Phase 2 Open Label Randomized Study of Pirtobrutinib and Brexucabtagene Autoleucel in R/R MCL

Inclusion Criteria:

• Patients with a histologically confirmed diagnosis of mantle cell lymphoma (MCL)will be eligible.

• Adult males or females who are 18 years of age or older at time of signing informedconsent.

• Must have ability to comprehend and the willingness to sign written informed consentfor study participation.

• Eligible to receive CAR T-cell therapy (Brexucabtagene autoleucel) for MCL by thestandard of care label, which states: "TECARTUS or Brexucabtagene autoleucel is aCD19-directed genetically modified autologous T-cell immunotherapy indicated for thetreatment of: Adult patients with relapsed or refractory mantle cell lymphoma (MCL)"

• ECOG performance status 0 to 2.

• Patients are required to have the following washout periods prior to leukapheresis.In addition, prior treatment-related AEs must have recovered to Grade ≤ 1 with theexception of alopecia and Grade 2 peripheral neuropathy.

• Targeted agents (i.e. BTK inhibitors), investigational agents, therapeuticmonoclonal antibodies or cytotoxic chemotherapy: 5 half-lives or 2 weeks,whichever is shorter

• Antibody-drug conjugates (ADC): 10 weeks

• Radiation therapy: Broad field radiation (≥ 30% of the bone marrow or wholebrain radiotherapy): 14 days. Palliative limited field radiation: 7 days. Note:In the case of known central nervous system (CNS) involvement by systemiclymphoma: Patients with previous treatment for CNS involvement who areneurologically stable and without evidence of disease may be eligible if acompelling clinical rationale is provided by the Investigator and withdocumented Sponsor approval.

• Bendamustine or other purine analogues: 3 months.

• Corticosteroids: 5 days

• The effects of Pirtobrutinib on the developing human fetus are unknown. For thisreason and because other therapeutic agents used in this trial are known to beteratogenic, women of child-bearing potential and men must agree to use adequatecontraception (hormonal or barrier method of birth control; abstinence) prior tostudy entry and for the duration of study participation as outlined in criteriabelow:

• Men must agree to take appropriate precautions to avoid fathering children (with at least 99% certainty) from screening through safety follow up and mustrefrain from donating sperm during this period. Permitted methods that are atleast 99% effective in preventing pregnancy should be communicated to theparticipants in their understanding confirmed.

• Willingness of women of reproductive potential and their partners to observehighly effective birth control methods for the duration of treatment and for 1month following the last dose of study treatment (see Section 4.3 and Section 4.4 for further details)

• Women of childbearing potential must have a negative serum pregnancy test atscreening and before the first dose of pirtobrutinib and must agree to takeappropriate precautions to avoid pregnancy (with at least 99% certainty) fromscreening through safety follow up. Permitted methods that are at least 99%effective in preventing pregnancy should be communicated to the participantsand their understanding confirmed.

• Women of non-childbearing potential (i.e. surgically sterile with ahysterectomy and/or bilateral oophorectomy OR >= 12 months of amenorrhea) areeligible.

• Patients must meet the following laboratory parameters at screening:

• Hematology (criteria the same regardless of bone marrow involvement; must beindependent of transfusions and G-CSF support within 7 days of assessment)

• Platelets >= 50 x 10^9/L

• Hemoglobin >= 8g/dL

• Absolute Neutrophil Count >=1.0 x 10^9/L

• Hepatic

• ALT < 2.5 x ULN for age, <5 x ULN in the presence of liver metastases

• AST < 2.5 x ULN for age, <5 x ULN in the presence of liver metastases

• Total bilirubin < 1.5 x ULN or <3 x ULN in the presence of documentedGilbert's syndrome unconjugated hyperbilirubinemia)

• Renal Creatinine clearance >= 30 mL/minute based on Cockcroft-Gault formula.

• Cardiopulmonary Cardiac LVEF >=40% confirmed by ECHO/multigated analysis

• Adequate pulmonary function <= Grade 2 dyspnea and <= Grade 2 hypoxia per CTCAEv5.0.

• Adequate coagulation, defined as activated partial thromboplastin time (aPTT)or partial thromboplastin time (PTT) and prothrombin (PT) or (internationalnormalized ratio (INR) not greater than 1.5 x ULN.

Exclusion Criteria:

• Patients who have previously received treatment with pirtobrutinib for >2 monthsprior to study enrollment are ineligible. Patients who are relapsed or refractoryand then received less than 2 months of pirtobrutinib as "holding therapy" whileawaiting CAR T-cell therapy evaluation, and who did not demonstrate diseaseprogression while on pirtobrutinib holding therapy, are eligible.

• Patients who have previously discontinued pirtobrutinib due to disease progression,intolerance, or toxicity.

• Patients who are currently receiving or who have received any investigational studyagent ≤4 weeks prior to screening visit are ineligible.

• Prior treatment with chimeric antigen receptor (CAR) T-cell therapy.

• Participants with clinically significant or uncontrolled cardiac disease, includingunstable angina or acute coronary syndrome within the past 2 months prior torandomization, history of myocardial infarction within 3 months prior torandomization, documented LVEF by any method of ≤ 40% in the 12 months prior torandomization, or ≥ Grade 3 NYHA functional classification system of heart failure.

• Uncontrolled or symptomatic arrhythmias, including prolongation of the QT intervalcorrected for heart rate (QTcF) > 470 msec. QTcF is calculated using Fridericia'sFormula (QTcF): QTcF = QT/(RR0.33). Correction of suspected drug induced QTcFprolongation can be attempted at the investigator's discretion and only ifclinically safe to do so with either discontinuation of the offending drug or switchto another drug not known to be associated with QTcF prolongation. Correction forunderlying bundle branch block (BBB) allowed. Note: Patients with pacemakers areeligible if they have no history of fainting or clinically relevant arrhythmiaswhile using the pacemaker

• Evidence of active uncontrolled/untreated infection (viral, bacterial, fungal,opportunistic) of any origin.

• Participants with active immunologic or inflammatory/autoimmune disease affectingthe CNS, and unrelated to their disease under study or previous treatment.

• Patients with active CNS involvement of Mantle Cell Lymphoma. A history of CNSMantle Cell Lymphoma is allowed, as long as it has cleared, and the patient is ableto comply with study procedures. Patients with previous treatment for CNSinvolvement who are neurologically stable and without evidence of disease may beeligible with documented Sponsor approval.

• Known positive Human immunodeficiency virus (HIV) status. For patients with unknownHIV status, HIV testing will be performed at Screening and result must be negativefor enrollment.

• Hepatitis B virus (HBV): Patients with positive hepatitis B surface antigen (HBsAg)are excluded. Patients with positive hepatitis B core antibody (anti-HBc) andnegative HBsAg require a negative hepatitis B polymerase chain reaction (PCR)evaluation before randomization. Patients who are HBV DNA PCR positive will beexcluded. Patients who are HBV DNA PCR negative with positive anti-HBc requireprophylaxis against Hepatitis B reactivation (see Section 6.4 "General Guidance forHepatic Monitoring").

• Hepatitis C virus (HCV): positive hepatitis C antibody. If positive hepatitis Cantibody result, patient will need to have a negative result for hepatitis Cribonucleic acid (RNA) before randomization. Patients who are hepatitis C RNApositive will be excluded.

• Known active cytomegalovirus (CMV) infection. Unknown or negative status areeligible.

• Participants who require the concurrent use of chronic systemic steroids orimmunosuppressant medications. Steroids should not be given within 5 days prior toleukapheresis. Concomitant bridging steroids (section 6.6) are allowed afterleukapheresis.

• Known hypersensitivity or severe reaction to pirtobrutinib, similar compounds, orexcipients.

• Participants who have not recovered from adverse events (AEs) due to prioranticancer therapy (i.e., have residual toxicities > Grade 1), with the exception ofstable Grade 2 peripheral neuropathy and/or any grade alopecia.

• Pregnant or nursing (breast-feeding) women are excluded from this study becausethere is an unknown but potential risk to using pirtobrutinib in pregnant or nursingwomen. Patients are excluded if they are pregnant or plan to become pregnant duringthe study or within 1 year of the last dose of study treatment. Patients are alsoexcluded if they are lactating or plan to breastfeed during the study or within 1week of the last dose of study treatment. Please see Section 4.3 and Section 4.4 forGeneral Guidance for Women of Child Bearing Potential and/or Use of ContraceptiveMethods.

• Any condition that would, in the investigator's judgement, interfere with fullparticipation in the study, including administration of pirtobrutinib and attendingrequired study visits (if outpatient); pose a significant risk to the participant;or interfere with interpretation of study data.

• Inability of the participant to swallow and retain oral medication. Or, if there isclinically significant active malabsorption syndrome or other condition likely toaffect gastrointestinal (GI) absorption of the study drug.

• Patients who experienced a major bleeding event or grade ≥ 3 arrhythmia on priortreatment with a BTK inhibitor. NOTE: Major bleeding is defined as bleeding havingone or more of the following features: potentially life-threatening bleeding withsigns or symptoms of hemodynamic compromise; bleeding associated with a decrease inthe hemoglobin level of at least 2g per deciliter; or bleeding in a critical area ororgan (e.g., retroperitoneal, intraarticular, pericardial, epidural, or intracranialbleeding or intramuscular bleeding with compartment syndrome)

• Major surgery within 4 weeks prior to enrollment.

• History of a previously diagnosed hereditary bleeding disorder.

• Patients requiring therapeutic anticoagulation with warfarin or another vitamin Kantagonist.

• Active second malignancy unless in remission and with life expectancy > 2 years.

• Vaccination with live vaccine within 28 days prior to randomization.

• History of stroke or intracranial hemorrhage within 6 months of enrollment.

• History of allogeneic or autologous stem cell transplant within 60 days ofenrollment, presence of either of the following regardless of prior stem celltransplant timing: active graft vs. host disease; cytopenias from incomplete bloodcell count recovery post-transplant.

• Active uncontrolled autoimmune cytopenia, including autoimmune hemolytic anemia oridiopathic thrombocytopenic purpura for which new therapy was introduced or existingtherapy was escalated within the 4 weeks prior to study enrollment to maintainadequate blood counts.