Acalabrutinib + Liso-Cel In R/R Aggressive B-Cell Lymphomas

Eligibility Criteria

• * Adult patients ≥18 years with histologically confirmed aggressive B-cell NHL including diffuse large B-cell lymphoma (DLBCL), either de novo or transformed from any indolent B-cell lymphoma, and including DLBCL NOS, T cell/histiocyte-rich large B-cell lymphoma, Epstein-Barr virus \[EBV\] positive DLBCL NOS, primary mediastinal \[thymic\] large B-cell lymphoma (PMBCL), high grade B-cell lymphoma NOS, or high grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements \[double/triple hit lymphoma (DHL/THL)\]; and grade 3B follicular lymphoma. Patients with primary CNS lymphoma are not eligible. Patients with secondary CNS involvement by lymphoma are eligible if they otherwise meet all eligibility criteria.
• * Relapsed or refractory to at least 2 prior lines of systemic lymphoma therapy. Previous therapy must have included a CD20-targeted agent and an anthracycline or alkylating agent.
• * PET-positive measurable disease
• * ECOG Performance status 0-2
• * Estimated creatinine clearance of ≥30 mL/min, calculated using the Cockcroft and Gault equation (if male, \[140Age\] x Mass \[kg\] / \[72 x creatinine g/dL\];multiply by 0.85 if female)
• * Alanine Aminotransferase (ALT) \<= 2.5 times the ULN
• * Bilirubin \<= 2 x ULN (or \<= 3.0 mg/dL for patients with Gilbert-Meulengracht syndrome or lymphomatous involvement of the liver)
• * Hemodynamically stable and Left Ventricle Ejection Fraction (LVEF) \>= 40% confirmed by echocardiogram or Multigated Radionuclide Angiography (MUGA)
• * For subjects with atrial fibrillation, atrial fibrillation must be controlled and asymptomatic
• * Absolute neutrophil count (ANC) \>= 1000/mm3
• * Platelets \>= 50,000/mm3
• * Adequate pulmonary function, defined as \<= CTCAE Grade 1 dyspnea and SaO2 \> 91% on room air
• * Adequate vascular access for leukapheresis procedure (either peripheral line or surgically-placed line)
• * Woman of childbearing potential (WOCBP) who are sexually active must use highly effective methods of contraception during treatment and for 2 days after the last dose of acalabrutinib.
• * Willing and able to participate in all required evaluations and procedures in this study protocol.
• * Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information.
• * Another active malignancy which requires concurrent cancer-directed therapy
• * Previous treatment with gene therapy product or adoptive T cell therapy
• * Allogeneic stem cell transplant within 90 days of leukapheresis
• * Active acute or chronic GVHD
• * HIV infection
• * Serologic status reflecting active hepatitis B or C infection
• * Subjects who are hepatitis B core antibody (anti-HBc) positive and who are hepatitis B surface antigen (HBsAg) negative will need to have a negative PCR result before enrollment and must be willing to undergo DNA PCR testing during the study. Those who are HbsAg-positive or hepatitis B PCR positive will be excluded.
• * Subjects who are hepatitis C antibody positive will need to have a negative PCR result before enrollment. Those who are hepatitis C PCR positive will be excluded.
• * Uncontrolled infection
• * Clinically relevant CNS pathology
• * History of cardiovascular conditions within the past 6 months, including class III or IV heart failure as defined by New York Heart Association (NYHA), cardiac angioplasty or stenting, myocardial infarction, unstable angina, or clinically significant arrhythmias: Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, participants should be class 2B or better.
• * Autoimmune disease requiring chronic systemic corticosteroids at a dose of greater than 10 mg of prednisone daily or an equivalent dose of another corticosteroid
• * Treatment with alemtuzumab within 6 months leukapheresis or fludarabine or cladribine within 3 months of leukapheresis
• * Therapeutic anticoagulation
• * Bleeding diathesis
• * Has difficulty with or is unable to swallow oral medication, or has significant gastrointestinal disease that would limit absorption of oral medication.
• * Known history of hypersensitivity or anaphylaxis to study drug(s) including active product or excipient components.
• * Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening.
• * Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer.
• * Prothrombin time (PT)/INR or aPTT (in the absence of lupus anticoagulant) \>2x ULN.
• * Requires treatment with proton pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Note: Subjects receiving proton pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment to this study.
• * History of significant cerebrovascular disease/event, including stroke or intracranial hemorrhage, within 6 months before the first dose of study drug.
• * Major surgical procedure within 28 days of first dose of study drug. Note: If a subject had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug.
• * Breastfeeding or pregnant: Pregnant women are excluded from this study because acalabrutinib is an agent with the potential for teratogenic or abortifacient effects.