A Phase 2 Trial of GlOfitamab anD pIrtobrutinib in Mantle Cell Lymphoma Patients With Prior BTK Inhibitor Exposure.

Inclusion Criteria:

1. Ages 18 years old or above
2. A confirmed diagnosis of MCL according to World Health Organization (2016) criteria
3. At least one site of measurable disease not previously irradiated (defined as at leastone bi-dimensionally measurable nodal lesion of greater than or equal to 1.5cm inlongest dimension)
4. Life expectancy (in the opinion of the investigator) of greater than or equal to 18weeks
5. Prior therapy with a BTK inhibitor alone or in combination and:
6. Progression or relapse post BTK inhibitor or
7. Failed to achieve PR following 12 weeks of BTK inhibitor therapy
8. Prior TRAEs must have recovered to Grade 1 or less with the exception of alopecia,peripheral neuropathy and lymphopenia.
9. ECOG 0-2
10. Adequate washout of prior therapies:
11. Broad field radiation (greater than or equal to 30% of the bone marrow or wholebrain radiotherapy) must be completed 14 days prior to study treatment
12. Palliative limited field radiation must be completed 7 days prior to studytreatment.
13. Targeted agents, investigational agents, therapeutic monoclonalantibodies/antibody drug conjugates or cytotoxic chemotherapy must be completed 5half-lives or 2 weeks (whichever is shorter) prior to study treatment (except forBTK inhibitors which may be continued until 1 day prior to planned first therapywith pirtobrutinib)
14. Steroids (prednisolone less than or equal to 100mg daily or equivalent for up to 14 days are permitted during screening for control of lymphoma related symptoms
15. Ability to take oral medications
16. Willing and capable of giving signed informed consent which includes compliance withthe requirements and restrictions listed in the ICF and in the protocol.
17. Willingness of men and women of reproductive potential to observe conventional andhighly effective and acceptable birth control methods for the duration of treatmentand for six months following the last dose of study treatment
18. Women of childbearing potential must have a negative serum pregnancy test within sevendays of enrolment
19. Adequate coagulation, defined as aPTT and PT not greater than 1.5xULN, unlesslaboratory abnormality is explained by concomitant anticoagulant medication, a lupusanticoagulant, or a factor deficiency not associated with an increased bleeding risk,as determined by the investigator.
20. Adequate liver function:

• ALT and AST less than or equal to 3X ULN, or less than or equal to 5X ULN ifdocumented liver involvement
• Total bilirubin less than or equal to 1.5X ULN or less than or equal to 5X ULN ifdocumented liver involvement and/or Gilbert's Disease

15. Adequate renal function

• Creatinine clearance greater than or equal to 30mls/minute according toCockroft-Gault formula

16. Adequate haematological parameters

• Haemoglobin greater than or equal to 80g/L (transfusion support permitted)
• Absolute neutrophil count greater than or equal to 1.0x10^9/L (May be G-CSFsupported)
• Platelets greater than or equal to 75 X 10^9/L. OR platelets greater than orequal to 50 X 10^9/L if documented marrow involvement or splenomegaly (must beplatelet transfusion independent for 7 days prior to first dose of obinutuzumab

17. Sufficient archival tissue is available for central review or after discussion withthe CPI

Exclusion Criteria:

1. Inability to comply with protocol mandated hospitalisations
2. For patients enrolling on the safety cohort, a history of allogeneic transplantationwithin 12 months of enrolment or ongoing chronic GVHD or immunosuppressive therapy.
3. Autologous SCT or CAR-T therapy within 6 weeks of enrolment
4. Active central nervous system involvement with MCL
5. Prior treatment with pirtobrutinib or demonstrated refractoriness to a CD20xCD3bispecific antibody.
6. Have a known severe hypersensitivity to any of the excipients of pirtobrutinib,glofitamab, tocilizumab or obinutuzumab.
7. History of stroke or intracranial haemorrhage within six months of enrolment.
8. Live vaccination within 28 days of enrolment.
9. Major surgery or significant traumatic injury within 28 days of study treatment or theanticipation of major surgery during study treatment (surgical procedures for thediagnosis of lymphoma such as lymph node resection/ laparoscopy are allowed providedpatient is considered fit for treatment as judged by investigator)
10. Significant cardiovascular disease defined as:
11. Unstable angina or acute coronary syndrome within 2 months of registration
12. History of myocardial infarction within 3 months prior to registration
13. Documented LVEF by any method of = 40% during screening
14. Grade 3 or higher NYHA functional classification system of heart failure
15. Uncontrolled or symptomatic arrhythmias
16. Prolongation of the QT interval corrected for heart rate (QTcF) greater than 470 msecon at least 2/3 consecutive electrocardiograms (ECGs), and mean QTcF greater than 470msec on all 3 ECGs, during Screening. QTcF is calculated using Fridericia's Formula (QTcF): QTcF euqal to QT/(RR0.33) Correction of suspected drug-induced QTcFprolongation can be attempted at the investigator's discretion and only if clinicallysafe to do so with either discontinuation of the offending drug or switching toanother drug not known to be associated with QTcF prolongation. Correction forunderlying bundle branch block (BBB) allowed. Patients with pacemakers are eligible ifthey have no history of fainting or clinically relevant arrhythmias
17. Known human immunodeficiency virus (HIV) infection
18. Known active HBV or HCV infection based on criteria below:
19. HBV: Patients with positive HbsAg are excluded. Patients with positive hepatitisB core antibody antiHBc and negative HbsAg require negative hepatitis B PCRbefore enrolment and must be treated with antiviral therapy. Patients who arehepatitis B PCR positive will be excluded.
20. HCV: If positive hepatitis C antibody, patient will need to have a negativehepatitis C RNA before enrolment. Patients who are hepatitis C RNA positive willbe excluded.
21. Known active CMV infection. Unknown or negative status are eligible.
22. Pregnancy, lactation or plan to breastfeed during the study or within 6 months of thelast dose of study treatment.
23. Clinically significant active malabsorption syndrome or other condition likely toaffect gastrointestinal (GI) absorption of pirtobrutinib.
24. Evidence of other clinically significant uncontrolled condition(s) including but notlimited to, uncontrolled systemic bacterial, viral, fungal or parasitic infection, orother clinically significant active disease process which in the opinion of theinvestigator and medical monitor may pose a risk for patient participation.
25. Active uncontrolled auto-immune cytopenia (e.g., AIHA, ITP) for which new therapy wasintroduced or existing therapy was escalated within the 4 weeks prior to studyenrolment to maintain adequate blood counts, unless auto-immune cytopenias aresecondary to MCL
26. Active second malignancy unless in remission and with life expectancy greater than 2years.
27. Current treatment with strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducersand/or strong P-gp inhibitors.
28. Patients requiring therapeutic anticoagulation with warfarin or another vitamin Kantagonist.