Acalabrutinib Plus RICE for Relapsed/Refractory DLBCL

Inclusion Criteria: 1. Histologically confirmed R/R DLBCL (per 2008 WHO classification) 1. GCB or ABC cell of origin (by IHC using Hans algorithim) 2. Transformation from prior indolent NHL is permitted 2. Relapsed or refractory to 1 prior line of anthracycline containing chemoimmunotherapy considered a standard 1st line therapy for DLBCL. Acceptable 1st line regimens are R-CHOP, R-EPOCH, or R-HyperCVAD chemotherapy regimens. Treatment with prior radiotherapy is allowed. 3. ECOG Performance status 0-2 4. Expected life expectancy of at least 3 months 5. Age 18 years or older 6. Disease measurable by FDG-PET that meets iWNHL size criteria (\>1.5cm in longest diameter for lymph node or nodal mass, or \>1.0cm in longest diameter for extranodal disease) 7. For Cohort A, patients must meet institutional eligibility guidelines for autologous HCT and all of the following 1. Ejection fraction \>40% by ECHO or MUGA 2. Pulmonary function testing with corrected DLCO \>50% of predicted 3. Charlson Comorbidity Index \<6 8. For Cohort B, patients must be considered medically ineligible for autologous HCT by fulfilling one or more of following. 1. Do not meet inclusion criteria 7a, 7b, or 7c 2. Age \>75 3. Any chronic medical condition, treated or untreated, for which the anticipated risks of autologous HCT are deemed by the investigator to outweigh potential benefit of autologous HCT. 9. Women of childbearing potential (WOCBP): Must use highly effective method of birth control during acalabrutinib treatment as well as for 2 days after the last dose of acalabrutinib Highly effective forms of contraception are defined in Section F13. 10. Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty. 11. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national and local subject privacy regulations). Exclusion Criteria: 1. Inadequate organ function, including the following 1. Hematologic: ANC \<1000/uL, PLT \<50,000/uL, and hemoglobin \<7.0g/dL. If the patient is known to have bone marrow involvement with cytopenias directly attributed to disease, eligibility may be permitted per investigator's discretion. 2. Hepatic: Total bilirubin ≥ 2.0 x ULN unless bilirubin elevation is due to Gilbert's syndrome or of non-hepatic origin. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≥ 3 x upper limit of normal (ULN) 3. Renal: Estimated creatinine clearance of \< 29 mL/min, calculated using the formula of Cockcroft and Gault \[(140-Age) • Mass (kg)/(72 • creatinine mg/dL); multiply by 0.85 if female\]. 4. GI: Malabsorption syndrome or gastrointestinal disease that limits oral absorption of medication 2. Prior history of autologous or allogeneic HCT 3. Any known contraindication to ifosfamide, etoposide, carboplatin, or rituximab 4. Active chronic hepatitis B infection, defined by positive Hep B DNA PCR. 5. Active chronic hepatitis C infection, defined by positive Hep C RNA PCR 6. Requires treatment with a strong CYP3A inhibitor/inducer 7. Any history of known significant bleeding diathesis 8. History of stroke or intracranial hemorrhage within 6 months before the first dose of study drug. 9. Pregnant or breastfeeding 10. Any uncontrolled active fungal, bacterial, or viral systemic infection that is untreated or not responsive to antimicrobial therapy. 11. Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of acalabrutinib, or put the study outcomes at undue risk. 12. Uncontrolled HIV/AIDS. Patients who are HIV positive, but clinically stable and compliant with HAART \>3months and with CD4 \>200 may be considered for eligibility at the investigators discretion unless taking excluded strong CYP3A inhibitor/inducer 13. Prior exposure to a BTK inhibitor 14. Prior malignancy (other than DLBCL or indolent NHL), except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the subject has been disease free for ≥ 2 years or which will not limit survival to \< 2 years. Note: these cases must be discussed with the principal investigator 15. Known central nervous system metastases and/or carcinomatous meningitis. Brain metastases, but not carcinomatous meningitis, are allowed if they had been previously treated (either surgically resected or by radiation therapy) and had remained stable by repeat imaging ≥ 4 weeks after treatment before enrolling on this protocol. 16. Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or corrected QT interval (QTc) \> 500 msec at screening (By Fridericia's formula). Atrial fibrillation that is controlled or considered stable by the investigator is permitted. 17. Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening. 18. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon) within 7 days of first dose of study drug. 19. Requires treatment with proton pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiving proton pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment to this study. 20. 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. 21. Subject has received anti-cancer therapy within a period of 14 days or 5 half-lives (whichever is shorter) or radiotherapy within 28 days of first dose of study drug. 22. Concurrent participation in another therapeutic clinical trial.