Glofitamab With Pirtobrutinib for Relapsed or Refractory Mantle Cell Lymphoma

Inclusion Criteria:

• Age ≥ 18 years at the time of signing the informed consent form.

• Have a life expectancy (in the opinion of the investigator) of at least 12 weeks.

• Eastern Cooperative Oncology Group (ECOG) performance status < 2 (Karnofsky > 60%).

• History of previously treated MCL meeting the following criteria: Relapsed after orfailed to respond to at least one prior line of systemic therapy including anti-CD20monoclonal antibody and alkylator-containing chemotherapy.

• At least one bi-dimensionally measurable nodal lesion ( > 1.5 cm in its largestdimension by PET/CT scan), or at least one bi-dimensionally measurable extranodallesion ( > 1.0 cm in its largest dimension by PET/CT scan) and FDG-avid.

• Availability of leftover tissue from the time of progression for pathologyconfirmation and correlative studies. Note: Formalin fixed paraffin embedded blocksare preferred. If blocks are not available, 12-15 slides containing unstained,serial sections are acceptable.

• Hemoglobin ≥ 9 g/dL (Independent of transfusions and within 7 days prior toscreening assessment).

• Absolute neutrophil count >= 1.0 x 10^9/L (Independent of growth factor support andwithin 7 days prior to screening assessment).

• Platelets ≥ 75 x 10^9/L or >= 50 x 10^9/L if due to bone marrow involvement (Independent of transfusions and within 7 days prior to screening assessment).

• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (or ≤ 3 x ULN for participantswith Gilbert syndrome, or <= 3 x ULN if due to underlying lymphoma).

• Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase (SGOT)) <= 2.5 X institutional upper limit of normal.

• Alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase (SGPT)) <= 2.5 Xinstitutional upper limit of normal.

• Creatinine clearance >= 50 mL/min (by Cockcroft-Gault formula).

• Activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT) <= 1.5 x ULN.

• Prothrombin (PT) or (international normalized ratio (INR) <= 1.5 x ULN.

• In women of childbearing potential, negative serum pregnancy test within 7 daysprior to study treatment and either abstinence or use of highly effectivecontraception methods from the time of screening for at least 18 months afterpre-treatment with obinutuzumab, 2 months after the final dose of glofitamab, 1month after last dose of pirtobrutinib, 3 months after the final dose of tocilizumab (if applicable), whichever is longer. Women of childbearing potential should notdonate oocytes for 1 month after last dose of pirtobrutinib.

• For men: agreement to remain abstinent or use contraceptive measures and agreementto refrain from donating sperm, with female partners of childbearing potential orpregnant female partners, men must remain abstinent or use a condom during thetreatment period and for at least 3 months after pre-treatment with obinutuzumab, 2months after the final dose of glofitamab, 28 days after last dose of pirtobrutinib, 3 months after the final dose of tocilizumab (if applicable), whichever is longer.

• Willing and capable of giving signed informed consent which includes compliance withthe requirements and restrictions listed in the informed consent form (ICF) and inthe protocol.

• Participants with prior treatment-related adverse events (AEs) must have recoveredto grade <= 1 with the exception of alopecia and grade 2 peripheral neuropathy.

• Participants must be able to swallow oral medications.

• Participants with positive hepatitis B core antibody (anti-HBc) and negativehepatitis B surface antigen (HBsAg) require a negative hepatitis B polymerase chainreaction (PCR) evaluation before initiating study treatment on cycle 1 day 1.Patients with positive anti-HBc antibody are required to receive prophylacticantiviral therapy with lamivudine, tenofovir, or entecavir for the duration oftreatment and for at least 6 months following the end of study treatment. HepatitisB PCR should be repeated as clinically indicated.

• Individuals with a history of hepatitis C virus (HCV) infection must have beentreated and cured. For individuals with HCV infection who are currently ontreatment, they are eligible if they have an undetectable HCV viral load.

Exclusion Criteria:

• Pregnant, or intention of becoming pregnant during the study or within 6 monthsafter treatment with obinutuzumab or 2 months after the last dose of glofitamab,whichever is longer; and 1 month after the last dose of pirtobrutinib.

• Participants should avoid chest-feeding until at least 1 week after discontinuingpirtobrutinib.

• Have received the following treatments/procedures prior to study entry:

• Participants who experienced a major bleeding event or grade ≥ 3 arrhythmia onprior treatment with a BTK inhibitor. NOTE: Major bleeding is defined asbleeding having one or more of the following features: potentiallylife-threatening bleeding with signs or symptoms of hemodynamic compromise;bleeding associated with a decrease in the hemoglobin level of at least 2g perdeciliter; or bleeding in a critical area or organ (e.g., retroperitoneal,intraarticular, pericardial, epidural, or intracranial bleeding orintramuscular bleeding with compartment syndrome)

• Participants who discontinued a covalent BTK inhibitor due to diseaseprogression or relapse. NOTE: Participants who discontinued covalent BTKinhibitor therapy due to intolerance will not be excluded. Covalent BTKinhibitor intolerance is defined as:

• Any grade 3 or higher non-hematologic toxicity, except a major bleedingevent or grade >= 3 arrhythmia which are exclusion criteria

• Any grade 1 or higher non-hematologic toxicity that lasted longer than 7days or recurred

• Any grade 4 hematologic toxicity

• Neutropenic fever

• Discontinuation due to drug interaction/expected toxicity with resolutionof prior covalent BTK inhibitor-related toxicities

• Any CD20/CD3-directed bispecific antibodies for treatment of lymphoma

• Allogeneic stem cell transplant (SCT) within 6 months or on activeimmunosuppression or active graft versus host disease (GVHD)

• Solid organ transplantation

• Have received the following treatments/procedures prior to study entry whetherinvestigational or approved, within the respective time periods prior to initiationof study treatment:

• Radiotherapy within 2 weeks prior to the first dose of study treatment. Note:If participants have received radiotherapy within 4 weeks prior to the firststudy treatment administration, participants must have at least one measurablelesion outside of the radiation field

• Autologous SCT within 90 days prior to first study treatment

• Chimeric antigen receptor (CAR) T-cell therapy within 60 days before firststudy treatment or if ongoing toxicity ≥ grade 2

• Use of monoclonal antibodies or antibody-drug conjugates within 4 weeks priorto first study treatment

• Use of radioimmunoconjugates within 12 weeks prior to first study treatment

• Systemic immunosuppressive medications (including, but not limited to,cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumornecrosis factor agents) within 2 weeks or five half-lives (whichever isshorter) prior to first dose of study treatment. Note: Systemic corticosteroidtreatment . 10 mg/day prednisone or equivalent and inhaled corticosteroids arepermitted. Administration of acute, low-dose, systemic immunosuppressantmedications (e.g., single dose of dexamethasone for nausea or B symptoms) ispermitted. The use of mineralocorticoids for management of orthostatichypotension and corticosteroids for management of adrenal insufficiency ispermitted

• Live, attenuated vaccine within 4 weeks before first dose of study treatment,or in whom it is anticipated that such a live attenuated vaccine will berequired during the study period or within 5 months after the final dose ofstudy treatment

• Evidence of active central nervous system (CNS) lymphoma or leptomeningealinfiltration

• Current or history of CNS disease, such as stroke, epilepsy, CNS vasculitis, orneurodegenerative disease. Note: Patients with a history of stroke who have notexperienced a stroke or transient ischemic attack within the past 2 years and haveno residual neurologic deficits, as judged by the investigator, are allowed

• Active second malignancy unless the patient is in remission and has a lifeexpectancy > 2 years.

• Major surgical procedure (under general anesthesia) within 30 days of day 1 ofprotocol therapy. Note: If a patient had major surgery, they must have recoveredadequately from any toxicity and/or complications from the intervention before thefirst dose of study drug

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

• 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, Sjogren'ssyndrome, Guillain- Barre syndrome, multiple sclerosis, vasculitis, orglomerulonephritis Note: Participants with a history of autoimmune-relatedhypothyroidism on a stable dose of thyroid replacement hormone, participants with ahistory of disease-related immune thrombocytopenic purpura or autoimmune hemolyticanemia, and participants with a history of type I diabetes mellitus who are wellcontrolled (defined as a screening glycosylated hemoglobin (hemoglobin A1c) ≤ 8% andno urinary ketoacidosis) may be eligible for this study. Investigators shouldconsult the sponsor-investigator.

• Significant or extensive history of cardiovascular disease such as New York HeartAssociation class III or IV or objective class C or D cardiac disease, myocardialinfarction within the previous 6 months, unstable arrhythmia, or unstable angina oracute coronary syndrome within the past 2 months prior to start of study treatment (cycle 1 day 1 (C1D1)), uncontrolled or symptomatic arrhythmias, and/or documentedleft ventricular ejection fraction (LVEF) by any method of ≤ 40% in the 12 monthsprior to start of study treatment (C1D1)

• Prolongation of the QTc for heart rate using Fridericia's Formula (QTcF) > 470 msec.Note: Correction of QTc for underlying bundle branch block is permissible.

• Significant pulmonary disease that is expected to interfere with therapy.

• History of confirmed progressive multifocal leukoencephalopathy (PML).

• Known active infection (including Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)), or reactivation of a latent infection, whether bacterial, viral (including, but not limited to, Epstein-Barr virus (EBV), cytomegalovirus (CMV),hepatitis B and hepatitis C), 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 within 4weeks (relating to the completion of the course of antibiotics) prior to first studytreatment administration.

• Participants requiring therapeutic anticoagulation with warfarin or another vitaminK antagonist.

• Known or suspected history of hemophagocytic lymphohistiocytosis (HLH).

• Participants who have tested positive for human immunodeficiency virus (HIV) areexcluded due to risk of opportunistic infections with both HIV and BTK inhibitors.For patients with unknown HIV status, HIV testing will be performed at screening andresult must be negative for enrollment.

• Participants with a history of bleeding diathesis.

• Clinically significant active malabsorption syndrome or other condition likely toaffect gastrointestinal (GI) absorption of the study drug.

• A known hypersensitivity to any of the excipients of pirtobrutinib or to any of theintended study medications.

• Participants requiring ongoing therapy with strong Cytochrome P450, family 3,subfamily A (CYP3A) inhibitors or inducers will be excluded. For patients who areable to discontinue therapy with a strong CYP3A modulator, a washout period of atleast 5 half-lives is required before beginning study treatment.