Glofit and Obin in Follicular Lymphoma and Marginal Zone Lymphoma

Inclusion Criteria:

• Histologically confirmed diagnosis of either FL (grade 1-3A) or MZL (any subtype)with review of the diagnostic pathology specimen at one of the participatinginstitutions. Patients with active histologic transformation are excluded.

• No prior systemic therapy for FL or MZL. Prior treatment with radiation therapy orshort course steroids is allowed.

• Meets at least one criterion to begin treatment based on the modified GELF 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

• Maximum diameter of disease > 7cm

• >3 nodal sites of involvement

• Risk of local compressive symptoms

• 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 ofthe treating investigator.

• 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

• Creatinine clearance > 40ml/min (by Cockcroft-Gault Formula)

• 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 the following provisions are met: 1) availability of atumor-containing formalin-fixed, paraffin-embedded (FFPE) tissue block, 2) if thetumor containing FFPE tissue block cannot be provided in total, sections from thisblock should be provided that are freshly cut and mounted on positively-chargedglass slides (SuperFrost Plus are recommended). Preferably, 25 slides should beprovided; if not possible, a minimum of 15 slides is required. Exceptions to thiscriterion may be made with approval of the sponsor-investigator.

• Willingness to remain abstinent 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 obinutuzumab or 2 months after the last dose of glofitamab,whichever is longer, if the patient is a male or (b) until at least 18 months afterpre-treatment with obinutuzumab or 2 months after the last dose of glofitamab,whichever is longer, if patient is a female. Examples of contraceptive methods witha 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.

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, not exceeding 40 mg dexamethasone or equivalent in a singleday) for symptom palliation is allowed, in which case patients should be offsteroids at least 7 days prior to treatment start.

• Patients with bulky cervical adenopathy that is 1) compressing the upper airway or

2. in close proximity to the upper airway and could result in airway compressionduring a tumor flare event).

• History of severe allergic or anaphylactic reactions to monoclonal antibody therapyunless in consultation with an allergy specialist they are deemed eligible forretreatment with desensitization.

• 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).

• Patients with known HIV infection or hepatitis B or C infection. Testing for HIV isoptional. Testing for hepatitis B and C is mandatory. Patients with hepatitis B coreAb positivity but negative surface antigen and negative viral load may be enrolledif they can be treated with a prophylactic agent (e.g., entecavir); patients withhepatitis C seropositivity who have a negative viral load can also be enrolled.

• Patients with a systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and withoutimprovement, despite appropriate antibiotics or other treatment).

• Prior history of another malignancy (except for non-melanoma skin cancer or in situcervical or breast cancer) unless disease free for at least 2 years. Patients withprostate cancer (Gleason score 6-7) are allowed if PSA is less than 1 ng/mL.

• Patients should not have received immunization with lives or live attenuated vaccinewithin one week of study entry or during study period.

• 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, or cerebrovascularaccident.

• Patients with New York Heart Association Class III or IV heart failure.

• Inability to comply with protocol mandated hospitalizations and 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 autoimmune disease, including but not limited to myocarditis,pneumonitis, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupuserythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosisassociated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren'ssyndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, orglomerulonephritis • Patients with a remote history of, or well controlled,autoimmune disease may be eligible to enroll after consultation with the study PI.