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

This is a phase 2, open-label, randomized, multicenter clinical trial in patients with relapsed/refractory mantle cell lymphoma (R/R MCL) who meet the criteria for standard-of-care FDA label for CD19 CAR T-cell therapy with brexucabtagene autoleucel (brexu-cel).

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 informed consent. * Must have ability to comprehend and the willingness to sign written informed consent for study participation. * Eligible to receive CAR T-cell therapy (Brexucabtagene autoleucel) for MCL by the standard of care label, which states: "TECARTUS or Brexucabtagene autoleucel is a CD19-directed genetically modified autologous T-cell immunotherapy indicated for the treatment 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 the exception of alopecia and Grade 2 peripheral neuropathy. * Targeted agents (i.e. BTK inhibitors), investigational agents, therapeutic monoclonal 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 whole brain radiotherapy): 14 days. Palliative limited field radiation: 7 days. Note: In the case of known central nervous system (CNS) involvement by systemic lymphoma: Patients with previous treatment for CNS involvement who are neurologically stable and without evidence of disease may be eligible if a compelling clinical rationale is provided by the Investigator and with documented Sponsor approval. * Bendamustine or other purine analogues: 3 months. * Corticosteroids: 5 days * The effects of Pirtobrutinib on the developing human fetus are unknown. For this reason and because other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation as outlined in criteria below: * Men must agree to take appropriate precautions to avoid fathering children (with at least 99% certainty) from screening through safety follow up and must refrain from donating sperm during this period. Permitted methods that are at least 99% effective in preventing pregnancy should be communicated to the participants in their understanding confirmed. * Willingness of women of reproductive potential and their partners to observe highly effective birth control methods for the duration of treatment and for 1 month 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 at screening and before the first dose of pirtobrutinib and must agree to take appropriate precautions to avoid pregnancy (with at least 99% certainty) from screening through safety follow up. Permitted methods that are at least 99% effective in preventing pregnancy should be communicated to the participants and their understanding confirmed. * Women of non-childbearing potential (i.e. surgically sterile with a hysterectomy and/or bilateral oophorectomy OR \>= 12 months of amenorrhea) are eligible. * Patients must meet the following laboratory parameters at screening: * Hematology (criteria the same regardless of bone marrow involvement; must be independent 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, \ 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 of enrollment, presence of either of the following regardless of prior stem cell transplant timing: active graft vs. host disease; cytopenias from incomplete blood cell count recovery post-transplant. * Active uncontrolled autoimmune cytopenia, including autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura for which new therapy was introduced or existing therapy was escalated within the 4 weeks prior to study enrollment to maintain adequate blood counts.