A Study of Glofitamab and Lenalidomide in People With Mantle Cell Lymphoma

Inclusion Criteria:

• Age ≥18 years at the time of signing Informed Consent

• ECOG 0-2

• Histologic diagnosis confirmed as relapsed/refractory mantle cell lymphoma accordingto WHO guidelines.

• Evidence of CD20 expression on neoplastic cells according to institutional pathologydepartment guidelines

• Previously treated with at least one prior line of systemic therapy for mantle celllymphoma. Prior BTKi failure is required. BTKi failure is defined as progression ofdisease during BTKi therapy or patients must have progressed or relapsed aftercompleting BTK inhibitor therapy, or failed to achieve a PR following 12 weeks ofBTK inhibitor therapy.

• Presence of evaluable disease

• Adequate bone marrow and organ function:

• Absolute neutrophil count (ANC) ≥1,000 cells/mcL, unless felt to be secondaryto underlying MCL (minimum ANC 500 cells/mcL)

• Hgb ≥ 8 g/dL, unless felt to be secondary to underlying MCL (minimum Hgb 7.0g/dL)

• Platelet count ≥50,000 cells/mcL, unless felt to be secondary to underlying MCL (minimum platelet count 25,000 cells/mcL)

• Renal function assessed by calculated Cockcroft-Gault creatinine clearance (CrCl; see Appendix A) ≥ 50 ml/min. See lenalidomide Treatment Plan, (Table 10-1), for lenalidomide dose adjustment for CrCl ≥ 30 mL/min and < 60 mL/min

• Adequate hepatic function as determined by:

• Total bilirubin ≤1.5X upper limit of normal (ULN) unless secondary to Gilbert'ssyndrome or documented liver involvement by lymphoma. Patients with Gilbert'ssyndrome or documented liver involvement by lymphoma may be included if their totalbilirubin is ≤ 5 x ULN

• Aspartate aminotransferase (AST, SGOT) and alanine aminotransferase (ALT, SGPT) ≤ 3x ULN or ≤ 5 x ULN in cases of documented liver involvement.

• Willingness to receive adequate prophylaxis and/or therapy for thromboembolicevents, unless contraindicated in the opinion of the investigator.

• Willingness to undergo confirmatory procedures for assessment of disease status andexperimental studies as required by protocol, including bone marrow (BM)aspiration/biopsy and gastrointestinal endoscopy/colonoscopy with biopsy, and/orbiopsy of other tissue when appropriate and medically feasible.

• Each patient must sign an informed consent form indicating that he or sheunderstands the purpose of and procedures required for the study and are willing toparticipate.Patients with impaired decision-making capacity (IDMC) who have alegally authorized representative (LAR) or caregiver and/or family member availablewill also be eligible.

• Willingness of patients who can become pregnant, according to Revlimid/lenalidomideRisk Evaluation and Mitigation Strategy (REMS) criteria, to undergo pregnancytesting in accordance with REMS requirements

• Willingness of all patients to complete surveys and adhere to contraceptionrequirements mandated by the Revlimid/lenalidomide REMS

• For women of childbearing potential: Agreement to remain abstinent (refrain fromheterosexual intercourse) or use two adequate methods of contraception, including atleast one method with a failure rate of <1% per year, for at least 28 days prior toDay 1 of Cycle 1, during the treatment period (including periods of treatmentinterruption), and for at least 2 months after the final dose of glofitamab, 28 daysafter the last dose of lenalidomide, 18 months after the last dose of obinutuzumab.

• For men: Agreement to remain abstinent (refrain from heterosexual intercourse) oruse contraceptive measures and agreement to refrain from donating sperm, as definedbelow: With female partners of childbearing potential or pregnant female partners,men must remain abstinent or use a condom during the treatment period and for atleast 2 months after the final dose of glofitamab, 28 days after last dose oflenalidomide, 6 months after the last dose of obinutuzumab. Men must refrain fromdonating sperm during this same period.

• Life expectancy ≥ 12 weeks as determined by patient's primary clinician

Exclusion Criteria:

• Investigational agent or anticancer therapy within 5 half-lives prior to start ofstudy therapy except therapeutic monoclonal antibody treatment must be discontinueda minimum of 4 weeks prior to study therapy. An exception is BTKi therapy, which canbe continued to prevent disease flare up until 1 day prior to start of studytherapy.

• Major surgery within 4 weeks prior to planned start of study therapy.

• Radiotherapy within 7 days of the start of study therapy.

• CART infusion within 30 days prior to Day 1 of Cycle 1

• Active hepatitis B or C, as defined below:

• HBV surface antigen positive

• HBV surface antigen negative, HBV core antibody positive and detectable HBVviral DNA. Note: subjects who are HBV core antibody positive and viral DNAnegative are eligible.

• HCV antibody positive and HCV RNA positive.

• History of human immunodeficiency virus (HIV) unless all of the following criteriaare met:

• CD4+ T cell count ≥ 250 cells/mcL

• No acquired immunodeficiency syndrome (AIDS)-defining opportunistic infectionswithin 1 year prior to signing Informed Consent Form

• Stable (no change in regimen for ≥ 4 weeks) and effective antiretroviralregimen, and HIV viral load < 400 copies/mL within 4 weeks prior to signingInformed Consent form

• Active concurrent malignancy requiring active therapy within the last 3 years withthe exception of basal cell carcinoma limited to the skin, squamous cell carcinomalimited to the skin, carcinoma in situ of the cervix or breast, adequately treatedlentigo maligna melanoma, or localized prostate cancer. Adjuvant or maintenancetherapy to reduce the risk of recurrence of other malignancy previously treated forcurative intent is permitted.

• Pregnant or lactating, intending to become pregnant, or unable/unwilling to complywith pregnancy testing and birth control measures and REMS enrollment, as describedin inclusion criteria.

• Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment, or any major episodeof infection requiring treatment with IV antibiotics or hospitalization (relating tothe completion of the course of antibiotics) within 4 weeks prior to cycle 1, day 1.

• Clinically significant history of liver disease, including active viral or otherhepatitis or current uncontrolled alcohol use disorder that would compromisepatient's ability to safely participate in the trial, per clinician's judgment

• Active central nervous system (CNS) involvement with lymphoma, either parenchymal orleptomeningeal

• Presence of ≥Grade 2 toxicity (CTCAE v5.0) due to prior cancer therapy

• History of severe allergic or anaphylactic reactions to monoclonal antibody therapy (or recombinant antibody-related fusion proteins)

• Patient with history of confirmed progressive multifocal leukoencephalopathy (PML)

• History of hypersensitivity to compounds of similar biological or chemicalcomposition to IMiDs® and/or the excipients contained in the study drug formulations

• Previous treatment with bispecific antibody therapy directed against CD20 and CD3

• Previous treatment with lenalidomide or other IMiDs® within 12 months of treatmentinitiation on this study.

• Documented refractoriness to lenalidomide, defined as no response (PR or CR) within 6 months of therapy

• Autologous stem cell transplantation (ASCT) within the period ≤3 months prior to thesigning of the informed consent form. Patients with a more distant history of ASCTmust exhibit full hematologic recovery before enrollment into the study

• Allogenic stem cell transplantation within the period of ≤3 months prior to signingof the Informed Consent form, evidence of graft-versus-host-disease (GVHD), orreceiving active immunosuppression for GVHD.

• A history of deep venous thrombosis/embolism, threatening thromboembolism or knownthrombophilia or are at a high risk for a thromboembolic event in the opinion of theinvestigator and who are not willing/able to take venous thromboembolic eventprophylaxis during the entire treatment period

• Concurrently use other anticancer or experimental treatments

• Administration of a live vaccine within 28 days prior to the start of studytreatment (Cycle 1 Day 1).

• Prior treatment with systemic immunosuppressive medications (including, but notlimited to, cyclophosphamide, azathioprine, methotrexate, thalidomide, andanti-tumor necrosis factor agents), within 2 weeks or five half-lives (whichever isshorter) prior to first dose of study treatment

• Corticosteroid therapy within 2 weeks prior to first dose of study treatment, withthe following exceptions:

• Short course systemic corticosteroids (total daily dose equivalent ofprednisone 100mg or dexamethasone 20 mg) is permissible for disease control,improvement of performance status, or non-cancer indication if administered for ≤ 5 days, and must be discontinued prior to study initiation of studytreatment. When clinically indicatedfeasible, tumor assessments such as imagingand biopsies should be performed prior to steroid administration, though thisis not required for enrollment.

• Chronic corticosteroid use of ≤20 mg prednisone equivalent per day, on a stabledose for ≥4 weeks prior to registration.

• Any life-threatening illness, medical condition, or organ system dysfunction that,in the opinion of the investigator, could compromise the subject's safety, or affectcompliance with the protocol or interpretation of results.

• Evidence of any significant, uncontrolled concomitant disease that could affectcompliance with the protocol or interpretation of results, including significantcardiovascular disease (such as New York Heart Association Class III or IV orObjective Assessment Class C or D cardiac disease, myocardial infarction ≤ 6 monthsfrom registration, symptomatic congestive heart failure, unstable arrhythmia, orunstable angina) or significant pulmonary disease (such as obstructive pulmonarydisease or history of bronchospasm)