excipient of epcoritamab.

• Known central nervous system involvement

• Neuropathy > grade 1(based on CTCAE grading)

• Treatment with CAR-T therapy within 100 days prior to first dose of epcoritamab.

• Treatment with an investigational drug within 4 weeks prior to the first dose ofstudy treatment.

• Chemotherapy and other non-investigational anti-neoplastic agents (except CD20 mAbs)within 4 weeks prior to the first dose of study treatment.

• Participants who require warfarin or other vitamin K antagonists foranticoagulation. Other anticoagulants including direct oral anticoagulants (i.e.apixaban, rivaroxaban) and low-molecular weight heparin are allowed.

• Participants who are known at the time of study entry to require concomitanttreatment with any medications or substances that are strong CYP3A inducers. Becausethe lists of these agents are constantly changing, it is important to regularlyconsult a frequently updated medical reference. As part of the enrollment/informedconsent procedures, the participant will be counseled on the risk of interactionswith other agents, and what to do if new medications need to be prescribed or if theparticipant is considering a new over- the-counter medicine or herbal product.

• Unable to swallow capsules or disease significantly affecting gastrointestinalfunction, such as malabsorption syndrome.

• History of severe bleeding disorder such as hemophilia A, hemophilia B, vonWillebrand disease, or history of spontaneous bleeding requiring blood transfusionsor other medical interventions. Requires ongoing treatment with warfarin or warfarinderivatives.

• Prior exposure to a BTK inhibitor

• Screening 12-lead ECG showing a baseline QTcF (Fridericia's correction) > 480 msec.

• History of stroke or intracranial hemorrhage within 6 months before first dose ofstudy drug.

• Major surgery ≤ 4 weeks before the first dose of study treatment or planned duringstudy.